Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>[Pd].C1COCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3[nH]ccc23)nc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 71.2 %

Procedure:
Palladium catalyst Pd(PPh3)4 (714 mg, 0.6 mmol) and freshly prepared aqueous sodium hydroxide (2.47 g, 61.8 mmol in 22 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (5 g, 20.6 mmol) and 2-bromopyridine (2 mL, 20.8 mmol) in THF (70 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 70° C. in an oil bath for 6 hours. It was then cooled to room temperature and 400 ml ethyl acetate was added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with dichloromethane to give 2.85 g (71%) of 4-pyridin-2-yl-1H-indole as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CO)cs2)CC1
Reaction time: 1 h

Procedure:
A solution of 4-(4-ethoxycarbonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.15 g, 3.37 mmol) in THF (15 mL) at 0° C. was treated with LiAlH4 (128 mg, 1 eq.). The mixture was stirred for 1 hour, then the reaction was quenched with 2 N NaOH solution. The solid was filtered off through a pad of celite and washed with EtOAc (100 mL). The filtrate was washed with water and dried over Na2SO4. Removal of the solvent afforded the desired product as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[OH:21][C:22]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:23]=1[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:27][C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:34]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:35]=[CH:36][C:22]=1[OH:21])=[O:32])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)c(CNC(=O)OC(C)(C)C)c3)ccn2c1=O
Yield: 80.7 %

Procedure:
Methyl 8-(3-(((tert-butoxycarbonyl)amino)methyl)-4-hydroxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (65 mg, 0.22 mmol) and tert-butyl 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (93.3 mg, 0.27 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (85 mg, 100%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:37])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([Cl:36])[CH:27]=2)[C@@H:20]([CH3:38])[C:19]1=[O:39])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[Li+].[BH4-].CO.CC(C)=O>C1COCC1>[Cl:36][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([N:9]3[CH2:16][CH2:15][C:12]4([CH2:13][CH2:14]4)[C@H:11]([OH:17])[CH2:10]3)=[O:8])[C:19](=[O:39])[C@@H:20]2[CH3:38])=[O:37])[CH:31]=[CH:30][C:29]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CO
Product: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A cooled (−20° C.) solution of 0.29 g (0.50 mmol) of (S)-2-[(S)-4-(3-Chloro-4-trifluoromethyl-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester in 1.5 ml of THF was treated with 0.25 ml (0.50 mmol) of LiBH4 (2 M in THF) and 0.04 ml (1.00 mmol) of MeOH in 0.3 ml of THF. The reaction was warmed to +15° C. (during 3 h) and stirred for 1.5 h at RT, cooled to 0° C. and stopped with 0.17 ml (2.28 mmol) of acetone. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (Na2SO4) and evaporated to give after flash silica gel column (dichloromethane/MeOH 96:4 to 95:5) and precipitation (dichloromethane/ether) 0.19 g (68%) of the title compound as white amorphous powder. MS: 561.21 (MH+, Cl).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(N=[C:18]=[O:19])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]=[C:18]=[O:19])(=[O:10])=[O:11]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1cccc(Cl)c1Cl
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 138 °C
Reaction time: 2 h

