Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc([N+](=O)[O-])ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)COC(=O)N1CCN(c2cc(N)ccn2)CC1
Yield: 11 %

Procedure:
2,2-Dimethylpropyl 4-(4-nitropyridin-2-yl)-1-piperazinecarboxylate (482 mg) obtained in Example 8 was dissolved in methanol (10 mL), and a catalytic amount of palladium hydroxide-carbon was added thereto, stirred in a hydrogen atmosphere at room temperature for 2 hours, and the reaction liquid was filtered. The filtrate was evaporated, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 48 mg of the entitled compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:10]=2[N:11]([CH3:20])[C:12](=[O:19])[C:13]=1[C:14]([O:16]CC)=[O:15].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:10]=2[N:11]([CH3:20])[C:12](=[O:19])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(CC)sc2n(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(-c3ccccc3Cl)c(C(=O)O)c(=O)n(C)c2s1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A mixture of ethyl 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-7-methyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (1.10 g), KOH (0.49 g) and 80% ethanol (10 ml) was heated at 80° C. for 20 minutes and water was added. Then, the mixture was made acidic with 2N HCl and extracted with ethyl acetate. The extract was washed with water and dried over MgSO4, and then the solvent was distilled off. To the residue was added hexane to obtain 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-7-methyl-6-oxothieno[2,3-b]pyridine-5-carboxylic acid as crystals (0.91 g, 89.3%). The crystals were recrystallized from ethanol to obtain colorless prisms, mp: 155°-156° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:22])[F:23])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (70 mg, 0.44 mmol), 4-hydroxy-3-(trifluoromethyl)benzonitrile (91 mg, 0.49 mmol), K2 CO3 (92 mg, 0.66 mmol) in DMF (2 mL) was stirred at 50° C. overnight. Water (4 mL) was added and a precipitate was formed. The solid was filtered-off and it was triturated with MeOH to give the title compound (85 mg) as a brownish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (1.04 g) in dry acetonitrile (30 ml) was added 2-bromoethylbenzene (0.96 ml) followed by milled potassium carbonate (1.78 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 48 hrs, warmed under reflux for 2 hrs, and cooled to ambient temperature. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and the residue was purified by flash column chromatography (silica gel, dichloromethane/0-100% ether). The appropriate fractions were collected and concentrated to afford 1.2 g (72%) of 2-(3-methoxyphenyl)-1-(2-phenylethyl)pyrrolidine.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][CH2:8]3)=[CH:4][C:3]=2[O:2]1.[OH2:13].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH2:1]1[O:2][C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH:7]([OH:13])[CH2:6]3)=[CH:10][C:11]=2[O:12]1
Reactant: C1=Cc2cc3c(cc2C1)OCO3
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1Cc2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 9.0 g of 5,6-methylenedioxyindene in 23 ml of tetrahydrofuran was cooled to 0° C. in a nitrogen atmosphere. A solution of 2.2 ml of 10.0 M borane/methyl sulfide complex in 5 ml of tetrahydrofuran was added dropwise thereto. The temperature of the mixture was elevated from 0° C. to room temperature over 4 h and then 1.8 ml of water was added dropwise thereto. 7.4 ml of a 3 M aqueous sodium hydroxide solution and then 5.5 ml of a 35% aqueous hydrogen peroxide solution were added thereto under cooling with ice and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate to obtain 6.4 g of the intended compound in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([NH:20][CH3:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[Cl:1][C:2]1[N:11]=[C:10]([N:20]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Product: CN(c1ccc([N+](=O)[O-])cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-nitro-N-methylaniline (46 mg, 0.302 mmol) by a procedure similar to Example 1b and was isolated as yellow powder (6 mg, 12%). 1H NMR (CDCl3): 8.24 (d, J=8.7 Hz, 2H), 7.81 (dd, J=8.1, and 2.4 Hz, 1H), 7.68 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.18 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 3.75 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]([Br:40])=[CH:28][C:24]=1[C:25](Cl)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]([Br:40])=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:26])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 82 %

