Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:29][CH:30]=1
Reactant: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
To a solution of the compound obtained in (1) above in ethanol (15 ml) was added 10% Pd carried on carbon (0.36 g), and the mixture was hydrogenated under a hydrogen atmosphere to obtain the titled compound (1.43 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=O)[CH3:2].I[C:15]1[CH:20]=CC=[CH:17][C:16]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>O.[Cu].C(O)CC(C)C>[CH2:10]1[C:11]2[C:7](=[CH:6][C:5]([NH:4][C:1]3[CH:20]=[CH:15][C:16]([CH3:21])=[CH:17][CH:2]=3)=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: Cc1ccccc1I
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: O
Product: Cc1ccc(Nc2ccc3c(c2)CCC3)cc1
Temperature: 200 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
5-(N-Acetylamino)indane (26.28 g (0.15 mol)), 43.61 g (0.20 mol) of iodotoluene, 25.88 g (0.188 mol) of anhydrous potassium carbonate and 2.38 g (0.038 mol) of copper powder were mixed, and heated up to 200° C. while introducing nitrogen gas, followed by stirring for 6 hours. After the termination of the reaction, cooling was conducted, and 22.3 g of potassium hydroxide dissolved in 20 ml of water and 50 ml of isoamyl alcohol were added to perform hydrolysis at 130° C. for 2 hours. After the termination of the hydrolysis, 250 ml of water was added, and isoamyl alcohol was removed by azeotropic distillation. Then, 200 ml of toluene was added to dissolve the reaction product. After filtration, dehydration was performed with magnesium sulfate. After magnesium sulfate was removed by filtration, the filtrate was concentrated, and purified by column chromatography (carrier: silica gel, eluent: toluene:hexane 1:4) to obtain 32.3 g of indane-5-yl-p-tolylamine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([N:17]([CH3:19])[CH3:18])=[O:20]
Reactant: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
((S)-1-Dimethylcarbamoyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (2.0 g, 6.85 mmol) was dissolved in methylene chloride (20 mL) at 0° C. Trifluoroacetic acid (20 mL) was added. The mixture was stirred for 2 h and evaporated. The residue was dissolved in methylene chloride and very carefully basified using saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted using methylene chloride. The combined organic extracts were washed with water and brine, and then dried over sodium sulfate to give (S)-2-amino-N,N-dimethyl-3-phenyl-propionamide (1.0 g, 76%) as yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[CH:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[CH3:37][C@@H:36]1[N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[C@H:33]([C:38]([O:40][CH2:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[CH:15]=2)=[O:13])=[O:39])[CH2:34][CH2:35]1
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3cc(Br)ccc3c2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
DIPEA (0.823 mL, 4.71 mmol) was added to a stirred slurry of 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (Intermediate 118) (1.03 g, 3.14 mmol) and (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (0.720 g, 3.14 mmol) in acetonitrile (50 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (40 g SiO2, 10-20% EtOAc/hexanes) to yield (2S,5S)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (1.09 g) as a yellow solidified foam. LC-MS retention time 4.413 min; m/z 476, 478.20 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.57 (br. s., 1H), 8.14 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.68 (dd, J=8.8, 1.8 Hz, 1H), 5.62-5.70 (m, 1H), 5.47-5.60 (m, 1H), 4.46 (t, J=7.3 Hz, 1H), 3.92-4.06 (m, 1H), 2.26-2.37 (m, 2H), 2.05-2.19 (m, 1H), 1.67-1.82 (m, 1H), 1.46 (d, J=6.8 Hz, 9H), 1.30 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O.C(O)(=O)C>[N+:17]([CH2:20][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:14][CH:13]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccn2)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(COc2ccccn2)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
To an acetic acid (20 mL) solution of 6-(pyridine-2-yloxymethyl)-pyridine-3-carbaldehyde (504 mg, 2.35 mmol) described in Manufacturing Example 154-1-6 were added nitromethane (635 μL, 11.8 mmol) and ammonium acetate (363 mg, 4.71 mmol), which was stirred for 4 hours at 100° C. under nitrogen atmosphere. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a solution of this residue in dimethyl sulfoxide (25 mL) and acetic acid (2.5 mL) was added sodium borohydride (178 mg, 4.71 mmol), which was stirred for 25 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (93 mg, 15%).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])(=O)=O.[C:22](#[N:26])[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:8]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:12])[F:13])[CH2:7][CH:23]([C:22]#[N:26])[C:24]#[N:25]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of compound 5b (15.0 g, 41.2 mmol), malononitrile (5.44 g, 82.4 mmol), and potassium carbonate (28.5 g, 206 mmol) in 1,2-dimethoxymethane (150 ml) was stirred overnight at room temperature under nitrogen. The reaction mixture was quenched with water (150 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with brine (200 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 85:15 hexanes/EtOAc) to provide 2-(2,2,3,3,4,4,5,5-Octafluoropentyl)malononitrile (5c) (7.5 g, 65%) as a white solid:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:36][NH:37][O:38][CH3:39]>C1COCC1>[CH3:39][O:38][N:37]([CH3:36])[C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:19]
