Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10]CC)=O)[N:6]=1.[Cl-].[NH4+:14].[Cl-].[Na+].Cl>N.O1CCCC1>[SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:14])=[O:10])[N:6]=1
Reactant: CCOC(=O)Cc1csc(S)n1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: NC(=O)Cc1csc(S)n1
Reaction time: 8 h
Yield: 990.5 %

Procedure:
To a mixture of ethyl 2-mercapto-4-thiazole acetate (203 mg) in ammonia solution (25%) (1.0 ml) was added ammonium chloride (5.3 mg) at room temperature. After stirring at the same temperature for 8 hours, the solution was poured into a mixture of tetrahydrofuran and saturated sodium chloride solution, and adjusted to pH 3.0 with 1N-hydrochloric acid and extracted with tetrahydrofuran twice. The combined organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazole acetamide (171 mg).
Reaction SMILES: [NH2:1][C:2]1([CH2:16][OH:17])[C:11]2([CH2:14][O:13][CH2:12]2)[CH2:10][O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:15])=[CH:6][CH:7]=2.C([O-])(O)=O.[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Br:15][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][CH2:10][C:11]1([CH2:14][O:13][CH2:12]1)[C:2]2([NH:1][C:25](=[O:26])[CH2:24][Cl:23])[CH2:16][OH:17]
Reactant: O=C(Cl)CCl
Reactant: NC1(CO)c2cc(Br)ccc2OCC12COC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NC1(CO)c2cc(Br)ccc2OCC12COC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (4-amino-6-bromo-4H-spiro[chromene-3,3′-oxetan]-4-yl)methanol (280 mg, 0.933 mmol), CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (10 mL) was added a mixture of chloroacetyl chloride (0.083 mL, 1.02 mmol) and CH2Cl2 (1 mL) at ambient temperature. After stirring for 30 minutes at ambient temperature, chloroacetyl chloride (0.016 mL, 0.197 mmol) was added to the reaction mixture. The mixture was stirred for 10 minutes at ambient temperature, diluted with CH2Cl2 and separated. The organic layer was washed with water, dried over MgSO4 and filtered. Concentration of the filtrate at reduced pressure gave crude N-[6-bromo-4-(hydroxymethyl)-4H-spiro[chromene-3,3′-oxetan]-4-yl]-2-chloroacetamide, which was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:36](=[O:37])[CH2:35][O:34][C:31]1=[O:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)COC2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (300 mg, enantiomer B, preparation as described in WO2004085404) was dissolved in absolute THF (10 ml) and admixed at room temperature with stirring with sodium hexamethyl-disilazide solution (0.5 ml; 2 M in THF). After 30 min, acetoxyacetyl chloride (77 μl) was added and the mixture was stirred at room temperature for 2 h. Subsequently, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water and basified with sodium hydrogencarbonate solution, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 380 mg of the desired product were obtained. 40 mg thereof were dissolved in acetonitrile/water, acidified with 0.1 N hydrochloric acid and freeze-dried.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:19]1[CH:28]=[CH:29][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][CH:18]=1)=[O:21]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccn2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.20 g, 7.6 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.90 g, 7.6 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 2-(4-Aminobenzoyl)pyridine (1.00 g, 5.0 mmol) was added in one portion and the reaction mixture stirred overnight at room temperature. The reaction mixture was poured into water and the aqueous solution extracted with ethyl acetate (2×50 mL). The combined organics were dried (MgSO4), filtered and the solvent removed in vacuo to yield a brown oil. Flash chromatography (eluted with 5% v/v ethyl acetate in methylene chloride) of the oil, evaporation of the eluent, and trituration with diethyl ether yielded the title propanamide (1.07 g, 63%) as a white solid; mp 151°-154° C. 1H-NMR (250 MHz, d6 -DMSO): 1.58 (s, 3 H, CH3), 7.58 (s, 1H, OH), 7.98 (d, 2H, J=8.9 Hz, aromatic), 8.06 (d, 2H, J=9.0 Hz, aromatic), 8.81 (m, 2H, aromatic), 8.97 (d, 1H, J=2.2 Hz, aromatic), 9.39 (s, 1H, aromatic), 10.48 (s, 1H, NH). MS (CI, CH4): 339(M+1). Analysis for C16H13F3N2O3 : Calculated: C, 56.81; H, 3.87; N, 8.28 Found: C, 56.50; H, 3.91; N, 8.21
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Nc1ccc(F)cc1F
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(F)cc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,4-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.37 (s, 3H), 4.71 (d, J=5.6 Hz, 2H), 6.06 (bs, 1H), 6.47 (bs, 1H), 7.75 (t, J=9.4 Hz, 1H), 7.85 (t, J=10.0 Hz, 1H), 7.17 (t, J=7.3 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 8.12 (bs, 1H), 8.58 (d, J=2.8 Hz, 1H); MS (ESI) m/z 342.6 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:38]([OH:40])=O)[CH:11]2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=O)(C)(C)C.[NH2:41][OH:42].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[OH:42][NH:41][C:38]([CH:10]1[CH:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH:12]2[NH:8][CH:9]1[CH2:14][CH2:13]2)=[O:40]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)O)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3C4CCC(N4)C3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 0.05 g (0.088 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester (Example 37, Step 5) and hydroxylamine, followed by treatment with TFA:CH2Cl2 (1:1, 0.2 mL) for 15 min, gave 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1]heptane-2-carboxylic acid hydroxyamide as a hygroscopic solid (0.0189 g, 37.2%). MS: 483 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][CH2:7][NH:8][CH3:9].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>CN(C=O)C>[F:20][S:17]([CH2:15][CH2:16][N:8]([CH2:7][CH2:6][C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:9])(=[O:19])=[O:18]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: C=CS(=O)(=O)F
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCS(=O)(=O)F)cc1OC
Yield: 3.1 %

