Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]4[CH2:22][O:21]4)[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32][CH2:22][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[OH:21]
Reactant: COC(=O)c1ccccc1S
Reactant: Clc1ccc2ccc(/C=C/c3cccc(C4CO4)c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1SCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a stirred solution of epoxide 30 (37 g, 0.120 mol) in a mixture of dimethylformamide (140 ml) and acetonitrile (200 ml) was added methyl-2-mercaptobenzoate (20.0 g, 0.145 mol), followed by addition of anhydrous potassium carbonate (19.8 g, 0.145 mol). The reaction mixture was stirred overnight, filtered and concentrated. The resulting mixture was poured into water (2.0 L), stirred and extracted with ethylacetate (1.0 L). The organic layer was washed with water (500 ml) and brine (500 ml), dried over anhydrous sodium sulphate, evaporated and subjected to FC (EtOAc/hexanes) to afford product as a pale yellow solid 46 (18.0 g, 31% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=[O:14])=[CH:9]2)([O-:3])=[O:2].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:16][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][C:10]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A suspension of 2.57 g (12.53 mmol) of 7-nitro-1H-indole-2-carboxamide in 35 ml of pyridine is cooled to 0° C. in a water/ice bath. A solution of 4.01 g (12.53 mmol) of pyridinium tribromide in 20 ml of pyridine is then added at 0° C. dropwise, and the reaction is then stirred at 0° C. for 30 minutes and at ambient temperature for 16 h. 70 ml of ice-cold water are then added to the reaction medium. The latter is then stirred at ambient temperature for 15 minutes and is then filtered over sintered glass, to give 2.81 g of 3-bromo-7-nitro-1H-indole-2-carboxamide in the form of a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.Cl.CN.[CH2:24]([N:26](CC)CC)C>C(O)C>[CH3:9][NH:8][C:6]1[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=[C:2]([NH:26][CH3:24])[N:7]=1
Reactant: CCN(CC)CC
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(F)cc2)n1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(F)cc2)nc(NC)n1
Temperature: 140 °C
Reaction time: 17 h
Yield: 43.8 %

Procedure:
0.36 g (0.0011 mol) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.2 g (0.018 mol) of methylamine hydrochloride and 4.0 ml (0.029 mol) of triethylamine and stirred in an autoclave at 140° C. for 17 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water, the insoluble constituents were filtered off under suction and extracted. The extract and the solid were combined and recrystallized from methanol/diethyl ether. There was obtained 0.15 g (43%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide as white crystals; m.p. 261-263° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:32]1[CH:45]=[N:44][C:35]2[NH:36][C:37](=[O:43])[C:38]([CH3:42])([CH3:41])[NH:39][CH2:40][C:34]=2[CH:33]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:41][C:38]1([CH3:42])[C:37](=[O:43])[NH:36][C:35]2[N:44]=[CH:45][C:32](/[CH:10]=[CH:9]/[C:8]([N:7]([CH3:12])[CH2:6][C:5]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][C:18]([F:19])([F:20])[F:21])[C:4]=3[O:3][CH2:1][CH3:2])=[O:11])=[CH:33][C:34]=2[CH2:40][NH:39]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1OC(F)(F)F
Yield: 45.7 %

Procedure:
A solution of N-(2-ethoxy-3-trifluoromethoxybenzyl)-N-methylacrylamide (0.447 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min and then treated with diisopropylethylamine (0.40 mL, 2.3 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 minutes. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were added and the solution deoxygenated with Ar for 20 min. The mixture was heated to reflux for 18 h then, allowed to cool. The mixture was diluted with EtOAc (30 mL) and was washed with H2O (3×50 mL) and brine (2×50 mL), dried (Na2SO4) and concentrated to a yellow-orange solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.25 g, 31%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.78 (m, 1H), 8.40-8.37 (m, 1H), 8.01-7.93 (m, 1H), 7.56-7.49 (m, 1H), 7.36-7.09 (m, 4H), 4.87-4.68 (m, 2H), 4.06-3.83 (m, 4H), 3.31-2.88 (m, 4H), 1.36-1.29 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[NH2:13][C:11]1[CH:12]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCCc1ccccc1
Product: Nc1ccccc1
Yield: 80 %