Reactant: CNOC
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−15° C. to −20° C.) and stirred solution of 1-[(benzyloxy)carbonyl]-3-piperidinecarboxylic acid (4.0 g, 15.2 mmol) in dry THF (50 mL) including methylmorpholine (2 mL) was added dropwise a solution of isobutyl chloroformate (2.28 g, 16.7 mmol) in THF (10 mL). After the mixture was stirred at the same temperature for 20 min, a solution of N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.7 mmol) in THF (20 mL) including methylmorpholine (2 mL) was added. The reaction mixture was allowed to warm to room temperature, and then stirred for 16 hrs. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The separated organic phase was washed with 1N HCl, saturated NaHCO3, and brine, successively. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give benzyl 3-{[methoxy(methyl)amino]carbonyl}-1-piperidinecarboxylate as a colorless oil (4.7 g, yield; quant.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:35])[CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[O:25][CH2:24][C:23]3[CH:22]=[CH:21][S:20][C:19]=3[C:18](O)([CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[C:17]=2[CH:34]=1.Cl.O1CCOCC1>ClCCl>[CH3:8][O:9][C:10](=[O:35])[CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[O:25][CH2:24][C:23]3[CH:22]=[CH:21][S:20][C:19]=3[CH:18]([CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[C:17]=2[CH:34]=1
Reactant: COC(=O)CSc1ccc2c(c1)C(O)(C1CCN(C)CC1)c1sccc1CO2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CSc1ccc2c(c1)C(C1CCN(C)CC1)c1sccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a dichloromethane solution of the compound obtained in Example 23 (5.7 g, 14 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to give a free compound. Thereafter, 4 mol/L hydrogen chloride-dioxane (8.0 mL, 32 mmol) was added thereto, and the mixture was stirred for 1 hour. The solvents were distilled off under a reduced pressure, and ether was added to the residue to allow crystallization. The precipitated crystals were separated by filtration and dried, to give 4.1 g (69%) of the captioned compound.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:8][C:7]1[C:2]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A mixture of 3.95 g of 2,3-difluoropyridine, 13.2 g of diethyl malonate, 38 ml of dimethyl sulfoxide and 26.85 g of cesium carbonate was stirred for 3 hours at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 12.18 g of the resultant residue was subjected to silica gel column chromatography, to obtain 6.38 g of diethyl (3-fluoro-2-pyridyl)malonate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[N:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:26][C:24]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][NH:26][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][N:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccncc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To the mixture of 3-nitroisonicotinic acid (4.78 g, 28.4 mmol), methylamine hydrogen chloride (2.88 g, 1.5 eq), EDC (6.53 g, 1.2 eq), HOBt (4.59 g, 1.2 eq) in DMF (50 mL) was added DIEA (25 mL, 5.0 eq). The mixture was stirred at room temperature overnight. It was concentrated and the crude was dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product N-methyl-3-nitroisonicotinamide (878 mg, isolated yield 17%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([OH:13])=[O:12])=[O:5]>ClCCl>[C:11]([C@H:7]1[CH2:8][CH2:9][CH2:10][N:6]1[C:4](=[O:5])[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([OH:13])=[O:12])=[O:5])([OH:13])=[O:12]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCS
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN1C(=O)CCSSCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 8.7 %

Procedure:
