Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[C:15]([CH3:16])=[C:14]([NH:17][S:18]([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)(=[O:20])=[O:19])[O:13][N:12]=1.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>C(Cl)Cl>[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[S:18]([NH:17][C:14]1[O:13][N:12]=[C:11]([CH3:10])[C:15]=1[CH3:16])(=[O:19])=[O:20]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
N,N-diisoproplyethylamine (222 μl, 128 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (300 mg, 1.16 mmol) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 2-(trimethysilyl)ethoxy methyl chloride (SEM chloride) (226 μl, 1.28 mmol) was added dropwise via syringe, and the resultant yellow solution was stirred at room temperature for 5 hours. Evaporation of solvents left an oil which was extracted into ethyl acetate, washed with water and brine solution and dried over magnesium sulfate. Flash chromatography of the residue using 10% ethyl acetate/hexanes yielded 321 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide as a clear colorless oil which solidified into a white solid upon standing (71% yield).
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].[I-]>CO>[CH2:18]([NH:25][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(NCc1ccccc1)C(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.51 g of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one and 2.25 ml of benzylamine in 20 ml of MeOH was added 10 mg of NaI and the solution was refluxed for 4 hours, then stirred at RT overnight. Crude 2-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was purified on an Al2O3 column to yield 2.51 g of pure compound. Compound 1071.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH:39]=[C:38]([CH2:41]O)[CH2:37][CH2:36]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:41][C:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH:37]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: CN1CC=C(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(OCC3=CCN(C)CC3)c(Br)cc21
Temperature: 32 °C
Yield: 73.6 %

Procedure:
A stirred suspension of powdered 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron, 1973, 29(8), 1115) (19 g, 0.074 mole) in dry THF (1700 ml) at room temp. under argon was treated with triphenylphosphine (19.6 g, 0.075 mole) and 1-methyl-1,2,3,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) (9.5 g, 0.075 mole), followed by the dropwise addition over 15 mins. of a solution of diethyl azodicarboxylate (11.8 ml, 0.075 mole) in THF (40 ml). A mild exotherm occured and the insoluble material dissolved. The solution was warmed at 32° C. for 1 hour, then concentrated in vacuo to approx. 500 ml volume. The solid which had formed was filtered off and dried according 16.1 g of beige solid. The filtrate was concentrated in vacuo and the residue treated with ethyl acetate (700 ml) and 1M HCl acid (500 ml), shaken well and the acid layer separated. This was washed with ethyl acetate, then basified with 40% NaOH and extracted with ethyl acetate, followed by chloroform. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow solid, which was recrystallised from ethyl acetate (3.8 g) giving a total yield of 19.9 g (74%) of 1-acetyl-6-bromo-2,3-dihydro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-ylmethoxy)-1H-indole.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](S)=[N:12][C:11]=2[CH:16]=1>>[Cl:4][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:16][C:11]=2[N:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Sc1nc2cc(Cl)ccc2s1
Product: Clc1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (10 mL) was added to 5-chloro-2-mercaptobenzothiazole at 0° C. After complete addition, the reaction mixture was allowed to warm to rt. After 2 h, the reaction mixture was poured into ice water (100 mL). This was allowed to warm to rt and was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was used without further purification. LC-MS: RT=10.03 min., compound does not ionize.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: COc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(C=O)cc2Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 24.9 mmol; 1 eq) in DCM (10 mL), was added 1-(bromomethyl)-4-methoxybenzene (6.0 g, 29.88 mmol, 1.2 eq, Aldrich, Milwaukee, Wis., USA) and DIEA (8.7 mL, 49.7 mmol, 2 eq). After stirring at room temperature for 18 h, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 8.0 g of 4-(4-methoxybenzyloxy)-3-bromobenzaldehyde (32).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([I:28])[C:26]=1[OH:27])[C:21](Cl)=[O:22].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([I:28])[C:26]=1[OH:27])[C:21]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:22]
Reactant: CCOC(=O)CCc1cc2ccccc2o1
Reactant: O=C(Cl)c1cc(I)c(O)c(I)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
218 g of compound 4 and 409 g of 3,5-diiodo-4-hydroxybenzoyl chloride are dissolved in 2L of anhydrous methylene chloride. Slowly add 287 g of tin(IV) chloride. Stir at room temperature for 12 hours and pour into 3L of ice-water. Wash the organic phase with 5% sodium bicarbonate solution and then with 2N HCl. Dry over sodium sulfate. Evaporate. The product is crystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[C:18](=[O:24])[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:26].S([O-])([O-])(=O)=O.[Mg+2]>O>[NH2:23][C:22]([C:21]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:24])=[CH:14][C:13]=1[NH:12][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: N#Cc1cc2c(cc1NC(=O)COCc1ccccc1)CCC2=O
