Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[C:34]([O:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:27])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
iv)—A solution of the aldehyde (12.3 g) mentioned above in dry pyridine (150 ml) was cooled to 4° C. Benzoyl chloride (8 ml) was added in 5 min. and the reaction mixture was stirred for 1.5 h at room temperature. Then it was poured into water (2 l) and the resulting mixture was stirred overnight. The product was extracted into dichloromethane and the combined organic phases were concentrated under reduced pressure to give (3β,5α,20R)-3-(benzoyloxy)-4,4,20-trimethylpregna-8,14-diene-21-carboxaldehyde (16.1 g). The product was used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>C(O)(=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[F:16]
Reactant: O=[N+]([O-])c1cnc2ccc(F)cc2c1Cl
Reactant: Nc1ccccc1F
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(F)cc2c1Nc1ccccc1F

Procedure:
0.4 g (1.8 mmol) of 4-chloro-6-fluoro-3-nitro-quinoline (Example 19c) and 0.17 ml (1.98 mmol) 2-fluoroaniline in 5 ml acetic acid are stirred overnight at rt. Crystals are formed. The mixture is poured into water, the solid material is filtered off and washed with water. The residue is dissolved in CH2Cl2 and washed twice with water. The organic phase is dried over MgSO4 and most of the solvent is evaporated. The title compound is obtained from this solution as yellow crystals by adding hexane. The compound is filtered off, washed with hexane and dried (70° C., high-vacuum). mp: 161-162° C.; MS: 302 (M++1); HPLC: tret=10.24 min (Grad 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[N:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11].N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6]([C:18]2[CH:19]=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[CH:15]=[CH:16][CH:17]=2)[C:5](=[O:9])[N:4]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: COc1cn[nH]c(=O)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cnn(-c2cccc(NC(C)=O)c2)c(=O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
According to Scheme 6 Step 1: To a stirred solution of 5-methoxy-1,2,4-triazin-3(2H)-one (1 g, 7.9 mmol) in DMF (5 mL) were successively added the 3-acetamidophenylboronic acid (1.4 g, 7.9 mmol), copper(II) acetate (1.4 g, 7.9 mmol) and pyridine (1.2 g, 7.9 mmol). The mixture was stirred overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 70 g column, CH2Cl2/MeOH 98/2 to afford(0.493 g, 24%) of N-(3-(5-methoxy-3-oxo-1,2,4-triazin-2(3H)-yl)phenyl)acetamide
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:22](=[O:24])[CH3:23])=[N:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)=[CH2:2]
Reactant: C=Cc1ccc(-n2cncn2)cc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2ncnc2C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]-triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](O)=[O:14].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([Cl:23])=[O:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
A mixture of 3-(2,4-difluorophenylthio)-4-nitrobenzoic acid (1 g) and phosphorus pentachloride (0.7 g) in benzene (10 ml) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give a powder of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1.2 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C(Cl)Cl>[Br:20][CH2:23][C:24]1[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)cc3ccccc32)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)cc3ccccc32)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of triphenylphosphine (20.2 g, 77 mmol) in dry CH2Cl2 (80 mL) was added dropwise a solution of bromine (11.9 g, 77 mmol) in dry CH2Cl2 (40 mL). The stirring was continued for one hour and then a solution of compound of step 2 (23.2 g, 77 mmol) in dry CH2Cl2 (40 mL) was added dropwise. The resulting mixture left stirring for 12 hours. After removing the solvent the residue was taken up in ethyl acetate and washed with water. The organic extract was dried over MgSO4 and the solvent evaporated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give a yellow oil (21.0 g, 75%); IR (film) 1600 cm-1, MS ((70 eV): m/z 363 (M+,12.6), 129 (100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)N=C(c2ccccc2)NC1c1cccc(C(F)(F)F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 3.8 %

Procedure:
To a solution of ethyl 1,6-dihydro-4-methyl-2-phenyl-6-(3-trifluoromethylphenyl)-5-pyrimidinecarboxylate (12 g) in ethyl acetate (240 ml) was added activated manganese dioxide (48 g) and the mixture was refluxed for 2.5 hours with stirring vigorously. After allowing to cool, manganese dioxide was filtered off. The filtrate was evaporated in vacuo and the residual precipitate was recrystallized from pet ether. The crystal was filtered off and dried in vacuo to give ethyl 6-methyl-2-phenyl-4-(3-trifluoromethylphenyl)-5-pyrimidinecarboxylate (0.45 g).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][C:7](=[N:9][OH:10])[CH3:8]>[OH-].[Na+]>[C:7](=[N:9][O:10][CH2:2][C:3]([OH:5])=[O:4])([CH3:8])[CH3:6]
Reactant: O=C(O)CCl
Reactant: CC(C)=NO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=NOCC(=O)O
Temperature: 30 °C

