Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:26]=[C:9]2[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[N:8]2[N:7]=1)=O)C.[NH3:27]>C(O)C>[C:20]1([C:12]2[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[N:8]3[N:7]=[C:6]([C:4]([NH2:27])=[O:3])[N:26]=[C:9]3[CH2:10][N:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N
Reactant: CCOC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CCO
Product: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
An amount of 3.67 g (0.010 mole) of 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]-benzodiazepine-2-carboxylic acid ethyl ester is dissolved at 40° in 300 ml of ethanol, and 50 ml of conc. aqueous ammonia solution is then added. The clear solution is allowed to stand for 24 hours at room temperature and thereupon concentrated at 40° in vacuo. The red residue is suspended in 100 ml of water, filtered under suction, and the filter residue subsequently washed with water. The resulting product is recrystallised from methanol and dried at 100°-120° in vacuo to obtain 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 252°-254°.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.O1CCCC1.[Li]CCCC.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([C:27](N(OC)C)=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+].O>>[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]2[NH:11][CH:10]=[N:9][N:8]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: Brc1ccsc1-c1nnc[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccsc1-c1nnc[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (15.05 g, 65.41 mmol) in Tetrahydrofuran (500 mL, 6000 mmol) was added dropwise 2.5M BuLi in hexanes (104 mL, 262 mmol) at −70° C. (internal temperature) and the solution was stirred for 30 min at −78° C. A solution of 4-chloro-N-methoxy-N-methylbenzamide (41.24 g, 206.6 mmol) in tetrahydrofuran (80 mL, 1000 mmol) was then added dropwise into the suspension. The resulting mixture was stirred for 60 min at −78° C. Ammonium chloride (17.49 g, 327.0 mmol) in water (100 mL, 6000 mmol) was added to the mixture at −78° C. and the mixture was stirred for 15 min before being warmed to rt. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and then filtered to remove drying agent. The solvent was evaporated and the residue was purified by chromatography to afford (4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone as white solid (16.8 g, 88.5%). LCMS: (FA) ES+ 289.9, 291.8
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].CI.[C:7]([NH:14][C@@H:15]([C:17]([OH:19])=[O:18])[CH3:16])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[H-].[Na+]>C1COCC1>[CH3:12][C:10]([CH3:13])([O:9][C:7]([N:14]([CH2:3][CH:2]=[CH2:1])[C@@H:15]([C:17]([OH:19])=[O:18])[CH3:16])=[O:8])[CH3:11]
Reactant: C=CCI
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C=CCN(C(=O)OC(C)(C)C)[C@H](C)C(=O)O
Yield: 99 %

Procedure:
Allyl iodide (6.72 g, 40.0 mmol) replaced methyl iodide and Boc-(D)-alanine (1.89 g, 10.0 mmol) replaced Z-(D)alanine in the reaction of Example 15. They were reacted using sodium hydride (30.0 mmol, 50% suspension in mineral oil) and THF (30 ml). 2.27 g of oil was obtained using the procedure and work-up of Example 15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([F:18])=[N:12][C:13]([F:17])=[CH:14][C:15]=1[F:16])[OH:9]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4].O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([F:18])=[N:12][C:13]([F:17])=[CH:14][C:15]=1[F:16])=[O:9]
Reactant: OC(c1ccccc1Cl)c1c(F)cc(F)nc1F
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1c(F)cc(F)nc1F
Yield: 32 %

