Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:11][CH2:12][O:13][C:14]([CH:16](P(OCC)(OCC)=O)[CH3:17])=[O:15].C[O-].[Na+]>CN(C=O)C.CO>[OH:10][CH2:9][C:7]1[N:8]=[C:3](/[CH:2]=[C:16](\[CH3:17])/[C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cccc(CO)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
6-hydroxymethylpyridine-2-carbaldehyde (2.95 g) and triethyl 2-phosphonopropionate (5.12 g) were dissolved in 20 mL of dry DMF, and to the solution was added a solution of 1.30 g of sodium methoxide in 10 mL of methanol dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was thrown into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=1:1) to give 2.42 g of ethyl (E)-3-(6-hydroxymethylpyridin-2-yl)-2-methylacrylate as a colorless oil.
Reaction SMILES: [C:1]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[BrH:24].[NH+]1C=CC=CC=1.CCOC(C)=O>C(O)C>[Br:24][CH:11]([C:1]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)=[O:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Br)C(=O)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of ethyl p-anisoylacetate (1.00 g, 4.5 mmol) in ethanol (14 mL) at 50° C. was added triethylamine (0.63 mL, 4.5 mmol) followed by pyridinium hydrobromide perbromide (1.44 g, 4.5 mmol) and the resulting mixture was then stirred at 50° C. for 2 hours. The reaction was cooled to room temperature and poured into EtOAc. The organic phase was then washed with saturated sodium bicarbonate solution and 0.5M aqueous HCl, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate (1.209 g, 4.0 mmol, 89%) which was used without further purification. 1H NMR (CDCl3) δ 1.26 (3H, t), 3.89 (3H, s), 4.28 (2H, q), 5.62 (1H, s), 6.96 (2H, d), 7.98 (2H, d). LCMS (2) Rt: 3.06 min; m/z (ES+) 301/303.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:22])C=1>CO.C(OCC)(=O)C>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N+:9]([O-:22])=[CH:8][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2cnccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc2c[n+]([O-])ccc2o1
Reaction time: 18 h
Yield: 83 %

Procedure:
To a warm (40° C.) solution of 2-sulfamoylfuro[3,2-c]pyridine (2.68 g, 13.5 mmol) in methanol (30 ml) and ethyl acetate (10 ml) was added dropwise a solution of m-chloroperbenzoic acid (3.22 g, 15 mmol) in ethyl acetate (13 ml). The reaction mixture was stirred for 18 hours as product precipitated. The pure product was collected by filtration and crystallized from hot dimethyl sulfoxide by dilution with ethanol to give 2.4 g (83% yield), m.p. 247°-248° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:41]([CH3:43])[CH3:42])[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=4)[N:27]=3)[N:22]=[CH:21][C:20]=2[C:38](=[O:40])[CH3:39])[CH2:14][CH2:13]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:64].Cl>>[ClH:37].[ClH:64].[C:38]([C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[NH:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[CH:8]([NH2:7])[CH:41]([CH3:43])[CH3:42])[CH2:13][CH2:14]1)=[N:27][C:26]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=1)=[CH:25][CH:24]=2)(=[O:40])[CH3:39]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(N)C(C)C)CC1