Procedure:
47.3 Grams (0.5 moles) of chloroacetic acid was dissolved in 55 g (0.55 moles) of an aqueous solution of 40% sodium hydroxide. To the solution, 36.5 g (0.5 moles) of acetone oxime was added, and then 55 g (0.55 moles) of an aqueous solution of 40% sodium hydroxide was added dropwise to the mixture while maintaining a temperature at not higher than 30° C. Reaction was subsequently performed with the solution being allowed to flow at a rate of 4 ml/min into a glass tube (10 mm in diameter and 100 mm in length) that was heated at 90°-100° C. The unreacted acetone oxime was removed from the reaction solution by two extractions with 100 ml of ether. The pH of the remaining aqueous solution was adjusted to 1 with concentrated HCl. The solution was subsequently saturated with sodium chloride. The resulting aqueous solution was subjected to two extractions with 100 ml of ether and the extract was dried with magnesium sulfate. Ether was distilled off under vacuum and the residue was distilled under vacuum to obtain isopropylidene aminooxyacetic acid (m.p. 76° C.) in an amount of 16.3 g (yield, 25 mol %).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:25](/[S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:23])=[O:24])\[C:26]#[N:27])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccc2)cc(C(C)C)c1O

Procedure:
M30 was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under the similar conditions as decribed for M26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=[O:24])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 106A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 5 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH3:24])([CH3:23])[CH2:20][CH2:21]O.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:21][CH2:20][Si:19]([CH3:24])([CH3:23])[CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCC1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixed liquid of 2.00 g of (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and 40 ml of dichloromethane were added 1.41 ml of 2-(trimethylsilyl)ethanol, 0.40 g of DMAP, and 2.21 g of WSC in this order, followed by stirring at room temperature for 60 hours. After evaporating the solvent, ethyl acetate was added thereto, followed by washing with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:17](=O)[CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH2:13][NH:14][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCC=O
Reactant: NCc1cccc(Oc2ccc(Cl)cc2)c1
Product: CCCCNCc1cccc(Oc2ccc(Cl)cc2)c1
Yield: 31.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (3-(4-chlorophenoxy)phenyl)methanamine (ASDI, 533 mg, 2.28 mmol) and butyraldehyde (210 μL, 2.28 mmol) were converted to the title compound (211 mg, 32%). 1H NMR (CDCl3) δ 7.41-7.19 (m, 4H), 7.14-7.06 (m, 1H), 6.99-6.87 (m, 3H), 3.98-3.86 (m, 2H), 2.80-2.66 (m, 2H), 1.66 (quin, J=7.5 Hz, 2H), 1.42-1.24 (m, 2H), 1.00-0.81 (m, 3H); MS (ESI+) m/z 290.1 (M+H)+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][C:7](=O)[C:8]([F:11])([F:10])[F:9].[NH2:13][C:14]1[C:18]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:17]([NH2:25])[NH:16][N:15]=1.[OH-].[K+]>O1CCOCC1>[NH2:25][C:17]1[C:18]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]2[N:13]=[C:7]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:2][N:15]2[N:16]=1
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Reactant: O=C(CC1OCCO1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 25 °C
Yield: 78.7 %

Procedure:
3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoro-propan-2-one (55.58 g, 301.9 mmol) and allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (55 g, 301.9 mmol) were dissolved in 1,4-dioxane (330 mL). KOH (1.694 g, 30.19 mmol) was added and the yellow suspension was stirred at room temperature for 4 h30 min. The reaction mixture was heated at 90° C. for 16 h. The mixture was cooled down to room temperature. The reaction mixture was concentrated and purified by column chromatography (CombiFlash Companion XL, 1.5 kg column, 0.5 to 40% EtOAc in DCM) to afford allyl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a as a bright yellow solid (68 g, 79% yield). LC-MS (M+H)+ 287.2; 1H NMR (500 MHz, DMSO-d6) δ 9.18 (m, 1H), 7.46 (m, 1H), 6.77 (s, 2H), 6.05 (m, 1H), 5.62 (m, 1H), 5.26 (m, 1H), 4.78 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8](COC(=O)C(C)(C)C)[C:5]2=[N:6][CH:7]=1.[OH-].[K+]>O.O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (370 mg, 1 mmol), potassium hydroxide (280 mg, 5 mmol) in 2.5 mL of water and 5 mL of 1,4-dioxane was heated to reflux for 90 mins. The reaction mixture was cooled to room temperature, solvent evaporated, residue acidified with 1N HCl, filtered and dried to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a brown solid (320 mg, crude), material used in the next step without further purification. LCMS: (M+H)+=242/244; (M+Na)+=264/266.
Reaction SMILES: C(OCC)(=O)C.C(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:40])[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)[CH2:16][CH2:15]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[OH-].[Na+]>O>[Cl:36][C:32]1[CH:31]=[C:30]([C:29]2[C:28]3[C:23](=[N:24][C:25]([CH3:37])=[CH:26][CH:27]=3)[N:22]([CH2:38][CH3:39])[C:21](=[O:40])[C:20]=2[N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)[CH:35]=[CH:34][CH:33]=1
Reactant: CCn1c(=O)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(=O)c(N2CCNCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a 10 ml ethyl acetate solution containing 570 mg of 3-(1-tert-butoxycarbonylpiperazin-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one was added a 10 ml 4M hydrogen chloride-ethyl acetate solution, followed by stirring at room temperature for 1 hour. After adding water, the reaction mixture was neutralized with 1M sodium hydroxide aqueous solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) and then recrystallized from diisopropyl ether to obtain 115 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperazin-1-yl)-1,8-naphthyridin-2(1H)-one as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[C:15]#[N:16])=[CH:4][CH:3]=1.[Br:17]Br.O>O1CCOCC1>[Br:17][C:10]1[C:9]([C:15]#[N:16])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:12][C:11]=1[C:13]#[N:14]
Reactant: N#Cc1cc(C#N)c(-c2ccc(Cl)cc2)[nH]1
Reactant: BrBr
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(C#N)c1Br
Temperature: 25 °C

