Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH:12]([OH:14])[CH3:13])[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(C)C)(C)C>CCO>[CH2:15]([NH:22][C:5]1[N:4]([CH2:11][CH:12]([OH:14])[CH3:13])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 5.8 %

Procedure:
A mixture of 1-(3,5-dibromo-4-nitropyrazol-1-yl)propan-2-ol (3-3) (22 g, 666 mmol), EtOH (300 ml) and benzylamine (102 g, 936 mmol) was refluxed for 1.5 hours. The reaction medium was concentrated to the maximum under reduced pressure. DCM (100 ml) was added to the residue. The organic phase was washed with dilute acid (5×50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The brown oil obtained was treated with diisopropyl ether at 0° C. to give the 1-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propan-2-ol (13.7 g, 58%) in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:16]([OH:17])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)Nc1c(N)ncc(Cl)c1C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(C)c21
Temperature: 25 °C
Yield: 17.9 %

Procedure:
To a room-temperature solution of 5-chloro-4-methyl-N3-(pentan-3-yl)pyridine-2,3-diamine (49 mg, 0.22 mmol, 1.0 equiv) in THF (10 mL) was added carbonyl diimidazole (211 mg, 1.3 mmol, 6.0 equiv) as a solid in one portion. The resulting mixture was heated to reflux overnight. After the reaction was cooled to room temperature, the excess carbonyl diimidazole was quenched by the careful addition of water. The mixture was then diluted with EtOAc, washed with saturated aq. NaHCO3, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel preparative thin layer chromatography (0.5% Et3N, 5% MeOH, 94.5% CH2Cl2) provided the title compound as a solid (10 mg, 22%). m/z=252.3 [M−H]−
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([C:10](OC)=[O:11])[N:7]=[C:4]2[S:5][CH:6]=1.O>C1C=CC=CC=1.C1COCC1>[CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: COC(=O)c1cn2c(C)csc2n1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1csc2nc(CO)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
100 ml of a 70% solution of NaAlH2 (CH3OCH2CH2O)2 in benzene are dropped at 25° into a suspension of 25 g of 3-methyl-6-carbomethoxy-imidazo-(2,1-b)thiazole, prepared as described in Example 8, in 250 ml of dry THF. The suspension is stirred for 2 hours at room temperature and thereafter 25 ml of water are slowly added. The suspension is then filtered and the filtrate concentrated to yield 21 g of 3-methyl-6-hydroxymethyl-imidazo-(2,1-b)thiazole; m.p. 155°-156° (methyl-ethyl-ketone).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (46 mg, 0.126 mmol) and TBTU (45 mg, 0.139 mmol) in DMF (2.0 mL) was added DIPEA (110 μL, 0.631 mmol). Then isopropylamine (12 μL, 0.139 mmol) was added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (34 mg, 66%) as a white foam. MS: m/e=406.3 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:29])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[S:23])[NH2:22])[C:15](=[O:24])[C:14]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:13]12>>[C:15]1(=[O:24])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[S:23][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[C:12](=[O:29])[C:13]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:14]12
Reactant: NC(=S)CCCCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2CC1Br
Product: O=C1c2ccccc2C(=O)N1CCCCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 5-phthalimidopentanethioamide
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:53]([CH3:55])[CH3:54].C(Cl)(=O)C>O.C(#N)C>[CH:53]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:8])=[O:9])[CH:18]=2)[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:15]1)([CH3:55])[CH3:54]
Reactant: CC(C)I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: CC(C)n1cc(-c2ccc(C(F)(F)F)cc2-c2ccnn2C)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate B) (57.4 mg, 0.088 mmol), cesium carbonate (86 mg, 0.263 mmol), acetonitrile (0.5 mL), and 2-iodopropane (26.3 μl, 0.263 mmol). The vial was sealed and heated to 70° C. for 1 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up on in MeOH (1 mL), then acetyl chloride (31.2 μl, 0.438 mmol) was added. After stirring for 1 h, the mixture was concentrated in vacuo. The residue was taken up in a solution of 2N ammonia in methanol, and the resulting slurry was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-isopropyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (38.52 mg, 0.070 mmol, 80% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.36 (s, 1 H), 8.00 (d, J=1.5 Hz, 1 H), 7.96-7.89 (m, 2 H), 7.79-7.75 (m, 1H), 7.70 (d, J=8.5 Hz, 1 H), 7.48 (dd, J=1.7, 8.5 Hz, 1 H), 7.44 (d, J=1.9 Hz, 1 H), 7.09 (s, 1 H), 6.42 (d, J=1.9 Hz, 1 H), 4.86 (td, J=6.5, 13.2 Hz, 1 H), 1.33 (d, J=6.6 Hz, 6 H). m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[C:16]([C:32]([F:35])([F:34])[F:33])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.I[CH:37]([CH3:39])[CH3:38].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:37]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[C:16]([C:32]([F:34])([F:33])[F:35])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1)([CH3:39])[CH3:38]
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(C)C)CC3)c2)ncc1C(F)(F)F
Yield: 70 %