Procedure:
2.8 l of o-toluidine and 2.5 l of pyridine are added to 50 l of dichloromethane at 3° C. 13.6 kg of 2,4-bisbenzyloxy-5-bromobenzoyl chloride (toluene-moist) suspended in 35 l of dichloromethane are added to this solution over the course of 2 h. The mixture is subsequently stirred overnight at 23° C., and the solid is filtered off and rinsed with dichloromethane (2× with 5 l each time). The crude product obtained in this way (8 kg) is dissolved in 40 l of dichloromethane and extracted successively with 40 l of distilled water, 50 l of hydrochloric acid (˜1 mol/l; prepared from 5 l of HCl w: 37% and 50 l of water). The organic phase is subsequently washed with 50 l of water. The organic phase is dried for 3 days using 6 kg of sodium sulfate. The drying agent is filtered off with suction via a suction filter, and the filtrate is evaporated to dryness in a rotary evaporator. Recrystallisation from ethanol (35 l, 65° C.) and drying (50° C./35 mbar) to constant weight gives 10.84 kg (82%) of 2,4-bisbenzyloxy-5-bromo-N-o-tolylbenzamide (m.p. 174.5° C.-176° C.; MW 502.4).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24](Cl)=[O:25]>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1c(F)cccc1F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,6-difluorobenzoyl chloride, there is obtained ethyl N-(2,6-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 406 (5), 377 (21), 194 (100), 141 (42);
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH3:15])[CH:9]=[C:8]2OC)(=O)C.[CH3:18][NH:19][CH3:20]>C(O)(=O)C>[CH3:18][N:19]([CH3:20])[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([NH2:4])[CH:6]=2)[N:11]=[C:10]([CH3:15])[CH:9]=1
Reactant: CNC
Reactant: COc1cc(C)nc2ccc(NC(C)=O)cc12
Solvent: CC(=O)O
Product: Cc1cc(N(C)C)c2cc(N)ccc2n1
Yield: 77 %

Procedure:
The procedure is carried out as in Step A of Example 6, but starting with 57.4 g (0.25 mol) of 6-acetamido-4-methoxyquinaldine, prepared according to J. Amer. Chem. Soc., 1948, 70, 4065, and 100 cm3 of a 40% aqueous dimethylamine solution in 250 cm3 of acetic acid heated at 100° C. for 2 hours in a 1-dm3 autoclave. 38.71 g (77%) of 4-dimethylamino-6-aminoquinaldine are then obtained, after acid-base purification, on carrying out the procedure as in Step A of Example 6.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][C:9]=1[O:10][CH3:11])=O>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([C:12]([F:15])([F:13])[F:14])=[N:8][C:9]=1[O:10][CH3:11])#[N:1]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(C(N)=O)c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(C#N)c1OC
Yield: 84.9 %

Procedure:
This material was obtained in 84.9% yield from the product of Example 22 (0.014 mol) and 100 ml of POCl3 by a procedure similar to that in Example 24 as a solid: mp 32°-34° C.
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:17]=[C:16]([O:27][CH3:28])[C:15]=2[N+:29]([O-])=O)=[O:12])[N:7]([CH3:32])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C>[NH2:29][C:15]1[C:16]([O:27][CH3:28])=[N:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:7]([CH3:32])[N:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:9]=1[Cl:10])=[O:12]
Reactant: [H][H]
Reactant: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1N
Reaction time: 3 h