Procedure:
A sample of 5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile (1.0 g, 0.004 mole) is dissolved in 20 mL of dioxane and a solution of bromine (0.8 g, 0.005 mole) in dioxane (10 mL) is then added thereto. The solution is stirred several hours at room temperature and then poured into water precipitating a white solid (1.2 g, 100%). The solid has a m.p. >225° C. and a mass spectrum of a sample gives a pattern consistent with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(OC([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)/[C:26](=[CH:34]/[C:35]2[CH:40]=[C:39]([Br:41])[CH:38]=[CH:37][C:36]=2[O:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)/[C:25]1=[O:56])=O)(C)(C)C>C1(C)C=CC=CC=1>[Br:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH:43]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]2)=[C:35]([CH:34]2[CH2:12][C:10](=[O:11])[NH:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:26]32[C:27]2[C:32](=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[NH:24][C:25]3=[O:56])[CH:40]=1
Reactant: C=C(N=Cc1cccc(F)c1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in example 36a (24 mmol) in toluene (100 mL) was added E/Z-3-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.85 g, 6 mmol). The reaction mixture was stirred under argon at 140° C. for 5 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography (20%-30% EtOAc:DCM) to give the title compound as a off white solid (Yield: 0.38 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(C=O)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(c2ccc(CO)cc2)CC1

Procedure:
This compound was prepared in the manner of Step A, Example 5, using 0.4 gram (0.019 mole) of [4-(4-ethylpiperazinyl)benzaldehyde and 0.4 gram (0.01 mole) of sodium borohydride in 40 mL of absolute ethanol (available from J. T. Baker Inc.) The yield of the title compound was 0.3 gram. The NMR Spectrum was consistend with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]=[C:10]([C:8]1[N:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cccc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-(6-Acetyl-pyridin-2-yl)-ethanone 2 (22.2 g, 0.0136 mole), 15.0 g (0.124 mol) of 2,6-dimethyl-phenylamine 3, 300 ml of n-propanol, and a few crystals of p-toluenesulfonic acid were stirred at room temperature for 36 h in 500 ml flask under a flow of nitrogen. The resultant yellow precipitate was filtered and washed by 20 ml of methanol. It was then dried at 1-mm vacuum overnight. The yield of 1-{6-[1-(2,6-dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 was 12.86 g (39%) as a yellow solid. 1H NMR (500 MHz, CD2Cl2, TMS): δ 2.00 (s, 6H, Me), 2.20 (s, 3H, Me), 2.70 (s, 3H, Me), 6.90 (t, 3JHH=8.1 Hz, 1H, Arom-H), 7.10 (d, 3JHH=8.1 Hz, 2H, Arom-H), 7.95 (t, 3JHH=8.0 Hz, 1H, Pyr-H), 8.10 (d, 3JHH=8.0 Hz, 1H, Py-H), 8.55 (d, 3JHH=8.0 Hz, 1H, Py-H). 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 167.1 (C═N), 200.1 (0=0). Anal. Calculated for C17H13N2O (Mol. Wt.: 266.34): C, 76.66; H, 6.81; N, 10.52. Found: C, 76.69; H, 6.84; N, 10.57.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH3:3].[BH4-].[Na+].[CH2:8]([N:10]([CH2:21][CH3:22])[C:11]([O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:12])[CH3:9].[OH-].[Na+]>C1C=CC=CC=1>[CH2:21]([N:10]([CH2:8][CH3:9])[C:11]([O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:1][CH2:2][CH3:3])=[O:12])[CH3:22]
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Reactant: CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCNc1ccncc1OC(=O)N(CC)CC
Temperature: 80 °C

Procedure:
A solution of propionic acid (58.5 ml) in 100 ml of benzene was treated with NaBH4 (9.6 g added portionwise). After the frothing subsided, 4-amino-3-pyridinol N,N-diethylcarbamate (5.30 g) was added and the mixture was heated at 80° C. for 2 hours. The reaction mixture was poured into a dilute NaOH solution and the aqueous phase was extracted with ethyl acetate (3×). The combined organics were washed with water and dried (saturated NaCl, MgSO4). The desired amine was purified via flash chromatography to give 3.2 g of solid, m.p. 60°-70° C. This product was combined with a crop obtained from another run and recrystallized from hexane to give analytically pure material, m.p. 75°-78° C.