Procedure:
(2-Chloro-phenyl)-(2,4,6-trifluoro-pyridin-3-yl)-methanol (8.02 g, 29.3 mmol) was taken up in 80 mL of dry toluene, and manganese dioxide 26 g) was added. The reaction mixture was refluxed for 2.5 hours, after which 2.5 g of additional MnO2 was added. The reaction mixture was refluxed for another hour and an additional 2.5 g of MgO2 was added. The reaction mixture was refluxed for three hours, and was then hot filtered through Celite. The Celite plug was washed with hot EtOAc (in several portions), and the organic solvents were combined. The solvent was evaporated under reduced pressure, and the residue was subject to flash chromatography 5% to 10% EtOAc in hexanes) to give 2.55 g of (2-Chloro-phenyl)-(2,4,6-trifluoro-pyridin-3-yl)-methanone. Mass Spec. M−H=270.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Na].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:22])[C:20]=1[SH:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:22])[C:20]=1[S:21][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a solution of 1-(5-chloro-4-nitro-2-thienyl)ethanone (113 mg, 0.55 mmol) in toluene (2 mL), was added 3,5-dichloropyridine-4-thiol sodium salt (100 mg, 0.55 mmol) and potassium carbonate (113 mg, 0.825 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 hours. After this time, the reaction mixture was filtered to remove the solid residues. The organic solution was diluted with ethyl acetate (15 mL) and was washed with water (2 mL×2) and brine (1 mL×2), dried (Na2SO4) and concentrated under vacuum. The residue was purified by silica gel chromatography using a mixture of 96:4 hexane and ethyl acetate as eluent to afford the title product as a solid (22 mg, 12% yield). 1H NMR (400 MHz, MeOD) δ: 8.85 (2H, m) 8.36 (1H, s), 2.52 (3H, s). MS m/z: 348.8 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][CH2:6]1)[OH:4].[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:15][C:16]1[C:21]([NH:1][CH2:2][C@H:3]([C@H:5]2[C@H:12]3[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]3)[CH2:7][CH2:6]2)[OH:4])=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)CC[C@H]2O1
Reactant: Clc1nccnc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)CC[C@H]2O1

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-6) (3.22 g, 15.0 mmol, 1.0 eq) was dissolved in dioxane (150 mL). 2,3-Dichloropyrazine (4.46 g, 29.9 mmol, 2 equiv) was added followed by triethylamine (8.34 mL, 59.8 mmol, 4 equiv) and the reaction mixture was heated to reflux overnight. Concentration and purification via flash chromatography on a silica gel column (ethyl acetate/hexanes) yielded desired (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-7) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.88 (dd, J=5.5, 2.7 Hz, 1H); 7.60 (d, J=2.7 Hz, 1H); 5.74 (d, J=31.9 Hz, 1H); 4.68-4.63 (m, 1H); 4.34 (t, J=5.4 Hz, 1H); 3.88 (ddd, J=14.5, 6.7, 2.5 Hz, 1H); 3.81-3.69 (m, 2H); 3.63-3.46 (m, 2H); 2.15-2.04 (m, 1H); 2.03-1.88 (m, 1H); 1.83-1.72 (m, 1H); 1.69-1.52 (m, 1H); 1.50 (d, J=13.2 Hz, 3H); 1.32 (d, J=4.5 Hz, 3H). LRMS m/z (M+H) 313.9 found, 314.1 required.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.S(Cl)(Cl)=O.Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21])=[O:9]
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C=Cc1cccc(F)c1)NN1CC(=O)NC1=O
Reaction time: 8 h

Procedure:
To 99.5 g (0.6 mole) of m-fluorocinnamic acid was added dropwise thionyl chloride (600 ml) followed by heating at reflux for 2 hours. The excess thionyl chloride was removed in vacuo and the residue remaining flushed with dry benzene. The reaction residue was chilled on an ice bath followed by the rapid addition of 1-aminohydantoin hydrochloride (91 g, 0.6 mole). To the cold reaction mixture was added dropwise pyridine (600 ml). After the addition was complete the cold reaction mixture was heated on a steam bath for 3 hours then poured into 6 l. of HCl/ice. Upon standing at room temperature overnight the acidic reaction mixture was filtered and washed with water to give 116 g (73.5%) which after recrystallization from CH3NO2 melted at 294°-296°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[C:7]#[N:8].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Cl)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]([C:12]2[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)([CH:9]([CH3:11])[CH3:10])[C:7]#[N:8])=[CH:25][CH:24]=1
Reactant: CNCCCC(C#N)(c1cc(OC)cc(OC)c1)C(C)C
Reactant: ClCCc1ccc(Cl)cc1
Product: COc1cc(OC)cc(C(C#N)(CCCN(C)CCc2ccc(Cl)cc2)C(C)C)c1
Yield: 65 %