Procedure:
A suspension of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide A67 (80 mg, 0.16 mmol), 2-iodopropane (25 μL, 0.25 mmol) and K2CO3 (68 mg, 0.49 mmol) in MeCN (5 mL) was irradiated in the microwave at 120° C. for 40 minutes. Additional 2-iodopropane (25 μL, 0.25 mmol) was added and the reaction mixture was irradiated in the microwave at 120° C. for another 40 minutes. Upon cooling, the liquid was decanted from the solid and the volatiles were removed in vacuo. The resultant solid was suspended in water (50 mL) and sonicated for 10 minutes before being filtered. The solid was dissolved in acetone (3 mL) and precipitated by the addition of petroleum benzine 40-60° C. before being collected by filtration and dried under high vacuum to give the title compound 60 as a tan solid (61 mg, 70%). LCMS-D: rt 3.060 min; m/z 530.4 [M+H]+.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[C:13](=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:13])=[C:6]([F:12])[CH:5]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cc(Br)cc1F

Procedure:
Add iodomethane (2.0 ml, 32.1 mmol) dropwise to a suspension of 4-bromo-2,6-difluorophenol (5.90 g, 28.2 mmol) and potassium carbonate (4.40 g, 31.8 mmol) in acetone (50 ml) at room temperature while stirring vigorously. Heat the mixture under reflux overnight. Evaporate acetone and add dichloromethane. Filter through silica eluting the product with dichloromethane/EtOAc. Concentrate to yield the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33]>>[C:32]([NH:31][CH2:30][CH2:29][NH:28][C:22]([C:5]1[C:4](=[O:27])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([C:6]=1[OH:21])=[N:8][CH:9]=[C:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH:11]=2)=[O:23])(=[O:34])[CH3:33]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: CC(=O)NCCN
Product: CCn1c(=O)c(C(=O)NCCNC(C)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 60.8 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and N-(2-aminoethyl)acetamide (66 mg, 0.648 mmol) was prepared N-[2-(acetylamino)ethyl]-1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 60% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.31 (br s, 1 H), 8.49 (s, 1 H), 7.38 (s, 1 H), 7.14-7.11 (m, 2 H), 7.01-6.96 (m, 2 H), 6.85 (br s, 1 H), 4.16 (m, 2 H), 4.10 (s, 2 H), 3.54 (m, 2 H), 3.42 (m, 2 H), 1.94 (s, 3 H), 1.20 (m, 3 H); HRMS m/z calcd for C22H24FN4O4: 427.1776 Found: 427.1783.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:47])=[N:4][O:5][C:6]=1[N:7]([CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([OH:40])[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)(=[O:10])=[O:9]>C(O)(=O)C.O.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:47])=[N:4][O:5][C:6]=1[N:7]([CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([OH:40])[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][OH:32])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2CCO[Si](C)(C)C(C)(C)C)OCO3)sc2ncccc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2CCO)OCO3)sc2ncccc12