Procedure:
A 2.25 L plastic coated Parr bottle was charged with 3-tert-butyl-4-chloro-N-(6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (55.30 g, 0.115 mol) and ethyl acetate (0.55 L). To the resulting slurry was added a slurry of 5% Pt(Sulfided)/C (2.80 g) in ethyl acetate (˜20 mL). The resulting mixture was agitated under 35-40 psi hydrogen gas, recharging with hydrogen gas as needed. After 3 h, hydrogen uptake ceased. The resulting mixture was filtered through CELITE to remove catalyst and the filter cake washed with ethyl acetate. The filtrate was concentrated to yield N-(3-amino-6-(2-chlorophenyl)-2-methoxypyridin-4-yl)-3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide as a off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.42 (s, 9H), 3.98 (br. s., 2H), 4.06 (s, 3H), 4.15 (s, 3H), 7.27-7.35 (m, 2H), 7.44 (dd, J=7.83, 1.22 Hz, 1H), 7.55 (s, 1H), 7.63 (dd, J=7.58, 1.71 Hz, 1H), 8.54 (br. s., 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][C:12](=[S:16])[N:13]([CH3:15])[CH3:14])[CH:5]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:18])[CH:7]=[C:6]([O:11][C:12](=[S:16])[N:13]([CH3:14])[CH3:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(OC(=S)N(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)cc(OC(=S)N(C)C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
To a stirred solution of 3-dimethylthiocarbamyloxy-5-hydroxybenzoic acid methyl ester (2.37 g, impure) in DMF (30 mL) at room temperature was added K2CO3 (3.85 g, 27.9 mmol), followed by iodomethane (1.16 mL, 18.6 mmol). After stirring for 3.5 h at room temperature the reaction mixture was partitioned between ethyl ether (200 mL) and H2O (200 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 33% EtOAc in hexanes as an eluent to furnish 3-dimethylthiocarbamyloxy-5-methoxybenzoic acid methyl ester (1.30 g, 4.83 mmol).
Reaction SMILES: C(COC)OC.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[N:27]=[CH:26][C:25]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)=[CH:24][N:23]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncc(Br)cn2)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncc(-c3ccncc3)cn2)CC1

Procedure:
To a mixed solvent of dimethoxyethane (60 ml) and methanol (120 ml) were added 1-(tert-butoxycarbonyl)-4-[(5-bromopyrimidin-2-yl)carbonyl]piperazine (2.97 g), (pyridin-4-yl)boronic acid (1.48 g), cesium fluoride (4.25 g) and tetrakis(triphenylphosphine)palladium (924 mg). After purging with argon, the reaction mixture was refluxed for 19 hours. The solvent was then distilled off under reduced pressure. The residue was purified by moderate-pressure chromatography on a silica gel column (size D, methanol methylene chloride=1:9), whereby the title compound (1.31 g) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[C:11]([CH2:12]O)=[C:10]([CH3:14])[NH:9][C:8](=[O:15])[C:7]=1[I:16].O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH2:12][C:11]1[C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([CH3:20])[CH:17]=2)=[C:7]([I:16])[C:8](=[O:15])[NH:9][C:10]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(Oc2c(CO)c(C)[nH]c(=O)c2I)c1
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2c(CCl)c(C)[nH]c(=O)c2I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The heterogeneous solution of compound 257 (450 mg; 1.2 mmol) in CH2Cl2 (30 ml) became homogeneous mixture by addition at room temperature of SOCl2 (2.6 ml). After 2 hours on stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected compound 125 in quantitative yield (470 mg); m.p.=256–258° C. This compound was used for the next step without any further purification.
Reaction SMILES: C(OC([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([C:33]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]6[C:34]=5[CH:35]=[CH:36][NH:37]6)=[N:21][C:20]=4[CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:42][C:40]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[C:33]([C:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:25]3[S:26][C:18]([CH2:17][N:13]4[CH2:14][CH2:15][C@@H:16]5[NH:8][CH2:9][CH2:10][C@@H:11]5[CH2:12]4)=[CH:19][C:20]=3[N:21]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(Cc3cc4nc(-c5cc(F)cc6[nH]ccc56)nc(N5CCOCC5)c4s3)CC[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC[C@@H]5NCC[C@@H]5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared by BOC-deprotection of (3aR,7aS)-5-[2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester using TFA:DCM (1:6). The title compound was obtained as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:4]=1.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][C:18]([I:22])=[CH:17][N:16]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:14][C:15]3=[N:16][CH:17]=[C:18]([I:22])[CH:19]=[C:20]3[N:21]=2)[CH:4]=1
Reactant: COc1ccnc(CCC(=O)O)c1
Reactant: Nc1cc(I)cnc1N
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Temperature: 140 °C
Yield: 61.2 %

