Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH:31]([NH:34][C@@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)([CH3:33])[CH3:32].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]([CH:31]([CH3:33])[CH3:32])[C@@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)N[C@@H](C)COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3ccc([N+](=O)[O-])cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Over a period of about 5 min, a solution of 0.42 g of 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridin-6-yl)benzoyl chloride In 10 ml of acetonitrile is added dropwise to a mixture, cooled with ice/water, of 0.31 g of 4-nitro-benzoic acid (S)-2-isopropylamino-propyl ester hydrochloride and 0.5 g of triethylamine in 10 ml of acetonitrile. The reaction mixture is stirred at RT for about 15 h and then substantially concentrated under reduced pressure, and the highly viscous residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The resin-like residue is purified by silica gel chromatography, and the product fraction is separated off and concentrated. This gives 0.34 g of the the compound as a solid foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14]O)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1>C(Cl)(Cl)Cl>[Cl:3][CH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH2:7]2
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)CCC2
Solvent: ClC(Cl)Cl
Product: ClCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Thionyl chloride (120 ml, 1.65 mol) was added drop-wise to a rapidly stirred mixture of (2,3-dihydro-1H-inden-5-yl)methanol (81.4 g, 0.55 mol) in chloroform (500 ml) at 0° C. After the addition was complete, the resulting mixture was allowed to warm to room temperature and the stirring was continued for an additional 12 h. The chloroform was evaporated under reduced pressure to give a residue, that was purified by column chromatography (petroleum ether:ethyl acetate=15:1) to afford 5-(chloromethyl)-2,3-dihydro-1H-indene (90.5 g, 99%). 1H NMR (300 MHz, CDCl3) δ 2.06-2.19 (m, 4H), 2.93 (t, J=7.5, 4H), 4.54 (s, 2H), 7.15-7.31 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)CC>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(OCc3ccccc3)ccc12
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol) and propionic acid (700 mL) was heated to 125° C. with vigorous stirring. Nitric acid (23.11 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature between 121° C. and 125° C. After the addition, the reaction was stirred at 125° C. for 1 hour then allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed with water, and dried in an oven for 1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinolin-4-ol as a grayish powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20](Cl)=[O:21])[N:14]=[N:13]2)=[CH:8][CH:7]=1>CC(C)=O.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:14]=[N:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)c1c(C(=O)Cl)nnn1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)c1c(C(=O)N=[N+]=[N-])nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (610 mg in 2.5 mL of H2O, 9.39 mmol) was added to a cooled (0° C.) solution of 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl chloride in acetone (7.5 mL). The resulting mixture was stirred at room temperature for 30 min, diluted with CH2Cl2 (100 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the crude 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl azide (777 mg) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
4.85 g (22.56 mmol) of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one was dissolved in 60 ml of ethanol. 3.13 g (45 mmol) hydroxylamine hydrochloride was then added followed by 1.8 g (45 mmol) of NaOH in 15 ml of water. The mixture was refluxed for 20 hrs and was cooled to ambient temperature. The solvent was removed in vaccuo. The residue was diluted with ethyl acetate and washed with water and the organic layer was dried over sodium sulfate. The solvent was removed to give 4.28 g of product as a light yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([OH:26])=O)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>C1COCC1>[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:24]([C:19]1[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: O=C(O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Reactant: CN(C)CCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 98.3 %

Procedure:
Prepared in the same manner as described for example 1. A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.85 g, 2.33 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.40 g, 2.45 mmol, 1.05 eq.) and warmed as described. The reaction was allowed to cool and then treated with 4-dimethylaminobutylamine (0.33 g, 2.80 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give a yellow oil. The oil was purified by silica gel flash chromatography using 5% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (4-dimethylamino-butyl)-amide (1.06 g, 98% yield) as a light yellow oil.
Reaction SMILES: [CH:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:18]([NH:22][C:23](=[NH:26])[O:24][CH3:25])([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:18]([NH:22][C:23](=[N:26][S:8](=[O:10])(=[O:9])[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:24][CH3:25])([O:20][CH3:21])=[O:19]
Reactant: O=S(=O)(Cl)NC1CCCCC1
Reactant: COC(=N)NC(=O)OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)NC(=NS(=O)(=O)NC1CCCCC1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
59.6 parts of cyclohexylaminosulfonyl chloride and 26.9 parts of pyridine were introduced through two feed lines, into a stirred solution of 39.6 parts of N-carbomethoxy-O-methylisourea in 300 parts of ethyl acetate, at from 15° to 20° C. After having been stirred for 4 hours at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid and was then dried and concentrated under reduced pressure. This gave 79 parts of N-carbomethoxy-N'-cyclohexylsulfamyl-O-methylisourea, of nD25 =1.4970. After trituration with a small amount of ether, the compound crystallized, and these crystals melted at 84°-86° C. 15 parts of this product were dissolved in a mixture of 9 parts of 50% strength by weight sodium hydroxide solution and 20 parts of water and the reaction solution was stirred for 4 minutes at from 55° to 60° C. It was then cooled, extracted once with ether, and stirred into a mixture of 9.5 parts of concentrated hydrochloric acid and 10 parts of water. Filtering off the product, washing with water and drying gave 9 parts of 6-cyclohexyl-3-methoxy-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide, of melting point 173°-177° C. This constitutes active compound No. 3.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([CH:36]2[CH2:41][CH2:40][N:39]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)[CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:33]=1
Reactant: O=S(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(S(=O)c2ccc(F)cc2)CC1
Yield: 66.2 %