Procedure:
The crude reaction mixture of 4-bromo-1-methyl-5-(5-nitro-2-phenethyloxy-phenyl)-1H-pyrazole (as described below) was reduced with SnCl2.2H2O (0.387 g, 1.68 mmol, 4.0 equiv.) in EtOH, in a similar manner as described in Example 1.1, providing aniline 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenylamine (0.124 g, 0.33 mmol, 80% for two steps) as an oil. LCMS m/z (%)=372 (M+H79Br, 94), 394 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.54 (s, 1H), 7.18-7.33 (m, 3H), 7.08 (d, J=7.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 1H), 6.77 (dd, J=2.7, 8.7 Hz, 1H), Hz, 1H), 3.99-4.15 (m, 2H), 3.53 (s, 3H), 3.10-3.40 (broad s, 2H), 2.83-3.00 (m, 2H).
Reaction SMILES: C[CH:2]([OH:26])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[C:12]([NH2:16])=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].[CH:27](=O)[CH3:28].[C:30](O[BH3-])(=O)[CH3:31].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+]>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:8]1[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:26])[C:11]2[C:12]([N:16]([CH2:27][CH3:28])[CH2:30][CH3:31])=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: CC=O
Reactant: CC(O)CCCCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reactant: [BH3-]OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCCCO)c12
Yield: 39.4 %

Procedure:
To a solution of methyl 5-{7-amino-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}pentan-1-ol (Reference Example 112; 308 mg, 1.85 mmol) in methanol (8 mL) and acetic acid (0.160 mL) was added acetaldehyde (0.304 mL, 4.88 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium acetoxyborohydride (1.03 g, 4.86 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 14 hr, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as a solid (317 mg, 0.729 mmol, 90%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:37]12[NH:44][CH:41]([CH2:42][CH2:43]1)[CH2:40][CH:39]([OH:45])[CH2:38]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:44]3[CH:37]4[CH2:43][CH2:42][CH:41]3[CH2:40][CH:39]([OH:45])[CH2:38]4)=[O:17])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: OC1CC2CCC(C1)N2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Temperature: 0 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.82 g, 0.00357 mol) in dry DMF (8.0 mL) was added with stirring HOBt (0.578 g, 0.00428 mol), DIPEA (1.9 mL, 0.0107 mol), 8-azabicyclo[3.2.1]octan-3-ol (0.5 g, 0.00393 mol) and the mixture was cooled to 0° C. To the resulting mixture was added EDCl (0.82 g, 0.00428 mol) and stirred for 15 h at ambient temperature. The reaction mixture was then diluted with ice water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×50 mL) and saturated brine solution (50 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording (1.1 g, 98%) of [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)methanone. MS-ESI m/z 341 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[CH:15]4)[CH3:2].O.[N+:22]([O-])([OH:24])=[O:23]>>[CH2:1]([O:3][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[C:15]4[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: CCOc1ncc2c(=O)c3cccn3c3cccc1c23
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reaction time: 0.25 h