Procedure:
The reaction between 3,4-dimethoxy-N-methylphenethylamine (15 mmol) and ethenesulfonyl fluoride (1.65 mL, 19 mmol) was carried out in DMF (30 mL) at ambient temperature for 3 hours as described in Example 16. There was obtained an orange liquid which was crystallized from ether/methanol to afford the title compound as a yellow solid (0.14 g, 11% yield), mp 200°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C2CCCCO2)=[C:5]([CH2:20][CH2:21][CH:22]=[CH:23][O:24]C)[CH:4]=1.O1CCCC1.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH:23]([CH2:22][CH2:21][CH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:13])=[O:24]
Reactant: COC=CCCc1cc(OC)c2ccccc2c1OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CCCC=O)c(O)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 140.6 %

Procedure:
A solution of 947 mg of (3EZ)-4-methoxy-2-(4-methoxy-3-butenyl)-1-[(tetrahydro-2-H-pyran-2-yl)oxy]-naphthalene dissolved in 10 ml of 3:1:1, acetic acid:tetrahydrofuran:water is stirred at 40° C. for 3 hrs. TLC analysis still indicates unhydrolyzed starting material. The temperature is increased to 50° C. and continued stirring for 1 hr affords complete hydrolysis. The solution is poured into 25 ml water and solid sodium bicarbonate is added portionwise until gas evolution ceases. This mixture is extracted with ether and the organic phase is washed with saturated aqueous sodium bicarbonate and brine (pH adjusted to 7), dried with magnesium sulfate, filtered and concentrated to give 0.95 g of crude title product as an orange colored oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[N:23]1([C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:35]2[CH:36]=[C:31]([C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[CH:32]=[CH:33][CH:34]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3cccc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
Cs2CO3 (858 mg, 2.64 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (250 mg, 0.88 mmol) and (3-(morpholine-4-carbonyl)phenyl)boronic acid (228 mg, 0.97 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (50 mg, 0.044 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. After completion of reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 210 mg (Yield: 60.34%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 208 mg as an off-white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH3:21][Si:22]([O:25][C:26](=[O:33])[CH2:27][O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[CH3:23]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:33][C:26]([O:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:27][O:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(=CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of trimethylsilyl-2-(trimethylsiloxy)acetate (24.4 mL, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath. The THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 min and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a mixture of geometrical isomers (4:1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH:13]1[CH2:14][CH2:15][CH:11]([CH3:10])[CH2:12]1)[CH3:3]
Reactant: CC1CCCC1=O
Reactant: CCOC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCNC1CCC(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of 9.2 g (0.060 mole) of 3-amino-propanoic acid ethyl ester HCl salt and 5.9 g (0.060 mole) of (rac)-2-methyl-cyclopentanone in 300 mL of dichloromethane was added 10.8 g (0.132 mole) of sodium acetate and 19.1 g (0.090 sodium triacetoxyborohydride (19.1 g, 90 mmol). The mixture was stirred at ambient temperature overnight and then quenched by the addition of 100 mL of 10% sodium bicarbonate solution. The aqueous layer was extracted twice with 200 mL of dichloromethane, and the combined dichloromethane layers dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and distilled at 0.0015 mm Hg (bp 75 degrees), to give 9.6 g of (rac)-3-(3-methyl-cyclopentylamino)-propanoic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)[C:8]2[N:13]=[N:12][N:11](CC3N(C)N=NN=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:34]1[C:38]2[N:39]=[C:40](C(C)(C)C)N=C(N3CCC(O)C3)[C:37]=2[N:36]=[N:35]1)C1C=CC=CC=1.ClCC1N(C)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:37][C:38]3[N:39]([CH3:40])[N:36]=[N:35][N:34]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1Cn1nnc2c(N3CC[C@@H](O)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3)c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (R)-1-(5-tert-butyl-3-((1-methyl-1H-tetrazol-5-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol (example 113, b) 1-(3-Benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was hydrogenated and subsequently reacted with 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as light yellow oil. MS (m/e): 359.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[CH:12]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:12]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 541.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH:10]([CH3:12])[CH3:11].O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 96 mg of 60% sodium hydride was suspended in 6 ml of N,N-dimethylformamide, and 388 mg of 4-iodo-1H-pyrazol was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Subsequently, 0.21 ml of 2-bromopropane was added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 328 mg of the objective compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:3]=[CH:2][CH2:1][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: C=CCOc1ccc(Br)cc1
Reactant: Oc1ccc(F)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Fc1ccc(OC=CCOc2ccccc2)cc1
Yield: 49.1 %