Procedure:
A solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-4,5-(methylenedioxy)-2-(2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}ethyl)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.29 g, 0.40 mmoles) in acetic acid (3 ml), H2O (1 ml) and THF (1 ml) was stirred at ambient temperature for 18 hours, then diluted with EtOAc (100 ml) and washed with sat. NaHCO3 (2×200 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.23 g (94%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>Cl.O1CCOCC1>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][NH2:13])[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCCNC(=O)OC(C)(C)C)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(CCCN)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Reaction time: 8 h
Yield: 106.2 %

Procedure:
Under a static nitrogen atmosphere 2.40 g (4.7 mmol) of 5-[4′-[[3-butyl-5-(N-Boc-3-aminopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 67 was dissolved in 30 mL of 4N HCl in dioxane at ambient temperature and allowed to stir overnight. The solvents were removed in vacuo; the residue was triturated with diethyl ether and filtered providing 2.08 g (98%) of 5-[4′-[[3-butyl-5-(3-aminopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the hydrochloride salt: NMR (DMSO-d6) δ 0.88 (t, J=7 Hz, 3H), 1.25–1.39 (m, 2H), 1.57–1.69 (m, 2H), 1.92–2.40 (m, 2H), 2.62 (t, J=7 Hz, 2H), 2.89 (q, J=8 Hz, 2H), 2.98 (t, J=8 Hz, 2H), 5.38 (s, 2H), 7.10 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 7.54 (d, J=8 Hz, 1H), 7.59 (dd, J=8 and 2 Hz, 1H), 7.66 (s, 1H), 7.70 (dd, J=8 and 2 Hz, 1H), 8.10 (br s, 2H); MS (FAB) m/e (rel intensity) 417 (38), 389 (10), 357 (10), 207 (100), 166 (50), 139 (10) 115 (10); HRMS. Calc'd for M+H: 417.2515. Found: 417.2563.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10]3[N:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH:28]1([C:8]2([OH:17])[C:7]3[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:12][CH2:11][C:10]3[N:13]=[CH:14][CH:15]=[CH:16][C:9]2=3)[CH2:27][CH2:31]1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)C(=O)c1cccnc1CO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(O)(C1CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one (5.0 g) in THF (50 ml) was added 1.1M cyclopropylmagnesium bromide THF solution (25 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give 5-cyclopropyl-5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-ol (5.0 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[O:17][C@H:18]4[CH2:41][N:21]([C:22](=[O:40])[C@H:23]([C:36]([CH3:39])([CH3:38])[CH3:37])[NH:24][C:25](=[O:35])[O:26][C@@H:27]5[CH2:34][C@H:28]5[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:8]=23)[C@H:20]([C:42]([NH:44][C@:45]2([C:50](=[O:59])[NH:51][S:52]([C:55]3([CH3:58])[CH2:57][CH2:56]3)(=[O:54])=[O:53])[CH2:47][C@H:46]2[CH:48]=[CH2:49])=[O:43])[CH2:19]4)[CH2:2]1.[CH2:60]=O.[BH4-].[Na+]>CO>[C:36]([C@H:23]1[C:22](=[O:40])[N:21]2[CH2:41][C@@H:18]([CH2:19][C@H:20]2[C:42]([NH:44][C@:45]2([C:50](=[O:59])[NH:51][S:52]([C:55]3([CH3:58])[CH2:56][CH2:57]3)(=[O:54])=[O:53])[CH2:47][C@H:46]2[CH:48]=[CH2:49])=[O:43])[O:17][C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:7]([O:6][CH2:5][CH:3]3[CH2:2][N:1]([CH3:60])[CH2:4]3)=[C:8]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[CH2:34][C@H:27]2[O:26][C:25](=[O:35])[NH:24]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: C=O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCC1CNC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCC1CN(C)C1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the amine from Step 1 (20.6 mg) in methanol (1 mL) was added formaldehyde (10 μl). Sodium borohydride (5.6 mg) was added slowly. The clear reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the product was dissolved in ethyl acetate and water (with acetic acid to a pH=5). The mixture was extracted (3×) with ethyl acetate. The combined organics were dried with sodium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO reverse phase, 0 to 95% water in acetonitrile followed by ISCO: 0 to 20% methanol in DCM) gave the desired product (1.4 mg). LRMS (ES+) m/z 849.55 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28]SC3C=CC=CC=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.[C:39]1(C)[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=O)=[CH:41][CH:40]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:45]([C:42]3[CH:41]=[CH:40][CH:39]=[CH:44][CH:43]=3)(=[O:47])=[O:48])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CS(=O)(=O)c2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl]-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (4 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from acetonitrile to afford 0.07 gm of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH2:6][CH2:7][CH2:8][N:9]=1)([CH3:3])[CH3:2].[H][H].[H][H].N#N>N1C=CC=CC=1.[Pt]>[CH:1]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C1=NCCCN1
Reactant: [H][H]
Agent: [Pt]
Agent: N#N
Solvent: c1ccncc1
Product: CC(C)c1ncccn1
Yield: 73 %

