Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@@H:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@@H:27]4[CH2:32][CH2:31][NH:30][C@@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
TFA (25 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (5.94 g, 10.63 mmol) in DCM (25 ml) at 0° C., was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 5%) to give (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.6 g, 74%) as a white solid: 1H NMR Spectrum: (DMSO d6) 1.60-2.03 (m, 4H), 2.50-2.58 (m, 1H), 2.59 (d, 3H), 2.78 (m, 1H), 3.53 (m, 1H), 3.84 (s, 1H), 3.96 (s, 3H), 4.84 (m, 1H), 7.27 (s, 1H), 7.35 (t, 1H), 7.47-7.60 (m, 2H), 7.85 (m, 2H), 8.38 (s, 1H), 9.56 (s, 1H); Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6](=[O:13])[CH2:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:4].Cl[CH:15](OCC)[CH2:16]Cl>O.C(OCC)C>[CH2:3]([O:5][C:6]([C:7]1[CH:16]=[CH:15][O:12][C:8]=1[CH:9]([CH3:10])[CH3:11])=[O:13])[CH3:4]
Reactant: CCOC(Cl)CCl
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccoc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2>O1CCCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(=O)c1cc(Br)cc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
Methyl 5-bromo-2,3-dihydro-1H-indole-7-carboxylate (6.5 g, 25 mmol) was dissolved in tetrahydrofuran (100 mL). Activated manganese dioxide (5 μm particle size, 22 g, 250 mmol) was added and the mixture stirred at room temperature for 16 hours. A further 22 g of activated manganese dioxide was added and the reaction stirred for 96 hours. The reaction was then filtered through celite and concentrated in vacuo to give 5.1 g (80%) of the title compound as a beige solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[O:24]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25]1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:26]3[CH:27]=[CH:28][O:24][CH:25]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ccoc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ccoc3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in dimethylformamide (2 mL) was added 3-furaldehyde (80.7 mg, 0.840 mmol) and oxone (258 mg, 0.420 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (171 mg, 69% yield) as pale yellow crystals.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn].O>CO.Cl>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CO
Product: Nc1ccccc1CS(=O)(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A stirred mixture of 2-(phenylsulfonylmethyl)-1-nitrobenzene (5.55 g, 20.0 mmol) and granular tin (10.4 g, 88 mmol) in methanol and concentrated HCl (60 mL) is stirred under nitrogen at 45° C. for 5 h, cooled to ambient temperature over an 18 h period, poured onto NaHCO3 (80 g) with stirring, treated with water and extracted with ethyl acetate. The combined extracts are washed with brine (2×100 mL), dried over MgSO4, and concentrated in vacuo to afford the title product as an off-white solid, 4.41 g (89%) mp 175-176° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5](=[O:13])[NH:4][C:3]1=[O:14].[H-].[Na+].[C:17]([O:23][CH2:24]Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].O>CS(C)=O>[C:17]([O:23][CH2:24][N:9]1[C:8](=[O:11])[N:7]([CH3:12])[C:6]2[C:5](=[O:13])[NH:4][C:3](=[O:14])[N:2]([CH3:1])[C:10]1=2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)n(COC(=O)C(C)(C)C)c2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
To a stirring solution of 3,7-dimethyluric acid (0.40 g, 2.04 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (49 mg, 2.04 mmol) in one portion. After stirring for 45 minutes, a solution of chloromethyl pivalate (0.29 g, 2.04 mmol) in dimethylsulfoxide (1 ml). After stirring for 24 hours, water (50 ml) was added. After cooling to room temperature, the solid was filtered, rinsed with water (4×20 ml), with ether (20 ml) and dried under vacuum to give 9-pivaloyloxymethyl-3,7-dimethyluric acid (0.18 g, 28% yield) as a white solid.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:13][C@@H:12]1[CH3:45])=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:29][O:28][C:26](=[O:27])[N:25]([CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)[C@H:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[NH:11][C@@H:12]([CH3:45])[CH2:13]1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)Nc2ccc(C(F)(F)F)cc21
Yield: 90 %