Procedure:
A mixture (150.4 cc) of equal volumes of about 50% by weight nitric acid (density 1.33) and about 97% by weight nitric acid (density 1.52) is added dropwise to a suspension, stirred and maintained between 5° and 10° C., of 4-ethoxy-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (30 g) in nitric acid (density 1.33; l34 cc). The addition takes 15 minutes. The mixture is stirred for a further 15 minutes, whilst allowing the red solution to return to ambient temperature. This solution is poured into water (1.7 liter) and the orange solid which precipitates is filtered off. The residue is washed with water (5 × 50 cc) and then dried under reduced pressure (1 mm Hg) at 50° C. Crude 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (31 g) is thus obtained. After recrystallisation from acetonitrile, the pure product melts at 192° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:31])=[CH:8][C:7]=2[O:32][CH3:33])[CH2:2]1.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH:34]1([N:1]2[CH2:4][CH:3]([O:5][C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]5[N:18]=[C:19]([C:21]6[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=6)[S:20][C:14]=5[C:13]4=[O:31])=[CH:8][C:7]=3[O:32][CH3:33])[CH2:2]2)[CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CN(C2CCC2)C1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-trifluoromethyl-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.909 g, 1.92 mmol) in dichloroethane (25 mL) and add cyclobutanone (0.502 mL, 6.72 mmol), sodium triacetoxyborohydride (0.814 g, 3.84 mmol), and acetic acid (0.22 mL, 3.84 mmol). Stir the mixture overnight, add saturated sodium bicarbonate, and extract with dichloromethane (3×). Dry the mixture using sodium sulfate, filter, and concentrate. Purify via silica gel chromatography using a 0-4.5% gradient of 2N ammonia in methanol/dichloromethane to give 0.400 g (39%) of the desired product. MS/ES m/z 528.0 [M+1]+.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH2:31][O:32]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[CH:34]=[C:33]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1)[CH2:29][CH2:30][CH2:31][O:32]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
H2O2 (70%, 0.47 mL, ca. 9.3 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.3 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 241 (270 mg, 0.9 mmol) and TFA (0.36 mL, 4.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 242 (71 mg, 22%) as a red solid: mp (MeOH/EtOAc) 152-154° C.; 1H NMR δ 7.99 (s, 1H, H-5), 7.61 (s, 1H, H-10), 7.27 (br s, 1H, NH), 4.30 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.62 (br t, J=5.9 Hz, 2H, CH2N), 3.05 (br t, J=6.3 Hz, 2H, H-6), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.05-2.12 (m, 2H, H-7); 13C NMR δ 154.7, 148.7, 136.2, 133.2, 130.1, 117.4, 105.2, 67.1, 57.6, 45.1 (2), 38.8, 26.1, 21.3. Anal. calcd for C14H19N5O3.½H2O: C, 52.7; H, 6.5; N, 22.0. Found: C, 53.0; H, 5.9, 21.6%.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([C:18]#[N:19])[CH:5]=1>ClCCl.C(O)(=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:6]([C:18]#[N:19])[C:5]=1[Br:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1C#N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 128.9 %

Procedure:
A solution of bromine (25.1 mmol) in dichloromethane (1.3 mL) was added dropwise, under an argon atmosphere, to a solution of amine II (27.9 mmol) in acetic acid (325 mL). After 2.5 h of stirring at room temperature, the solvent was removed in vacuo. The excess of acetic acid was co-evaporated with heptane to afford the expected compound III (10.1 g, quantitative yield) as a beige solid; mp 163° C.; IR (KBr) νmax/cm−1 3327, 2826, 2605, 2566, 2236, 1955, 1716, 1610, 1561, 1496, 1481, 1398, 1369, 1280, 1238, 1193, 1153, 1059, 963, 906, 838; 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H, NH), 7.11 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.01 (s, 2H, NH2), 1.43 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 153.6, 144.1, 131.6, 126.9, 119.6, 116.1, 112.8, 107.8, 79.5, 28.1; HRMS calcd for C12H15N3O2Br (M+H+): 312.0348, found 312.0354.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13]O2.[CH3:29][NH2:30].O>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:30]([CH3:29])[CH:13]=[CH:14][N:15]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[N:22]=1
Reactant: CN
Reactant: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n(C)ccn34)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
6-(2,4-Difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)imidazo[2,1-b]oxazole (0.200 g, 0.526 mmol, Example #8), 40% methylamine in water (1.50 mL, 15.4 mmol) and 1,4-dioxane (1 mL) were heated in a CEM® microwave at about 120° C. (250 psi maximum pressure, 10 min ramp, 300 max watts) for about 55 min. The mixture was concentrated under reduced pressure then treated with HOAc (1.5 mL). The solution was stirred at ambient temperature for about 1 h then the material was purified by RP-HPLC (Table 1, Method f). The desired fractions were collected and concentrated under reduced pressure to remove most of the ACN. The precipitate which formed was collected by filtration and washed with water (3 mL) then dried overnight under vacuum at about 70° C. to give the title compound (0.115 g, 56%): LC/MS (Table 1, Method g) Rt=1.88 min; MS m/z: 394.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:26]=1[Cl:25])=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1ccc(O)cc1Cl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(O)cc1Cl
Yield: 35 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-chloro4-hydroxyphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 35% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-chloro-4-hydroxybenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 521.0433. Calcd. mass, 521.0438 (M+H).
Reaction SMILES: [C:1]1([S:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30]>CO>[C:19]1([S:18]([CH2:17][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:30])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: c1ccc(SCc2[nH]c3ccccc3c2Sc2ccccc2)cc1
Agent: [Mg+2]
Solvent: CO
Product: O=S(Cc1[nH]c2ccccc2c1Sc1ccccc1)c1ccccc1