Procedure:
To 350 mL of dry xylenes was added 44 g of 2,3-dichlorobenzenesulfonamide, 23 mL of n-butyl isocyanate and 0.3 g 1,4-diazobicyclo[2.2.2]octane. This mixture was heated to reflux (138° C.) under a nitrogen atmosphere. After two hours, liquid phosgene was added to the refluxing mixture in portions over 1.5 hours at such a rate that kept the temperature between 130°-138° C. The phosgene addition was ceased when the reflux temperature had fallen to 130° C. and failed to rise, indicating that consumption of the starting material was complete (13.5 mL phosgene). The mixture was refluxed for an additional hour, cooled to room temperature, and filtered under nitrogen. Evaporation of the filtrate under reduced pressure gave 55 g of crude 2,3-dichlorobenzenesulfonyl isocyanate as a dark oil. This oil was taken up in dry acetonitrile (total solution volume 140 mL) and used as such for subsequent experiments: IR (Neat): 2250 (NCO) cm-1
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([O-])=[O:4].[Li+].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[CH2:20]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:3](=[O:4])[CH:2]([OH:1])[CH2:6][CH3:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CCC(O)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCC(O)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
1.50 g (13.6 mmol) of lithium 2-hydroxybutanoate, 4.60 g (13.6 mmol) of glycine benzyl ester p-toluenesulfonic acid salt, and 1.84 g (1.36 mmol) of 1-hydroxybenzotriazole monohydrate (HOBt) were added to 80 mL of acetonitrile and stirred at room temperature for 20 minutes. The mixture was further mixed with 2.61 g (13.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and stirred at room temperature overnight. After the reaction mixture was filtered, the filtrate was vacuum-concentrated and the residue was dissolved in 200 mL of ethyl acetate. Washing with 1N hydrochloric acid and an aqueous solution saturated sodium hydrogen carbonate was carried out successively and drying over anhydrous sodium sulfate was carried out. After the solvent as removed by distillation, the residue was purified by flash column chromatography on silica gel (No. 9385, Merck) using a solvent mixture of hexane and ethyl acetate at 1:2 ratio to obtain N-(2-hydroxybutanoyl)glycine benzyl ester as a colorless oily substance (1.67 g, yield 49%).
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1.C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[CH3:34])=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH2:12]>S(=O)(=O)(O)O.CO>[CH3:11][NH:12][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CNC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Phenylacetic acid (10 g, 73.5 mmol) and methanol (60 ml) were added to a 250 ml three-necked flask, followed by addition of 10 drops concentrated sulphuric acid. The resulting solution was heated to reflux for 2 hours. Then, the solution was cooled to room temperature, followed by adding 25-30% aqueous solution of methylamine (50 ml, approximately 403 mmol), and heated to reflux for another 3 hours. After the reaction was completed, it was cooled to room temperature. Most of the solvent was removed by rotary vacuum evaporation, 30 ml of water was added thereinto, and then the mixture was extracted with ethyl acetate (3×80 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to yield 10.1 g of N-methyl phenylacetamide (white solid, yield: 91.8%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([O:25][CH3:26])[CH:19]=1)=O>>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: N#Cc1ccnc(NN)c1
Reactant: COc1cc(C(=O)/C=C/N(C)C)ccc1C
Agent: Cl
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1C
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-methoxy-4-methylphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 2.24 (3H, s), 3.73 (3H, s), 6.51 (1H, d, J=1.6 Hz), 6.71-6.75 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=5.2, 1.2 Hz), 7.77 (1H, d, J=1.2 Hz), 7.90 (1H, s), 8.47(1H, d, J=5.2 Hz). [M+H] Calc'd for C17H14N4O, 291; Found, 291.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CC(C)(CO)CBr
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)CO)c1OC
Temperature: 80 °C
Yield: 19.4 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.80 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (133 mg, 0.80 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 19%).
Reaction SMILES: O1C2C1CCOC1C=CC([N+]([O-])=O)=CC=12.[N+:16]([C:19]1[CH:20]=[CH:21][C:22]2[O:28][CH2:27][CH2:26][C@@H:25]([O:29][Si](C)(C)C)[C@H:24]([N:34]3[CH:38]([CH3:39])[CH2:37][CH2:36][C:35]3=[O:40])[C:23]=2[CH:41]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]2[O:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C@H:24]([N:34]3[CH:38]([CH3:39])[CH2:37][CH2:36][C:35]3=[O:40])[C:23]=2[CH:41]=1)([O-:18])=[O:17]
Reactant: CC1CCC(=O)N1[C@@H]1c2cc([N+](=O)[O-])ccc2OCC[C@H]1O[Si](C)(C)C
Agent: O=[N+]([O-])c1ccc2c(c1)C1OC1CCO2
Product: CC1CCC(=O)N1[C@@H]1c2cc([N+](=O)[O-])ccc2OCC[C@H]1O

Procedure:
Starting from 10.4 g (50 mmol) of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepin, 6.7 g of trans-7-nitro-5-(5-(R,S)-methyl-2-oxo-pyrrolidin-1-yl)-4-trimethylsilyloxy-2,3,4,5-tetrahydro-1-benzoxepin melting in the range 179°-185° C. are isolated. After elimination of the silyl group and after crystallization and chromatography on silica gel (ethyl acetate/cyclohexane 7:3) the diastereomers A and B are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][C:25](OC)=[O:26])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1=C(COCCCC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCCCO)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 1.17 h
Yield: 59.3 %