Reactant: O=CO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: NC(=O)c1cc2c(cc1NC(=O)COCc1ccccc1)CCC2=O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A 22 L, 3 neck flask, equipped with an overhead stirrer, electric heating mantle, condenser, an N2 inlet, and a type-J Teflon® covered thermocouple, was charged with nitrile 10 (797 g, 2.49 moles—corrected for a purity of 75% by weight), formic acid (6400 ml) and magnesium sulfate (510 g). The resulting brown viscous mixture was heated to 40° C. with stirring and was allowed to stir at that temperature for 4 hours. At that time the reaction was judged to be complete by TLC and LC analysis. The reaction mixture was allowed to cool to 20° C. and stir at that temperature overnight. The following morning the reaction mixture was poured into 24 liters of water. The resulting yellow solid was collected by vacuum filtration rinsing with water (2×1500 ml) followed by isopropanol displacement wash (1×1500 ml). The crude product was allowed to air dry to a constant weight to afford 1030 g (886 g corrected for purity of 86% by weight-103%). The water content was 1.02% by Karl Fischer titration. The material was used directly in the next step without further purification. Rf=0.37 (65% EtOAc/hexanes) HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 nm, Phenomenex Jupiter C18 column 4.6 mm×250 mm at 29° C.: (st. material 11.6 min, amide 9.26 min, 87 A %) 1H NMR (DMSO, 300 MHz): 2.61-2.65 (m, 2H), 3.09-3.13 (m, 2H), 4.13 (s, 2H), 4.64 (s, 2H), 7.29-7.49 (m, 5H), 7.84 (br, 1H), 8.12 (s, 1H), 8.49 (br, 1H), 8.74 (s, 1H), 12.57 (br, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([Li])CCC>C1COCC1>[C:1]1([CH2:7][C:8]([N:33]2[C@@H:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][O:35][C:34]2=[O:37])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 10 gm of phenylacetic acid (73 mmol) and 12.2 mL of triethylamine (87.6 mmol) in 200 mL of THF was cooled to −78° C. To this solution was added 9.8 mL of trimethylacetyl chloride (80 mmol) and the reaction was warmed to 0° C. and stirred for 1 hr. This solution was recooled to −78° C. (Solution #1) Meanwhile, to a solution of 14.2 gm of (S)-(−)-4-benzyl-2-oxazolidinone in 200 mL of THF at −78° C., was added 50 mL of a 1.6M solution of n-butyl lithium in THF (80 mmol)over 20 min. (Solution #2) After stirring for 20 min., this solution (#2) was slowly cannulated into the solution (#1) containing the mixed anhydride at −78° C. This reaction mixture was allowed to warm to room temperature and stirred for 2 hr. The reaction was quenched with a solution of saturated NH4Cl and extracted with ethyl acetate. The combined organic fractions were washed with water, sat. NaHCO3 solution, sat. NaCl solution, dried over MgSO4, filtered and concentrated. The crude product was purified by chromatograpy (silica, hexanes:ethyl; acetate=4:1) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[C:24]([O:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][CH2:2][C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:29][CH:28]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(NCc2cccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of tert-butyl 3-(chloromethyl)benzoate (500 mg) in N,N-dimethylformamide (10.0 mL) were added tert-butyl 4-aminobenzoate (426 mg), potassium carbonate (610 mg), and potassium iodide (36.6 mg), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-({[4-(tert-butoxycarbonyl)phenyl]amino}methyl)benzoate (671 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15](OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([CH2:25][OH:26])[N:11]([CH2:15][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12][C@H:13]1[CH3:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A mixture of (2R,5R)-2-hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (3.48 g, 15.1 mmol), benzaldehyde (1.76 g, 16.6 mmol), sodium triacetoxyborohydride (3.84 g, 18.1 mmol) and 1,2-dichloroethane (30 mL) was stirred at 20° C. for 18 h, then partitioned between saturated aqueous NaHCO3 (150 mL) and DCM (3×50 mL). Combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give an oil. Chromatography (SiO2, 0-30% EtOAc in petrol) gave the title compound (4.588 g, 74%) as a colourless solid. MS: [M+H]+=321.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12]P(=O)(OC)OC)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>C1COCC1>[O:33]1[CH2:38][CH2:37][C:36](=[CH:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:5]=3[N:11]=2)[CH2:35][CH2:34]1
Reactant: O=C1CCOCC1
Reactant: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(C=C3CCOCC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate from Example 117 (0.45 g) in anhydrous THF (6 mL) at 0° C. was added 2.0 M of lithium diisopropylamide in tetrahydrofuran (1.5 eq). The resulting solution was allowed to warm to RT before adding a solution of dihydro-2H-pyran-4(3H)-one (1.5 eq) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 1 h, then partitioned between brine and Ethyl Acetate. The organic layer was isolated, dried (MgSO4), concentrated and recrystallized from methanol. The light yellow solid was filtered and collected to give 0.36 g of 4-(6-((2H-pyran-4(3H,5H,6H)-ylidene)methyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine as a light yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:12][C:11]=1[C:36]([F:39])([F:38])[F:37].CCN(C(C)C)C(C)C>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[C:22]([F:23])([F:24])[F:25])=[O:19])=[CH:12][C:11]=1[C:36]([F:37])([F:38])[F:39])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 mg (1.2 eq, 0.28 mmol) of isobutyryl chloride were dissolved in 1 ml of dichloromethane. To this were added 113 mg (1.0 eq, 0.24 mmol) of the hydrochloride of (2E)-3-[4-(aminomethyl)-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl)acrylamide from Stage 5 and 93 mg (3 eq) of Hünig's base. The mixture was stirred at room temperature for 16 h then concentrated. The crude product was purified by means of preparative HPLC (Phenomenex Gemini C18 5 μm; 125A; Aqua 50×21.2 mm; gradient: 0-1.5 min 78% water, 20% acetonitrile, 1.5-10.0 min linear gradient to 18% water, 80% acetonitrile, 10.0-14.00 min 18% water, 20% acetonitrile; modifier: 10% NH4HCO3 added at 2 ml/min). This gives 57 mg (44%) of (2E)-3-{4-[(isobutyrylamino)methyl]-3-(trifluoroethyl)phenyl}-N-{2,2,2-trifluoro-1-[3-(trifluoro-methyl)phenyl]ethyl}acrylamide.