Procedure:
Following general procedure IV-2, tert-butyl[1-(trans-4-{[3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}cyclohexylamino)-3-methyl-1-oxobutan-2-yl]carbamate (0.19 mmol) was reacted with TFA (2 mL) followed by formation of the dihydrochloride salt to afford the desired product (35 mg, 30% over two steps) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.87 (dd, J=11.4, 2.2 Hz, 1H), 5.63-5.57 (m, 1H), 3.88-3.83 (m, 1H), 3.62 (d, J=6.0 Hz, 1H), 2.76 (s, 3H), 2.51-2.40 (m, 2H), 2.10-2.12 (m, 3H), 1.81-1.53 (m, 4H), 1.08 (t, J=7.4 Hz, 6H); ESI MS m/z 528 [M+H]+; HPLC 98.9% (AUC), tR=9.99 min.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH2:12]([CH:15]([NH2:18])C=O)[C:13]#C.C([O:22][CH2:23][CH3:24])(=O)C>>[CH2:15]([N:18]([CH2:24][CH:23]=[O:22])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[C:12]#[CH:13]
Reactant: CCOC(C)=O
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: C#CCC(N)C=O
Product: C#CCN(CC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-propargyl-aminoacetaldehyde (5 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]-acetaldehyde as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[S:30][C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.CCOC(C)=O>C(#N)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)=[CH:32][CH:33]=2)[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2ccc(Cl)s2)cc1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc(-c4ccc(Cl)s4)cc3)CC2=O)cc2cnccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2-(2-oxo-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.10 g, 0.30 mmol) in acetonitrile (5 mL) is added 4-(5-chloro-thiophen-2-yl)-benzaldehyde (0.067 g, 0.30 mmol) followed by triacetoxyborohydride (0.13 g, 0.60 mmol) and glacial acetic acid (1 drop). The resulting mixture is stirred at room temperature overnight then poured into EtOAc and washed with water (×2) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness then purified by column chromatography using EtOAc as the eluent to yield the title compound (0.90 g, 0.17 mmol). ESI MS [M+H]+=537.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH3:19])[N:8]=[N:9]2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[CH:3][CH:4]=2)[N:9]=[N:8][C:7]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19]
Reactant: C[C@@H]1CCCN1CCc1nnc2cc(Br)ccc2c1O
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1nnc2cc(-c3ccc(C#N)cc3)ccc2c1O
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of the product from Example 168D (0.30 g, 0.805 mmol), 4-cyanophenylboronic acid (0.15 g, 1.05 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.04 mmol), and 1 M Na2CO3 (2.01 mL, 2.01 mmol) in isopropanol (15 mL) was heated to 90° C. under a dry nitrogen atmosphere for 2 days. After cooling, the reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 90:10 dichloromethane/methanol) to afford the product in 33% yield as a light brown solid. 1H NMR (CD3OD, 300 MHz) δ 8.29 (d, J=9 Hz, 1H), 7.95 (q, J=9 Hz, 4H), 7.83 (d, J=3 Hz, 1H), 7.75 (dd, J=3, 9 Hz, 1H), 3.49-3.42 (m, 2H), 3.17-3.12 (m, 2H), 2.78-2.73 (m, 2H), 2.62-2.59 (m, 1H), 2.12-2.09 (m, 1H), 1.92-1.84 (m, 2H), 1.61-1.53 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 359.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH2:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11].C([BH3-])#N.[Na+].C(N(CC)CC)C>CCCCCC.C(OC(=O)C)C>[CH2:1]([NH:8][CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH:10]([CH3:11])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)CC(C)C
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCCC(CC(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Benzylamine (3.1 ml, 28 mmol) was added to a stirred mixture of 2-methyloctan-4-one (4.0 g, 28 mmol) and 3A molecular sieves in dry, methanol (40 ml) under argon. The mixture was stirred at room temperature overnight. Sodium cyanoborohydride (1.77 g, 28 mmol) was added and the mixture stirred overnight. Stirring was stopped and the solution was decanted, from the molecular sieves, into saturated aqueous ammonium chloride. The mixture was filtered, concentrated, ethyl acetate added and the mixture washed with water. The organics were dried over anhydrous magnesium sulphate, filtered and concentrated to give a yellow oil. Chromatography (silica: 1% triethylamine and 10% ethylacetate in hexane) gave N-benzyl -2-methyl-4-aminooctane (3.0 g, 46%) as a yellow oil.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](I)=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][C:34]=2[O:41][CH3:42])[CH3:31])=[CH:26][CH:25]=1>O1CCCC1>[C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:37]([C:36]2[CH:39]=[CH:40][C:33]([O:32][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH3:31])=[C:34]([O:41][CH3:42])[CH:35]=2)[OH:38])=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Reactant: COc1cc(C=O)ccc1OC(C)c1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C)(C)C(C)(C)C)c3ncccc23)ccc1OC(C)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (69, 647.0 mg, 1.81 mmol, prepared as described in Example 23) was dissolved in tetrahydrofuran (10.0 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.98 mL) was added to the reaction. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzaldehyde (77, 420 mg, 1.4 mmol) in tetrahydrofuran (3.00 mL) was added. The reaction was stirred for 2 hours during which time the temperature rose to 10° C. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound, (78, 463 mg, 61%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: [CH2:1]1[CH2:23][O:22][C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:17])[C:15]#N)=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]2=3)[O:2]1.[OH-:24].[K+].Cl.[OH2:27]>>[CH2:1]1[CH2:23][O:22][C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:17])[C:15]([OH:27])=[O:24])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]2=3)[O:2]1
Reactant: [OH-]
Reactant: O
Reactant: CC(C#N)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: Cl
Agent: [K+]
Product: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Yield: 75 %