Procedure:
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester. (Example 56) (2.8 g, 4.3 mmol), ethanol (50 mL), and 10% palladium on carbon (280 mg) were combined in a Parr bottle and agitated under 50 psi of hydrogen gas on a Parr shaker for 0.5 h. The mixture was then filtered through a bed of Celite®, eluting with ethyl acetate, and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography using 5% ethyl acetate/hexanes as eluent to afford 2.0 g of the title product (90%): MS m/z 516 (M+ +2); 1H NMR (CDCl3) δ 1.18 (C2-Me, d, 3H, J=5.8 Hz), 6.50 (C8, d, 1H, J=8.3 Hz), 7.21 (C7, d, 1H, J=8.5).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=[O:17].[CH2:18]([O:20][C:21]([CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[CH3:19]>CO.C(O)C>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[C:16](=[O:17])[CH:19]=[CH:18][O:20][CH2:21][CH3:23]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC=CC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Reaction time: 3 h

Procedure:
36 ml of a 15% strength solution of sodium methylate in methanol were added dropwise, at 20° C., to a suspension of 22.6 g of 3,7-dichloro-8-formylquinoline and 38.4 g of ethoxycarbonylmethyl-triphenyl-phosphonium chloide in 200 ml of ethanol. The mixture was stirred for 3 hours, after which the precipitate was filtered off under suction, washed with water and dried.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:23])([CH3:22])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:21])[CH2:9][CH:10](O)[CH2:11][C:12]([CH:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)=[O:13].O>CO>[CH3:2][O:3][C:4]([CH3:22])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:21])[CH2:9]/[CH:10]=[CH:11]/[C:12]([CH:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)=[O:13]
Reactant: COC(C)(C)CCCC(C)CC(O)CC(=O)C1COC(=O)C1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(C)(C)CCCC(C)C/C=C/C(=O)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
1 ml of methanol saturated with hydrochloric acid is added to a solution of 2.1 g (0.007 moles) of 3-(9-methoxy-3-hydroxy-5,9-dimethyl-decanoyl)-4-butyrolactone in 15 ml of dry methanol, and the mixture is allowed to stand at room temperature for 12 hours. 2 ml of water are added to the mixture, and the mixture is stirred at room temperature for 5 hours. The solvent is distilled off in vacuo, the residue is taken up in ether, the etheral solution is washed with water, dried, and the solvent is distilled off. The residue is purified by chromatography (adsorbent: Kieselgel 60, solvent: a 10:0.1 mixture of benzene and methanol). 1.4 g (70%) of the aimed compound are obtained; Rf =0.75 (developed with a 10:0.1 mixture of benzene and methanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[C:13]1([CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:20][CH2:21][CH2:22][NH2:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([CH:4]([NH:23][CH2:22][CH2:21][NH:20][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: NCCNC(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(NCCNC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
A solution of 9.2 g of α-chlorophenylacetic acid methyl ester, dissolved in 10 ml of acetonitrile, is added dropwise in the course of 10 minutes, while stirring, to a mixture of 11.3 g of N-diphenylmethyl-ethylenediamine, 5.05 g of triethylamine and 70 ml of acetonitrile. The mixture is then heated under reflux for 18 hours. It is then concentrated to dryness by evaporation under reduced pressure, triturated with 100 ml of 10% sodium hydroxide solution and extracted twice by shaking with 100 ml of diethyl ether each time. The ether phases are combined, washed three times with 30 ml of saturated sodium chloride solution each time, dried over magnesium sulphate and concentrated by evaporation. The residue obtained after concentration by evaporation is shaken with 10% (by weight) sodium hydroxide solution and diethyl ether in order to remove any excess triethylamine. The ether phases are further treated as indicated above. Finally, drying is effected at approximately 0.15 mbar. N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine is obtained which is converted into the diacetate for characterisation. For that purpose, 14.8 g of base are dissolved in 15 ml of diethyl ether and 15 ml of hexane, and glacial acetic acid is added dropwise while stirring and cooling. The precipitate is filtered with suction, recrystallised from approximately 360 ml of diethyl ether and 90 ml of hexane and dried under reduced pressure (under 0.2 mbar). The N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine acetate melts at 78°-81° C. Pure N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine can be freed from this by treatment with 10% sodium hydroxide solution, extraction by shaking with diethyl ether, drying over magnesium sulphate and evaporating off the solvent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.ClC(Cl)(Cl)Cl>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[CH3:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)cccc1OC
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(OC)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of ethyl 6-methyl-2-methoxybenzoate (8.4 g, 43.2 mmol), bromine (6.9 g, 43.2 mmol) and tetrachloromethane (170 ml) is stirred at room temperature for 60 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated. The crude product is obtained as a yellow oil, 10.3 g (87%) and is used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>O1CCCC1.CCCCCC>[Br:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:37]=[CH:38][CH:39]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCCCCBr
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1cccc(Br)c1
Reaction time: 0.25 h