0.9 g (4 mmol) 1-(3-mercapto-propionyl)-(R)-pyrrolidine-2-carboxylic acid (raw material) were dissolved in dichloromethane and extracted with 50 ml of an saturated aqueous solution of CuSO4. The aqueous phase was extracted twice with dichloromethane, the combined organic phases filtered, dried with magnesiumsulfate and evaporated. Chromatography with dichloromethane/acetone/formic acid 80/20/1 gave 70 mg (R)-1-[3-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyldisulfanyl]-propionyl]-pyrrolidine-2-carboxylic acid as a colorless oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:46]2[C:41]([CH:39]=[O:40])=[N:42][CH:43]=[N:44][CH:45]=2)[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccncn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(-c3cncnc3C=O)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-4-carboxamide
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:15]([O:25][CH2:26][CH3:27])=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[C:15]([O:25][CH2:26][CH3:27])=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: CCOc1cc(OC)c(C(=O)O)cc1Cl
Reactant: CN1CCc2c(N)cccc2C1
Product: CCOc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1Cl

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-4-ethoxy-2-methoxybenzoic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:25]1[CH2:27][C@H:26]1[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>>[OH:25][C@@H:26]([CH2:27][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:13][CH2:14]2)=[CH:23][CH:24]=1)[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Product: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)cc2)CC1
Yield: 14.4 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methyl-2-thienyl)methanone (0.174, 0.507 mmol) was reacted with 4-[(2S)oxiranylmethoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.108 g, 524 mmol) according to Procedure G to give the title compound (0.04 g, 0.073 mmol).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[C:4]([I:18])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([I:18])[CH:3]=1
Reactant: Fc1cc(I)c(NCCOC2CCCCO2)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OCCNc1cnc(F)cc1I
Temperature: 50 °C
Yield: 28.4 %

Procedure:
Dissolve 6-fluoro-4-iodo-N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)pyridin-3-amine (0.20 g, 0.55 mmol) in ethanol (5.5 mL). Add pyridinium p-toluenesulfonate (0.014 g, 0.055 mmol). Heat the reaction mixture at 50° C. overnight. Remove the solvent under reduced pressure. Purify by FCC (0.1% to 1% 2 M NH3 methanol solution/CH2Cl2) to give the title compound (44 mg, 28%) with 100% HPLC purity. MS (ES) m/z 283 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][O:54][CH3:55])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:55][O:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: COCOc1ccc(OB([O-])[O-])cc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(methoxymethoxy)phenyl borate (262 mg) and potassium carbonate (292 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was stirred 100° C. for 9 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) to give 7-(4-methoxymethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 86) (340 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1OC.[NH3:11]>CO>[NH2:11][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[O:2][CH3:1]
Reactant: N
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1c(N)c(=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3,4-Dimethoxy-3-cyclobutene-1,2-dione (1.3 g, 9.2 mmol) in of MeOH (10.0 ml) was treated with aqueous ammonia (10.0 ml of a 2.0M solution) and stirred at ambient temperature for 2 h. The yellow precipitate thus formed was recovered by filtration, washed with MeOH and Et2O and dried in vacuo to afford the title compound (0.87 g, 75%) as an amorphous yellow powder δH (d6 DMSO) 8.32 (2H, br s), 4.28 (3H, s). m/z (ES+, 70V) 127 (MH+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[BrH:13].S(=O)(=O)(O)O>O>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Br
Reactant: CCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCCBr
Yield: 62.8 %

Procedure:
Undecanol (14 g), 48% aqueous hydrobromic acid (30 g) and concentrated sulphuric acid (5 ml) are heated together under reflux for 51/2 hours. After cooling, water is added and the organic layer is separated, washed with concentrated sulphuric acid (20 ml), brine (50 ml) and dilute aqueous sodium carbonate (50 ml), and is then dried over calcium chloride. Distillaion under vacuum gives 1-bromoundecane (12 g) as a yellow oil, b.p. 60°-70° C./0.1 mm.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[F:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH:44]=[CH:45][C:46]=1[F:47]>CC(O)=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][C:46]([F:47])=[C:41]([F:40])[CH:42]=3)=[CH:53][CH:52]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: Nc1ccc(-c2ccc(F)c(F)c2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (116 mg, 0.55 mmol) was added to a DCM solution (1 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (95 mg, 0.27 mmol), 3′,4′-difluoro-[1,1′-biphenyl]-4-amine (73 mg, 0.36 mmol), and 1 drop of AcOH and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture diluted with DCM and saturated aqueous NaHCO3 and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.