Procedure:
A solution of methyl 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}butanoate (0.50 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes to a stirred, ice-cooled suspension of lithium aluminium hydride (76 mg) in tetrahydrofuran (25 ml). The mixture was stirred at 0° for 70 minutes, quenched by pouring into excess iced-water and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed twice with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica (7 g) using dichloromethane plus 0→20% v/v ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue was recrystallised from diisopropyl ether to give the title compound, (0.28 g), m.p. 103°-104°.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][C:3]=1[F:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[O:16]=[C:14]1[NH:13][C:9]2=[N:10][CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=4)=[O:29])=[C:3]([F:19])[CH:4]=3)=[C:8]2[NH:15]1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1F
Yield: 83 %

Procedure:
Method H2 was used with 7-(4-amino-3-fluorophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (26 mg, 0.1 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (23 mg, 0.1 mmol) to afford the title compound (40 mg, 83%). 1H-NMR (δ, ppm, DMSO-d6): 6.45 (d, 1H, HPy,5, J=5.91 Hz), 6.98 (d, 1H, Harom,Ph), 7.23 (d, 1H, Harom,Ph), 7.63 (broad s, 2H, Harom), 7.79 (d, 1H, HPy,6), 8.05 (s, 1H, Harom,Ph), 8.12 (s, 1H, Harom′), 8.69 (s, 1H, NHurea,1), 9.49 (s, 1H, NHurea,3), 11.22 (s, 1H, NHPy3), 11.42 (s, 1H, NHPy2). LC-MS (m/z): 481 (M+H, 100).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[N:42][N:43]([CH2:45][CH3:46])[CH:44]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH3:46])[CH:44]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCn1cc(CCl)cn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCn1cc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 65.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-chloromethyl-1-ethylpyrazole (0.43 g) as starting materials, 5-benzyloxy-N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]Br>C(O)(=O)C>[C:1]([O:5][C:6](=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[C:22]([Br:26])[CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2N)cc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2cc(Br)ccc2N)cc1
Yield: 38.7 %

Procedure:
4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester (12.16 g, 33.5 mmol) was dissolved in 150 mL of acetic acid at 10° C. A solution of bromine (2.06 mL, 40.2 mmol) in 50 mL acetic acid was added dropwise. After complete addition, a thick yellow precipitate was observed. The reaction was filtered, and the solid washed with water. Chromatography of the solid (20% ethyl acetate/hexanes, SiO2) gave 5.72 g (39%) of 4-[(2-Amino-5-bromo-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as a white solid. 1H-NMR (CDCl3); 7.86 (d, 2H), 7.74 (d, 1H), 7.37 (dd, 1H), 7.23 (m, 2H), 6.65 (d, 1H), 5.19 (bt, 1H), 4.14 (d, 2H), and 1.58 (s, 9H). MS: M+=441.0 Da Step (4): Synthesis of 4-(7-Bromo-1,1,3-trioxo-3,4-dihydro-1H-1λ6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=O)(C)(C)C.[ClH:29]>>[ClH:29].[CH2:19]([C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:26])[N:11]3[CH2:27][CH2:28][NH:8][CH2:9][C@H:10]32)=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)[CH2:20][CH3:21]
Reactant: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Product: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (25 mg, 0.06 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 5 min, the solution was concentrated, diluted with water, and lyopholized to give the desired product as an off-white solid (19 mg, 89%). %). MS (ESI) 299.3 (M−Cl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16].O>CCOCC>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
100 g (0.585 mol) of 1-bromo-4-methylbenzene was dissolved in 500 mL of anhydrous ether in an argon atmosphere, and then cooled to −78° C. 252 mL (2.5M in hexane, 0.615 mol) of an n-butyl lithium solution was slowly added dropwise. The mixture was stirred for 15 minutes, and a solution of 122.6 g (0.615 mol) of trimethyltin chloride in 500 mL of ether was added. The mixture was stirred for 2 hours while the temperature was gradually increased to room temperature, followed by the addition of 700 mL of distilled water and then stirring. The organic layer was separated, treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding trimethyl(p-tolyl)tin as represented below in a 77% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH3:11]
Reactant: Cc1ccnc(C=O)c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cc(C)ccn1

Procedure:
prepared by reaction of the commercially available 4-methyl-pyridin-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1F

Procedure:
From 3-chloro-2-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=401.2, tR (minutes, Method D)=0.84
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1Cl

Procedure:
In a similar manner as described for example 49 (step 1), 428 mg of 3-[(1R)-1-(2-chlorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 229 mg of methanesulfonyl chloride, and 202 mg of triethylamine in 10 ml dichloromethane give (1-{5-carbamoyl-4-[(1R)-1-(2-chlorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.