Procedure:
0.7 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionitrile is refluxed for 9 hours in 40 ml. of water containing 1.1 gm. of potassium hydroxide. The solution is cooled and neutralized with dilute hydrochloric acid, and extracted with ether. The ether extract is washed, dried and evaporated to afford a 75% yield of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid. Use of 2-(5,5-ethylenedioxy)-5H-dibenzo[a,d]cyclohepten-2-yl)acetonitrile gives a similar yield of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A solution of 4-(4-azidomethylbenzyl)-nitrobenzene (5.835 g) in tetrahydrofuran (175 mL) was treated with water (0.43 mL) and triphenylphosphine (6.45 g, 1.1 eg). The mixture was stirred at room temperature for 18 hours, and the solvent was evaporated. The residue was suspended in water, and suspension made acidic by the dropwise addition of hydrochloric acid to about pH 1, then extracted with diethyl ether (3×). The aqueous phase was made alkaline with 50% aqueous sodium hydroxide, extracted with dichloromethane (3×) to afford a crude brown oil (5.66 g). Chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide, gave 4-(4-aminomethylbenzyl)-nitrobenzene (3.91 g, 79%) as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][N:26]([C:30](=[O:37])[CH2:31][CH:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)[CH2:27]4)=[CH:22][CH:21]=3)[N:17]=[C:16]([NH2:38])[N:15]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:38][C:16]1[N:17]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:30](=[O:37])[CH2:31][CH:32]4[CH2:36][CH2:35][N:34]([C:2]([O:4][CH3:5])=[O:3])[CH2:33]4)[CH2:27]3)=[CH:22][CH:21]=2)[CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:13][CH2:12]2)[N:15]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNC3)CC4)nc(N)n2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (2.1 uL, 0.028 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-[2-(pyrrolidin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (0.013 mL, 0.092 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at r.t. for 30 min The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=494.3.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[F:11][C:12]1[C:17](F)=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22].[OH-].[K+].CS(C)=O>O>[F:11][C:12]1[C:17]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22]
Reactant: CC(C)c1ccccc1O
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccccc1Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 50.0 g (0.36 mol) of 2-isopropylphenol, 137 g (0.72 mol) of hexafluorobenzene, 50.4 g (0.90 mol) of KOH powder, and 1000 ml of DMSO was stirred for 48 h at 80° C. This mixture was cooled to room temperature and then poured in 3000 ml of water. The product was extracted with 4×500 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated on Rotavap. The residue was distilled in vacuum, 130-140° C./13 mm Hg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][N:22]([C:25]4([CH2:29][C:30]#[N:31])[CH2:28][NH:27][CH2:26]4)[CH:21]=3)[N:17]3[CH:32]=[CH:33][N:34]=[C:16]3[CH:15]=2)[CH:11]=[N:10]1.CCN(C(C)C)C(C)C.FC(F)(F)S(OCC(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][N:22]([C:25]4([CH2:29][C:30]#[N:31])[CH2:28][N:27]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:26]4)[CH:21]=3)[N:17]3[CH:32]=[CH:33][N:34]=[C:16]3[CH:15]=2)[CH:11]=[N:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)c3)n2)cn1
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.2 %

Procedure:
A solution of 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrrol-1-yl)azetidin-3-yl)acetonitrile trifluoroacetate (Example 127, 100 mg, 0.182 mmol) in dry DMF (1.0 mL) was cooled on an ice bath and DIEA (191 μL, 1.09 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (63.5 mg, 0.273 mmol) were added sequentially. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 17 hours. The mixture was added to H2O (5 mL), mixed and extracted with DCM. The combined organic extracts were washed with 0.5M Na2CO3 and H2O, and dried over Na2SO4. The crude material was eluted through a SiO2 plug eluting first with DCM then 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated to give a colorless glass. The glass was dissolved in minimal DCM and treated with hexanes to afford a white suspension. The suspension was concentrated providing the title compound (25 mg, 31% yield) as a white solid. MS (apci) m/z=441.2.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([NH:34][NH2:35])=[O:33])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:35][NH:34][C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NNC(=O)CN1CCOCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)CN1CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in CH2Cl2:EtOAc (20 mL, 2:1) and cooled to −60° C. where 2-morpholinoacetohydrazide (0.23 g, 1.0 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.27 mL, 1.5 eq.) was added dropwise followed by DIPEA (0.96 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-morpholinoacetyl)acrylohydrazide (0.1 g, yield: 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15](N)[CH2:16][NH2:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]1[NH:17][CH2:16][CH2:15][N:14]=1
Reactant: N#CCc1cc(C(F)(F)F)ccc1F
Reactant: NCCN
Product: Fc1ccc(C(F)(F)F)cc1CC1=NCCN1

Procedure:
2-(2-Fluoro-5-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-fluoro-5-trifluoromethyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): brown solid; MS (ISP): 247.3 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=O.[C:15]([BH3-])#[N:16].[Na+].C(O)(=O)C.O>C(O)C.CN>[CH3:15][NH:16][CH:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: [BH3-]C#N
Reactant: COCOc1cccc2c1CCC2=O
Agent: CN
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CNC1CCc2c(OCOC)cccc21
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a solution of 1.00 g of 4-(methoxymethoxy)-1-indanone in 10 ml of ethanol, 2.8 ml of 40% methylamine (methanol solution) and 367 mg of sodium cyanoborohydride were added. While stirring at room temperature, 0.55 ml of acetic acid was added dropwise and the mixture was heated at reflux for 4 hours. The reaction solution was air-cooled, combined with water and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 0.61 g of the desired compound as a deep green oily substance.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[CH:27](O)[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([CH:27]1[CH2:26][CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:30]=[CH:29][C:28]1=2)=[N+:47]=[N-:48]
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-ol (2.0 g, 4.63 mmol) in 25 mL of toluene at −10° C. was added DPPA (1.2 mL, 5.56 mmol). To this stirred solution was then added DBU (0.83 mL, 5.56 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/DCM=1:2) to afford the desired product as a white solid.