Procedure:
A solution of 3-phenylthio-2-phenylthiomethylindole (0.750 g, 2.94 mmol) in methanol (100 mL) was cooled to 0° C. with stirring. Monoperoxyphthalic acid magnesium salt (0.908 g, 80% peracid) in methanol (50 mL) was added slowly dropwise. After addition, the reaction was stirred an additional 30 min., then quenched with 10% aqueous sodium thiosulfate (2 mL). The methanol was removed in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed successively with water and saturated brine, then dried over magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave an oil which was purified by chromatography on silica gel using 20-30% ethyl acetate in hexane. The title compound was obtained as a foam, mp 71°-74° C. Exact mass calculated for C21H17NOS2 : 364.082982. Found: 364.084549. NMR (DMSO-d6) δ11.82 (1H, s), 7.50 (6H, m), 7.23 (1H, d, J=8 Hz), 7.15 (3 H, m) 7.05 (2H, m) 6.90 2H, m), 4.43 (1, d, J=13 Hz), 4.38 (1H, d, J=13 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][O:9][C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrophenethyl alcohol (55 g, 0.33 mol) (Aldrich) was dissolved in pyridine (1.2 L) (Aldrich). Acetic anhydride (215 mL, 2.14 mol) (Aldrich) was added slowly, and the mixture was stirred overnight at room temperature (TLC: 30% ethyl acetate in hexanes showed complete conversion). Ice and water (200 mL) were poured into the reaction mixture. The mixture was diluted with ethyl acetate, then successively washed with aqueous 1N hydrochloric acid (pH=˜1), water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give acetic acid 2-(3-nitro-phenyl)-ethyl ester as a yellow oil. (Yield 58.86 g, 0.28 mol, 85%).
Reaction SMILES: O.C([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:25]([O:27][CH3:28])[CH3:26])=[N:15][N:16]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH3:28][O:27][CH:25]([C:14]1[C:13]2[C:17](=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)[N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1)[CH3:26]
Reactant: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)c1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
5% Palladium on carbon-STD-type-50% wet with water (79.5 mg; manufactured by N. E. Chemcat Corp.) and 6-(benzyloxy)-3-(1-methoxyethyl)-1-(tetrahydro-2H-pyran-2-yl)-indazole (195 mg) which can be prepared according to the method described in Reference example 25, etc. were dissolved in THF (5.6 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature under hydrogen atmosphere. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (167 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:2]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:31]>N1C=CC=CC=1>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:31])=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH2:12]4)[CH:23]=3)[C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: c1cncc(C2CNCCN2)c1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4cccnc4)C3)c(F)cc2c1=O
Temperature: 135 °C
Yield: 19.6 %

Procedure:
A mixture of 733.5 mg of 2-(3-pyridinyl)piperazine, 421.5 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was heated at 135° C. for 24 hours. The solvent was removed and the residue purified by chromatography on silica gel using chloroform:methanol:triethylamine:water (9.5:0.5:0.01:0.01), giving 120 mg of the desired product.