Procedure:
4-[[7-(Trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (14.7 g) was added slowly to a stirred mixture of 4-[(4-fluorophenyl)sulfinyl]piperidine hydrochloride (10.0 g) and triethylamine (26.4 ml) in dry methylene chloride (440 ml) at room temperature. The resultant mixture was stirred at the same temperature for 3 hours, and concentrated to dryness in vacuo. Water was added to the residue and the precipitated powder was collected by filtration, washed with water, and dried to give a powder. The powder was washed with methylene chloride to give 4-[(4-fluorophenyl)sulfinyl]-1-[4-[[7-(trifluoromethyl)-4-quinolyl]amino]benzoyl]piperidine (13.60 g) as colourless powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16](O)[CH:17]2[CH2:22][CH2:21][O:20][N:19]([CH:23]([CH3:25])[CH3:24])[C:18]2=[O:26])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:10]=1[OH:11])[CH:16]=[C:17]1[CH2:22][CH2:21][O:20][N:19]([CH:23]([CH3:24])[CH3:25])[C:18]1=[O:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1OCCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)N1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
The dihydro-4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-isopropyl-2H-1,2-oxazin-3(4H)-one of Step B was refluxed in 40 ml of benzene with a catalytic amount of p-toluenesulfonic acid monohydrate for 6 hours and concentrated in vacuo. The concentrate was triturated in ether and filtered to yield 0.9 g (2.5 mmol) of dihydro-4-(3,5-di tert-butyl-4-hydroxybenzylidene)-2-isopropyl-2H-1,2-oxazin-3(4H)-one, mp 181°-183° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[N+:17]([O-])=O)[C:8]1=[O:21])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[NH2:17])[C:8]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reaction time: 0.75 h

Procedure:
A round bottom flask was charged with 2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (450.00 mg, 0.0014484 mol), ethanol (20 mL, 0.3 mol), and ammonium chloride (774.8 mg, 0.01448 mol) in water (10 mL, 0.6 mol) was added at 85° C., followed by iron (324 mg, 0.00579 mol) in two portions. The reaction was stirred at that temperature for 45 minutes and then poured onto methylene chloride (200 mL) and extracted. The solvent was removed under reduced pressure to afford the pure product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.CC([O-])=O.[Na+].Cl.[NH2:19][OH:20]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[N:19][OH:20]
Reactant: COc1cc(Cl)cc(Cl)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A sol. of 2,4-dichloro-6-methoxybenzaldehyde (2.39 mmol) in 5 mL DMF was cooled to 0° C. and NaOAc (2.63 mmol) followed by hydroxylamine HCl (2.63 mmol) were added. The ice bath was removed and the reaction mixture was stirred at RT for 10 min. The mixture was diluted with EtOAc and washed once with water and brine. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired compound as white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.CS(C)=O>C(#N)C>[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:41]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(OC)c2)C3)cc1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
In a glass tube was weighed 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 (0.32 mmol), acetonitrile (2.5 mL), 4-methoxybenzylamine (0.66 mmol), and dimethylsulfoxide (1.11 mmol). The stirred solution was heated at 80° C. for 20 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (5 mL), washed twice with water, dried over anhydrous sodium sulfate, and evaporated. Flash chromatography on silica gel using hexane/ethyl acetate/dichloromethane (3:1:1) provided 0.155 g (86%) of the title compound as a white solid, which was recrystallized from ethyl acetate/hexane, m.p. 178-179° C. MS [(+)ESI, m/z]: 570 [M+H]+Anal. Calcd for C36H33N3O4: C, 75.64; H, 5.82; N, 7.35. Found: C, 75.31; H, 5.83; N, 7.27.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[NH:8][C:9](=O)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]([C:18]3[C:23]([Br:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=3[Br:29])[C:11]=2[N:12]=1>O>[Cl:3][C:9]1[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]([C:18]3[C:23]([Br:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=3[Br:29])[C:11]=2[N:12]=[C:7]([CH3:6])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(C)c(C)n2-c2c(Br)cc(C(F)(F)F)cc2Br)c(=O)[nH]1
Solvent: O
Product: Cc1nc(Cl)c2c(C)c(C)n(-c3c(Br)cc(C(F)(F)F)cc3Br)c2n1
Temperature: 100 °C