Procedure:
29.0 g (0.1 mole) of 5-methylamino-2-(3,5-dimethoxyphenyl)-2-isopropylvaleronitrile and 21.0 g (0.12 mole) of 4-chlorophenethyl chloride were reacted similarly to Example 5, and 27.9 g (60%) of base were isolated after chromatographic purification. The base was converted to the amidosulfonate. Mp. 122°-123° C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([CH:13]3[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=4)[NH:14]3)[CH:10]=[CH:11][CH:12]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([CH:13]3[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=4)[NH:14]3)[CH:10]=[CH:11][CH:12]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)C3CC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)C2CC2)c1
Yield: 58.2 %

Procedure:
In a round bottom flask, to a mixture of methyl 2-(3-(cyclopropane-carboxamido) phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (109 mg, 0.29 mmol) in methanol (5 mL) and water (2.5 mL) was added a solution of sodium hydroxide (196 mg, 4.90 mmol) in water (2.5 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford 2-(3-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid product. (61 mg, yield: 58.2%). MS (ESI+APCI) M+1=347.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[I:26]I>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([I:26])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ncnc32)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [5.4 g, Reference Example 3], in tetrahydrofuran (96 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (12.1 mL, 1.6M) under inert atmosphere. The solution was stirred at −78° C. for 3 hours and iodine (8.9 g) was added. The reaction mixture was stirred at −78° C. for 2 hours, and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (1.52 g) as an amorphous solid. MS: 434 [MH]+. LCMS (Method B) RT=4.26 minutes.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:24][CH:25]1[CH2:29][CH2:28][O:27][CH2:26]1>>[O:27]1[CH2:28][CH2:29][CH:25]([NH:24][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:26]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: NC1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOC2)[nH]n1
Yield: 33 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using rac-3-aminotetrahydrofuran instead of morpholine, to the title compound (39 mg, 33%), which was obtained as a white solid. MS: m/e=369.2 [M+H]+.
Reaction SMILES: [Na].[F:2][C:3]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:4][CH2:5][OH:6].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:14]=1.Cl>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:15]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]([O:6][CH2:5][CH2:4][C:3]([F:11])([F:2])[C:7]([F:10])([F:9])[F:8])[N:14]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: OCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na]
Product: COc1cc(Nc2nc(C)cc(OCCC(F)(F)C(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
Sodium (6.9 mg, 0.3 mmol) was dissolved under stirring and heating under an atmosphere of argon in 3,3,4,4,4-pentafluorobutan-1-ol (676 mg, 4.0 mmol). To this solution (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (66 mg, 0.20 mmol) was added and the reaction mixture was stirred for 16 h at 20° C. and then heated to 100° C. for 4 h. The reaction mixture was poured onto water and was acidified with 1N aqueous hydrochloric acid solution. It was extracted twice with diethyl ether. The aqueous layer was set to basic pH with 1N aqueous sodium hydroxide solution and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (59 mg, 64%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24]O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].P(Br)(Br)[Br:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][Br:27])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reactant: BrP(Br)Br
Product: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 7, 5-chloro-2',6'-difluoro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide to give 5-chloro-2',6'-difluoro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH3:12])[CH3:2].[Li+].CC([N-]C(C)C)C.C(=O)=O.CC(C)=O.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([Si:32]([CH3:34])([CH3:33])[CH3:31])[CH3:12])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: CCc1ccccc1C(=O)N(CC)CC
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccccc1C(C)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 5.13 g (25 mmol) of N,N,2-triethylbenzamide in THF (50 mL) at -78° C. was added a solution of LDA (Aldrich 2.0M, 15.63 mL, 31.25 mmol). The solution was warmed to -10° C. with ice water over 1 hr, then cooled to -78° C. with dry ice-acetone. TMSCl (6.34 mL, 50 mmol) was added neat at -78° C. and then reaction brought to room temperature after 1 hr. The reaction was quenched with saturated NH4Cl and extracted with ether (2×100 mL), dried over MgSO4, stripped and the residue distilled in a Kugelrohr (130°-140° C., 0.65 mm) to obtain 6.51 g (94%) of N,N-diethyl-2-[1-(trimethylsilyl)ethyl]benzamide.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6](=[N:13][OH:14])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])(=[O:3])[NH2:2].[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C(#N)C>[CH3:15][NH:16][C:17]([O:14][N:13]=[C:6]([S:5][CH2:4][C:1](=[O:3])[NH2:2])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])=[O:18]
Reactant: CN=C=O
Reactant: CC(C)(C(=NO)SCC(N)=O)[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(SCC(N)=O)C(C)(C)[N+](=O)[O-]
Yield: 71.5 %