Procedure:
To 14.7 gm of the Wittig salt prepared from 1-bromopentane and triphenylphosphine in 80 ml of tetrahydrofuran at 0° C. is added 22.5 ml of n-butyl lithium (1.6M) in hexane. The mixture is stirred for 15 minutes, and 3.8 ml of 3-bromobenzaldehyde is added. This mixture is stirred for 30 minutes; and after concentrating and diluting with ether, the solids are filtered off. Further concentration of the filtrate and chromatography over silica gel eluting with 3:2 hexane:ether yields pure 3-bromo-(1-hexenyl)benzene as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:14](O)=O>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:18][C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: Nc1cccnc1N
Reactant: COc1cc(C(=O)O)ccc1NS(C)(=O)=O
Product: COc1cc(-c2nc3ncccc3[nH]2)ccc1NS(C)(=O)=O

Procedure:
Prepared analogously to Example 14 from 2,3-diaminopyridine and 3-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]1[N:17]([C:18]2[S:19][C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:22]=2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]([CH3:37])=[N:15][N:14]=1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([C:22]1[CH:21]=[C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[S:19][C:18]=1[N:17]1[C:16]([CH3:37])=[N:15][N:14]=[C:13]1[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])=[O:31]
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: Cc1cccc(N=C=O)c1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(C)c2)s1

Procedure:
3-Methylphenyl isocyanate and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methylphenyl)ureidomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2I.C([Mg]Cl)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
5-(Difluoromethoxy)-3-iodo-1H-indazole (0.175 g, 564 μmol) was dissolved in THF (3 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath), isopropylmagnesium chloride 2M in THF (621 μL, 1.24 mmol.2) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (220 mg, 184 μL, 677 μmol.2) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum and taken into next step without further purification yielding 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole, crude mass exceeded yield, assumed quantitative.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC(N)CC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC(CC)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-aminopentane (Alfa) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27]OC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H]([CH2:49][O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)CC2)CCCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:21]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH2:49][O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:22][CH2:23][CH2:24][CH2:27][CH2:25][CH2:26]1
Reactant: COc1ccc(OC[C@H]2CC[C@H](NC3CCCCCC3)CC2)cc1
Reactant: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(OC[C@H]2CC[C@H](N(C(=O)Nc3ncc(SCC(=O)O)s3)C3CCCCCC3)CC2)cc1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-[trans-4-(4-methoxy-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[C:6]([C:29]4[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=4)[CH:7]=[CH:2][CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (101 mg, 0.286 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (150 mg, 0.57 mmol) and K2CO3 (236 mg, 1.71 mmol) in DME-water (2:1) was added Pd(PPh3)4 (33 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide. 1H NMR (TFA salt, CD3OD) d (ppm): 8.97 (s, 1H), 8.23 (d, 1H), 8.12 (d, 1H), 7.85 (d, 1H), 7.78 (m, 2H), 7.5 (d, 1H), 7.37 (s, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.08-3.21 (m, 5H), 3.0 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [SH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH2:2]([S:1][CH2:12][C:13]#[N:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CS)c1ccccc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCSCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Part A. A mixture of 2-mercaptoacetophenone (6.96 g, 45.7 mmol), chloroacetonitrile (3.00 mL, 47.4 mmol), and potassium carbonate (7.21 g, 52.2 mmol) in tetrahydrofuran (100 mL) was stirred at ambient temperature for 12 hours. The mixture was poured into water (400 mL), and this was extracted with ethyl acetate (400 mL), then methylene chloride (400 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, phenacylthio-acetonitrile, as a pale pink oil (7.51 g, 39.3 mmol, 86%). 1H NMR (CDCl3): δ 7.96 (2H, dd, J=8.0, 1.1 Hz); 7.65-7.56(1H, m); 7.50 (2H, t, J=7.7 Hz); 4.13 (2H, s); 3.45 (2H, s). Mass spectrum (NH3 -CI/DDIP): m/z 210 (21%); 209 (100%); 192 (2%); 170 (1%); 139 (1%).