Procedure:
Phosphorus oxychloride in an amount of 1.3 ml was added to 0.67 g of 2,5,6-trimethyl-7-(2,6-dibromo-4-trifluoromethylphenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, and the reaction mixture was heated for 0.5 hours at 100° C. and was then cooled. The reaction mixture was poured into water with ice and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and was allowed to stand for crystallization to yield 0.66 g of 4-chloro-2,5,6-trimethyl-7-(2,6-dibromo-4-trifluoromethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=O)[N:2]=1.ClC(OCC)=O.[CH3:23][NH2:24]>O1CCCC1.C(N(CC)CC)C>[CH3:23][NH:24][C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:16]
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5 g of β-carbolin-3-carboxylic acid in a mixture of 900 ml of tetrahydrofuran and 3.6 ml of triethylamine is boiled under reflux for 15 minutes and cooled to room temperature. Freshly distilled ethyl chloroformate (2.5 ml), dissolved in 100 ml of tetrahydrofuran, is added dropwise with stirring over a period of 11/2 hours. After the reaction mixture has been stirred for an additional 30 minutes, a large excess of methylamine is added. Stirring is continued for one hour, whereafter the mixture is filtered and concentrated to approximately 50 ml under reduced pressure. Addition of water (250 ml) causes the amide to precipitate. The mixture is left at 5° C. overnight, filtered and dried at 60° C. for 15 hours. β-carbolin-3-carboxylic acid methylamide thus formed (4.1 g; 77%) is recrystallized from toluene. The melting point is 275° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:15]=[N:14][CH:13]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH:15]=[N:14][CH:13]=1
Reactant: Cc1ccccc1B(O)O
Reactant: N#Cc1ccc(Cn2cncc2Cn2ccc3c(Br)cccc32)cc1
Product: Cc1ccccc1-c1cccc2c1ccn2Cc1cncn1Cc1ccc(C#N)cc1

Procedure:
Following the procedure described for Example 21, Step 3, 4-bromo-1-(1-(4-cyanobenzyl)-5-imidazolylmethyl)indole (Example 28) was coupled with 2-methylphenyl boronic acid to give the title compound.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([NH2:13])=[N:9][NH:10]2)=[C:6]([O:14][CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].Cl>CS(C)=O.O>[NH2:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][C:6]=2[O:14][CH3:15])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:9]=1
Reactant: N#Cc1cccc(CCl)c1
Reactant: COc1cc(F)cc2[nH]nc(N)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)cc2c1c(N)nn2Cc1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
Potassium hydroxide (85% pure, 0.84 g, 12.7 mmol) was powdered and added to DMSO (25 mL) and the mixture was stirred for 5 min. A solution of 1:1 mixture of 6-fluoro-4-(methyloxy)-1H-indazol-3-amine and 4-fluoro-6-(methyloxy) regioisomer) (1.085 g, 6 mmol) in DMSO (5 mL) was added and the mixture was stirred for 5 min. The colour of the reaction mixture turned to dark red. Solid 3-(chloromethyl)benzonitrile (1.0 g, 7.1 mmol) was added and the mixture stirred for 1 h. The mixture was diluted with water, treated with 2M HCl (3 mL) and extracted with ethyl acetate. The organic solution was washed with water (4 times) and once with brine, dried (MgSO4) and evaporated. The residue was dissolved in DCM and MeOH and pre-absorbed on florisil (5 g). The pre-absorbed compound was placed on two 100 g Silica cartridges and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane over 60 min. The appropriate fractions (RT=48 min) were evaporated under reduced pressure to give impure title compound as an orange solid. This required further purification and was pre-absorbed on florisil and purified by chromatography on Flashmaster silica 100 g using a 0-100% ethyl acetate-cyclohexane over 100 min. The appropriate fractions (RT=46-70 min) were combined and evaporated in vacuo to give the title compound (362 mg, 20%) as a yellow solid: LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+, NMR δ (CDCl3) 7.57-7.53 (1H, m), 7.43-7.38 (3H, m), 6.37 (1H, dd, J 10, 2 Hz), 6.15 (1H, dd, J 12, 2 Hz), 5.23 (2H, s), 4.45 (2H, br), 3.94 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(O)(C)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:13]([CH3:18])[CH3:14])[CH:6]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl(3-hydroxyphenyl)acetate (200 mg) in tetrahydrofuran (5 ml), 0.15 ml of isopropyl alcohol, 480 mg of triphenylphosphine, and 0.82 ml of diethyl azodicarboxylate (45% toluene solution) were added, and the reaction solution was stirred overnight at room temperature. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-25:75-60/40)) to afford the title compound as a colorless oil.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>O.C(O)C.[Cu]>[N+:21]([C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6.5 g of potassium hydroxide in 80 ml of water is treated under a nitrogen atmosphere at 50° C with 10.3 ml of thiophenol and the mixture is then stirred for 30 minutes. After the addition of 0.5 g of copper powder and 22.5 g of 4-chloro- 3-nitro-benzotrifluoride in 100 ml of ethanol, the mixture is heated under reflux for 48 hours. After filtration, the mixture is poured into water and extracted with ether. The ethereal phase is washed successively with aqueous sodium carbonate solution, water, aqueous sodium chloride solution, 2-N aqueous hydrochloric acid and water, dried, filtered and evaporated. There is obtained 3-nitro-4-(phenylthio)-benzotrifluoride as a red oil.