Procedure:
With stirring, a mixture of 8.06 g of 3-(4-methoxypyridin-2-yl)propionic acid (starting material B1), 9.5 g of 2,3-diamino-5-iodopyridine (Cugola et al., Bioorg.Med. Chem.Let 22, 2749-2754 (1996)) and 150 g of polyphosphoric acid (PPA) is heated at 140° C. for 22 hours. After cooling, the mixture is poured into about 1000 ml of ice-water and then neutralized (pH 7-8) using 6N aqueous sodium hydroxide solution. The mixture is extracted four times with ethyl acetate and the combined organic phases are evaporated to dryness. The residue is crystallized first from ethyl acetate and then from methanol, giving 9.4 g of the title compound as a light-beige powder of m.p. 207-208° C.; the mass spectrum shows the molecular peak MH+ at 381.2 Da.
Reaction SMILES: Br[CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccn(CCC(CO)CBr)c(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(CO)CCn1ccc(=O)[nH]c1=O
Temperature: 70 °C
Yield: 51.8 %

Procedure:
A solution of compound 38 (10.9 g, 0.042 mol) in dry DMF (40 mL) was treated with NaN3 (4.1 g, 0.062 mol) and heated to 70° C. for 24 h. The reaction mixture was concentrated under vacuum and crude purified by column chromatography over silica gel (30% methanol in chloroform) to give the title compound (5.2 g, 47%). TLC: Chloroform/Methanol, 1:1, Rf=0.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccc(Br)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(Br)c4)nc23)CC1
Yield: 89.3 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0095 mL (0.072 mMol) 3-bromobenzoyl chloride, 0.024 gm (90%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1cccnc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(Cc3cccnc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 3-picolylchloride hydrochloride as described for compound 105. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 117°-120° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=1.C(N(CC)CC)C>CCO>[Br:1][C:2]1[C:3]([NH:16][C:13]2[CH:12]=[C:11]([CH3:10])[NH:15][N:14]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.29 g, 5.66 mmol) in EtOH (15 ml) at room temperature was added a solution of 5-methyl-1H-pyrazol-3-amine (549 mg, 5.66 mmol) in EtOH (3 ml) and triethylamine (628 mg, 6.22 mmol) and the reaction mixture was stirred at room temperature overnight. The suspension was filtered and washed with water and dried to give the desired product as a white solid (1.27 g, 78%). NMR (CDCl3) 2.24 (s, 3H), 6.24 (s, 1H), 8.41 (s, 1H), 9.29 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])[CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.[OH-:40].[Ca+2].[OH-:42]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])(=[O:42])=[O:40])[CH:25]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1Sc1ccc2nc(-c3ccc(F)cc3)ccc2c1
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc2nc(-c3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chloroperoxybenzoic acid (77%; 597 mg, 2.67 mmol) was added to a solution of methyl 2-{[2-(4-fluorophenyl)quinolin-6-yl]thio}benzoate (346 mg, 0.89 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature under nitrogen for 1 hour 20 minutes. Calcium hydroxide (308 mg, 4.16 mmol) was added and the resulting slurry stirred for 1 hour 15 minutes. The mixture was filtered and the filter cake washed thoroughly with dichloromethane. The filtrate was evaporated and the residue given a preliminary purification by elution from a silica pad with dichloromethane then 2.5% ethyl acetate/dichloromethane to afford an oil. Crystallisation from diethyl ether gave the title compound, in two crops, as pale yellow crystals (301 mg, 80%). 1H NMR (500 MHz, CDCl3) δ 8.57 (1H, d, J 1.7 Hz), 8.36 (1H, d, J 8.7 Hz), 8.25-8.15 (5H, m), 7.95 (1H, d, J 8.6 Hz), 7.67-7.65 (2H, m), 7.61 (1H, m), 7.22 (2H, t, J 8.6 Hz), 3.95 (3H, s); m/z (ES+) 422 [MH+].