Procedure:
A mixture of 10 g (0.045 m) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldoxime, 150 ml. acetonitrile, 8.0 g (0.14 m) of methylisocyanate and three drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for twenty hours. The acetonitrile and excess methyl isocyanate was removed from the product under reduced pressure. The solid residue was recrystallized from isopropanol and then dried at room temperature to give 9.0 g (72% yield) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldehyde O-(methylcarbamoyl)oxime; melting point=125-127° C. The nmr spectra confirmed the structure.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([Cl:26])=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([Cl:26])=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(Cl)c4ccccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3nc(Cl)c4ccccc43)nc12
Reaction time: 15 h
Yield: 38 %

Procedure:
To a stirred solution of N-tert-butyl-2-(3-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 200 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(3-Chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (28 mg, 38%). MS (M−H)−=367; 1H NMR (DMSO-d6) δ: 8.96 (s, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (ddd, J=8.4, 7.2, 1.0 Hz, 1H), 7.61 (s, 1H), 7.47-7.54 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)C>[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Reactant: Cc1ccccc1N
Solvent: CCO
Product: Cc1ccccc1N1CCc2c(C)nc3ccccc3c21
Yield: 43.5 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloroquinoline (45 g, 0.16 mol), 2-methylaniline (35 ml, 0.32 mol) and ethanol (300 ml) were heated to 150° C. in a pressure vessel for 17 hours, then concentrated in vacuo. The product crystallised as the hydrochloride salt. Conversion to free base and recrystallisation from ethyl acetate yielded 1-(2-methylphenyl)-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (19.1 g, 43%), m.p. 148°-150°.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20]Br.O>C(O)C>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC#CCOC1CCCCO1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C(#CCOC1CCCCO1)COc1ccccc1

Procedure:
To a solution of 2.35 g (0.025 mol) of phenol in 20 ml of absolute ethanol, there was added 1.10 g (0.0275 mol) of sodium hydroxide. The mixture was refluxed until complete disolution and 2.92 g (0.0125 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether were added, and the reflux resumed for 2 additional hours. It was then cooled, poured into water and extracted with ether. The organic extracts were washed with 20% aqueous sodium hydroxide solution and water, dried and evaporated in vacuo. The residue was purified by column chromatography on 50 g of silica gel, using hexane-ethyl acetate (98:2) as eluant, to yield 4-phenoxybut-2-yn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: COc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Product: COc1cccc(C(=O)/C=C/N(C)C)c1
Yield: 89 %

Procedure:
The title compound was prepared in 89% yield from 1-(3-methoxyphenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.94 (3H, s), 3.13 (3H, s), 3.85 (3H, s), 7.69 (1H, d, J=12.4 Hz), 6.98-7.01 (1H, m), 7.29-7.46 (3H, m), 7.79 (1H, d, J=12.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(F)c1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(OCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 58.8 %

Procedure:
To a mixture of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) and N,N-dimethylformamide (50.0 mL) were added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) was added at 0° C. under nitrogen atmosphere, which was stirred for 50 minutes at room temperature. 2-Fluoro-4-methylpyridine (1.80 g, 16.2 mmol) was then added thereto at 0° C., and stirred for 2 hours and 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.65 g, 58.8%).