Procedure:
A solution of 4-allyloxybromobenzene (42.24 g, 198.3 mmol), 4-fluorophenol (14.82 g, 132.2 mmol), potassium carbonate (27.41 g, 198.3 mmol) and copper (4.20 g, 66.1 mmol) in pyridine (200 mls) was refluxed for 2 days. It was then filtered through Celite and diluted with ethylacetate(500 mls). The organic was then washed with water (3×200 mls), dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, hexanes:ether, 99.75:0.25) to afford 15.85 g (49%) of 4-(4-fluorophenoxy)allyloxybenzene as a lemon yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:14]=2.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2cc(N3CCNCC3)ccc2cc1-c1nc2ccccc2s1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccc3cc(-c4nc5ccccc5s4)c(=O)oc3c2)CC1
Reaction time: 4 h
Yield: 47.3 %

Procedure:
100 mg (0.28 mmol) 3-Benzothiazol-2-yl-7-piperazin-1-yl-chromen-2-one were dissolved in 15 mL DMF and treated under argon with 183 mg (2 eq.) cesium carbonate, cooled below 5° C. and treated with 1 eq (0.018 mL) Mel. After stirring for 4 h, the reaction mixture is diluted with 100 mL dichloromethane and washed twice with ice-water. The organic phase is evaporated and the residue column chromatographed (silica gel, dichloromethane/EtOH 9:1). Recrystallization from methanol/dichloromethane yields 50 mg (47%) desired product as an orange powder.
Reaction SMILES: N1N=C(S(CC2C=CC(C(O)=O)=CC=2)=O)NC=1.[N:18]1[N:19]=[C:20]([S:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)(=[O:25])=[O:24])[NH:21][CH:22]=1.[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[N:18]1[N:19]=[C:20]([S:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:41][C:40]3[CH:42]=[CH:43][C:37]([Cl:36])=[C:38]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[CH:39]=3)=[O:33])=[CH:34][CH:35]=2)(=[O:24])=[O:25])[NH:21][CH:22]=1
Reactant: O=C(O)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: O=C(O)c1ccc(CS(=O)c2nnc[nH]2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1

Procedure:
107 mg of a mixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 454.3 (M)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:23])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[N:9]1[C:24](=[O:38])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:35](=[O:37])[NH2:36])[CH:27]=1)=O)(C)(C)C.O1CCOCC1>Cl>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:13]([CH:10]1[N:9]([C:24](=[O:38])[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([C:35]([NH2:36])=[O:37])[CH:27]=2)[NH:8][CH2:12][CH2:11]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2cccc(Cl)c2)N1C(=O)Cc1cn(C(N)=O)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)n1cc(CC(=O)N2NCCC2C(=O)NCc2cccc(Cl)c2)c2ccccc21

Procedure:
A solution of 2-[2-(1-carbamoyl-1H-indol-3-yl)-acetyl]-3-(3-chloro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester (15 mg, 0.03 mmol) in HCl 4N in dioxane (69.4 μL, 0.278 mmol) was stirred at 23° C. for 1 h. The crude material was directly purified by preparative HPLC (waters SunFire C18 ODB 5 um, 19×50, 5-100% CH3CN/H2O/15 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% of TFA, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. MS (LC-MS): 440 [M+H]+; tR (HPLC conditions b): 3.49 min.