Procedure:
A solution of 70 g of 2-isopropyl-1, 4, 5, 6-tetrahydropyrimidine in 100 ml of pyridine was fed at about 1 ml/min to a column 1"×20" containing about 50 g of 0.5 percent platinum on α-alumina at 300° to 325° C. while sweeping out the column with a mixture of nitrogen and hydrogen. The catalyst had been activated by passing a 2:1 H2 /N2 stream over the bed for two hours. The effluent was distilled giving 2-isopropylpyrimidine at 152° to 155° C. The yield was 73 percent.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([C:12]#[N:13])=[N:10][CH:11]=1.O>C(Cl)(Cl)Cl>[N:5]([C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([C:12]#[N:13])=[N:10][CH:11]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(N)cnc1C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(N=C=S)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Thiophosgene (0.24 mL, 3.1 mmol) was added to a stirred biphasic solution of 5-amino-3-methylpicolinonitrile (Intermediate 2, 275 mg, 2.07 mmol) in CHCl3 (6 mL)/water (10 mL) and the resulting orange mixture was stirred at room temperature overnight. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 300 mg of 5-isothiocyanato-3-methylpicolinonitrile as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.06 (s, 1H), 2.5 (s, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=1)[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:31]3[CH:30]=[N:29][C:28]([CH2:26][CH3:27])=[CH:33][CH:32]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCc1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 153 mg (0.66 mmol) of 2-ethyl-5-iodo-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 62 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 1.6 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.[OH-].[NH4+]>C1COCC1.CCCCC.C(OCC)C.[Cl-].[Zn+2].[Cl-].[Ni].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(Br)nc1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: [Ni]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccc(-c2cccc(OC(F)(F)F)c2)nc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromotrifluoromethoxybenzene (0.590 mL, 4.00 mmol) in THF (12 mL) at -78° C. was added t-butyl lithium (4.71 mL, of a 1.7M solution in pentane, 8.00 mmol. After 10 minutes zinc chloride(4.0 mL, of a 1M solution in diethylether, 4.00 mmol) was added. The reaction was stirred for 10 minutes at -78° C. and then allowed to warm to 0° C. and stirred for 30 minutes. This solution was added via cannula to a solution of 2-bromo-5-methyl pyridine and bis(triphenylphosphine) Nickel II chloride. The reaction stirred for 1 hour at 0° C. and then at ambient temperature for a furthur 1 hour. Saturated ammonium hydroxide solution (3 mL) was added and the mixture stirred until homogenous, extracted with Et2O and the organic extracts washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (Silica gel, 25-50% CH2Cl2 in hexanes).