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[N:17]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:21]=[C:20]([C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1)[N:19]=2>CS(C)=O>[CH:39]1([CH2:38][N:17]2[C:16]([N:12]3[CH2:13][CH2:14][CH:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH2:11]3)=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)=[N:21][C:22]=3[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:40][CH2:41]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCC(S(=O)(=O)c5ccccc5)C4)n(CC4CC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
3-(Phenylsulfonyl)pyrrolidine (110 mg, 0.52 mmol) and dimethyl sulfoxide (0.8 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (80 mg, 0.21 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give the title compound (20 mg, 17%) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[N:16]1[N:15]([CH2:11][CH2:12][C:13]#[C:14][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=2)[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: C#CCCn1nc2ccccc2n1
Reactant: CCNc1cccc(Br)n1
Product: CCNc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 24 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-ethyl-amine (100 mg, 0.50 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.13 g, 0.75 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.12 mmol, 24%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine as a brown solid (M.P.=73-78° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:42])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:41])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:40])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:39])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:38])[C:35]([OH:37])=[O:36]>>[C:35]([C:34]([CH3:38])=[CH:33][CH2:32][CH2:31][C:30]([CH3:39])=[CH:29][CH2:28][CH2:27][C:26]([CH3:40])=[CH:25][CH2:24][CH2:23][C:22]([CH3:41])=[CH:21][CH2:20][CH2:19][C:18]([CH3:42])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:37])=[O:36]
Reactant: COc1c(C)cc(O)c(OC)c1OC
Reactant: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: COc1c(C)c(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Yield: 59.8 %

Procedure:
The procedures of Example 1 were repeated except that 5 g of 2,3,4-trimethoxy-5-methylphenol and 3.2 g of 20-hydroxy-2,6,10,14,18-pentamethyl-2,6,10,14,18-eicosapentaenoic acid were employed as the starting materials to give 2.8 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CCCCCC(=O)Cl
Solvent: c1ccccc1
Product: CCCCCC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
A 9 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 6.3 g. (6.6 ml.) of hexanoyl chloride in 100 ml. of benzene is refluxed for 3 hours. The benzene is distilled off. The residue is triturated in ether, washed with ether and dried. This solid is heated to boiling in 250 ml. of benzene, filtered and the filtrate is diluted with 250 ml. of hexane. This mixture is filtered and then cooled. The solid is collected, washed with hexane and dried giving the desired product, mp. 127°-129° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:15].[Cl:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:10]1[C:5]2[NH:4][C:3](=[O:15])[N:2]([CH3:1])[C:6]=2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Yield: 2.9 %

Procedure:
A solution of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (500 mg, 2.42 mmol), N-chlorosuccinimide (355 mg, 2.66 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg, 0.12 mmol) in carbon tetrachloride (40 mL) was refluxed for 2 days. After cooling, the reaction mixture was concentrated in vacuo. The resultant was extracted with ethyl acetate and water. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 167 mg (0.07 mmol, 29%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CCBr
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A commercially available reagent of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionate (4.84 g, 15.6 mmol) was dissolved in N,N-dimethylformamide (39 mL), and 1-bromo-2-butyne (1.65 mL, 18.8 mmol) and potassium carbonate (3.25 g, 23.5 mmol) were then added at room temperature. After stirring at 60° C. for 6 hours, and the reaction solution was cooled to room temperature. 1-Bromo-2-butyne (0.55 mL, 6.28 mmol) was added at room temperature, and the mixture was then stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, and potassium carbonate (0.433 g, 3.13 mmol) was then added. After stirring at 60° C. for 4.5 hours, the reaction solution was cooled to room temperature. Water (70 mL) was added, and the mixture was then extracted twice with ethyl acetate (70 mL). The organic layer was washed with saturated aqueous solution (30 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 5.02 g (13.9 mmol, yield 89%) of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate.