Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(Cl)c1
Yield: 96 %

Procedure:
To a solution of 3-chloro-4-methylbenzoic acid (20 g, 117 mmol) in MeOH (200 mL) was added dropwise thionyl chloride (25.6 mL, 352 mmol) at 0° C. with stirring. The mixture was stirred at room temperature for 5 days. The reaction was concentrated. The residue was dissolved in EA (500 mL), washed with 10% Na2CO3 (250 mL×2), water (250 mL) and brine (250 mL), dried over Na2SO4, filtered and concentrated to afford product as a yellow solid (20.8 g, 96%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]([CH:14]=[CH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[CH2:2]([N:9]1[C:13]([CH2:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: C(=Cc1cncn1Cc1ccccc1)CC(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(Cn2cncc2CCCC(c2ccccc2)c2ccccc2)cc1

Procedure:
1-benzyl-5-(4,4-diphenyl-1-butenyl)-1H-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount of Pd/C (10%) is added. The reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by flash chromatography eluting with methylene chloride-methanol mixture. Yield 1,3 g. M.p. of the hydrochloride salt is 200°-202° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:37])[CH:14]([CH2:18][S:19]([N:22]1[CH2:34][CH2:33][C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:35][CH3:36])[CH:30]=3)[NH:25][C:24]=2[CH2:23]1)(=[O:21])=[O:20])[CH:15]([CH3:17])[CH3:16])(C)(C)C.ClCCl.CO>ClCCl>[CH3:36][O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]1[CH2:23][N:22]([S:19]([CH2:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([OH:37])=[O:12])(=[O:21])=[O:20])[CH2:34][CH2:33][C:32]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)OC(C)(C)C)C(C)C)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)O)C(C)C)C3
Reaction time: 2 h
Yield: 62 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 2-(6-methoxy-1,3,4,9-tetrahydro-β-carboline-2-sulfonylmethyl)-3-methyl-butyric acid tert-butyl ester (237 mg) in dichloromethane (10 ml) at room temperature under nitrogen. The mixture was stirred for 2 h before being evaporated under reduced pressure. The residue was partitioned between 1M aqueous sodium hydroxide (15 ml) and diethyl ether (15 ml). The organics were extracted with 1M aqueous sodium hydroxide (15 ml). The combined aqueous portions were acidified to pH=5 with 10% citric acid and extracted with ethyl acetate (4×20 ml). The combined organics were washed with water (2×10 ml) and brine (10 ml), then dried (MgSO4), filtered and the solvent removed under reduced pressure to give, after chromatography (SiO2, 20:1 dichloromethane-methanol), the title compound (128 mg, 62%) as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[CH:11]=1)([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:15])([CH3:16])[CH2:14][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:11]1
Reactant: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC1(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1(C)C=C(c2ccccc2N)CC1(C)C
Temperature: 90 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a mixture of 1-nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene (441 mg, 1.8 mmol) produced in Example (54b), ethanol (10 mL) and water (3.3 mL) were added ammonium chloride (48.1 mg, 0.899 mmol) and iron powder (352 mg, 6.3 mmol), followed by stirring for 5 hours at an external temperature of 90° C. After further adding ammonium chloride (9.63 mg, 0.18 mmol) and iron powder (100 mg, 1.8 mmol) to the reaction mixture, stirring was continued for 12 hours at an external temperature of 75° C. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 331 mg of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].N1CCCCC1.C(O)(=O)C>C(Cl)Cl.CN(C=O)C.C(O)C.CCOC(C)=O>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[CH:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[C:9]([O:17][CH2:18][CH3:19])=[O:16])[CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ncc(C=O)s1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1cnc(N)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.2 %

Procedure:
To a solution of 2-amino-thiazole-5-carbaldehyde (47%; 6 g; 23 mmol) in CH2Cl2 (30 mL) and DMF (30 mL), was added 4A molecular sieves, diethyl malonate (3.5 mL; 23 mmol), piperidine (1.1 mL; 11.5 mmol) and acetic acid (0.7 mL; 11.5 mmol). The reaction mixture was stirred at room temperature for 96 hours. Then EtOAc was added, and the reaction mixture was filtered through celite in order to remove the precipitate formed. EtOAc (500 mL) was added to the filtrate, and the organic phase was washed with NaHCO3 and brine. The organic phase was dried and concentrated to yield 4.9 g of the crude product. Addition of petroleum ether to a solution of the crude product in ethanol followed by filtration afforded 2-(2-amino-thiazol-5-ylmethylene)-malonic acid diethyl ester (1.13 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].[C-]#N.[K+]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:32][C@@H:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]3[CH3:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: C[C@@H]1CCCC[C@H]1O
Agent: [C-]#N
Agent: [K+]
Product: C[C@@H]1CCCC[C@H]1OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 6 h

Procedure:
A mixture of 3.45 (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 11.4 g (100 mmol) of trans-2-methylcyclohexanol and 100 mg of powdered potassium cyanide is stirred at 130° for 6 hours, the solution obtained is evaporated to dryness and the residue is chromatographed on a silica gel column. By recrystallization from ethyl acetate there is obtained trans-2-methylcyclohexyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 213°-215° (1:1 mixture of the two diastereoisomers).
Reaction SMILES: [CH3:1][Si:2]([CH3:43])([CH3:42])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:44]1([C:50]2[CH:55]=[CH:54][C:53](B3OC(C)(C)C(C)(C)O3)=[CH:52][N:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][Si:2]([CH3:43])([CH3:42])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:53]3[CH:52]=[N:51][C:50]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:55][CH:54]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2c(I)cnn12
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: [Na+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 80 °C
Yield: 61 %

Procedure:
To a pressure tube were charged benzyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (1 g, 2.85 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 g, 4.1 mmol), Pd(PPh3)4 (164 mg, 0.14 mmol), DME (20 mL) and 2 M Na2CO3 (10 mL). The mixture was briefly degassed with Argon and the tube was capped and heated at 80° C. for 15 hours. On cooling, H2O (40 mL) and EtOAc (100 mL) and aqueous layer was extracted with EtOAc (3×) and combined organic layers were washed with brine once and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-30%) gave the title compound (1.33 g, 61%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][C:29]3=S)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH3:34].O1CCOCC1>>[NH2:34][C:29]1[C:30]2[C:25](=[CH:24][CH:23]=[C:22]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[Cl:21])=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:31]=2)[CH2:26][CH2:27][N:28]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=S)NCC3)n1
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(N)=NCC3)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
1-[3-t-Butyl-1-(1-thioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (0.170 g, 0.348 mmol) was dissolved in 0.5M NH3/dioxane (30 mL). Mercuric chloride (0.142 g, 0.522 mmol) was added and the mixture was stirred at 80° C. After 18 h, H2O (2 mL) was added. The mixture was stirred for 30 min and filtered through a pad of Celite®. The solvent was removed under vacuum and the residue was purified by reverse-phase chromatography to yield 1-[1-(1-amino-3,4-dihydroisoquinolin-7-yl)-3-t-butyl-1 H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (25 mg, 15% yield). 1H NMR (400 MHz, CD3OD): □ 8.14 (d, J=2.0 Hz, 1H), 7.99-7.96 (m, 1H), 7.84 (dd, J=8.0, and 2.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.23-7.21 (m, 2H), 6.46 (s, 1H), 3.62 (t, J=6.8 Hz, 2H), 3.14 (t, J=6.8 Hz, 2H), 1.35 (s, 9H); MS (ESI) m/z: 471.3 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[O:23]1[CH2:24][CH:21]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2COC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(C2COC2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-hydroxy-1-(hydroxymethyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (7.62 g, 0.029 mol) in anhydrous THF (100 mL) at 0° C., a solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, then a solution of toluenesulfonyl chloride (5.26 g, 0.028 mol) in anhydrous THF (50 mL) was added by canula. The thick reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. A solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise and the reaction mixture heated at 60° C. for 2 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, pentane:EtOAc; gradient from 100:0 to 20:80) to afford 4-oxetan-3-ylpiperidine-1-carboxylic acid tert-butyl ester as a white solid (5.33 g, 75%). TFA (10 mL) was added to a solution of 4-oxetan-3-yl-piperidine-1-carboxylic acid tert-butyl ester (7.1 g, 0.029 mol) in DCM (100 mL) and the mixture stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (50 g), the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10 to 85:15 to 80:20) to afford 4-Oxetan-3-ylpiperidine as a colourless oil which solidified on standing (2.05 g, 49%). 1H NMR (CDCl3, 300 MHz) δ 4.75 (dd, J=7.9, 6.0 Hz, 2H); 4.52-4.42 (m, 2H); 3.14-3.04 (m, 2H); 2.81-2.67 (m, 1H); 2.61 (td, J=12.2, 2.6 Hz, 2H); 1.85-1.68 (m, 1H); 1.60 (m, 2H) and 1.02 (qd, J=12.2, 4.0 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21](CC)[CH2:22]C)[CH3:20].CNCC.C1CCCCC1.C(O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[CH2:19]([N:21]([CH3:22])[C:16]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH:10]=1)=[O:18])[CH3:20]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(-c2ccccc2)c2sccc2c1
Agent: CCNC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(C)C(=O)c1cc(-c2ccccc2)c2sccc2c1

Procedure:
The reaction is carried out as in Example 1, starting with 7-phenylbenzo[b]thiophene-5-carboxylic acid (3 g) in toluene (30 cc) and thionyl chloride (2.64 cc) and then triethylamine (5 cc) and N-methylethylamine (1.01 cc) in toluene (30 cc). After chromatography of the residue on silica gel using a cyclohexane:ethanol:ethyl acetate (90:5:5 by volume) mixture as the eluent, a residue is obtained, which is stirred overnight in 40°-60° petroleum spirit (50 cc). After filtering and drying, N-ethyl-N-methyl-7-phenylbenzo[b]thiophene-5-carboxamide (1.5 g), m.p. 93° C., is isolated.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:43]6[CH2:42][CH2:41][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:45][CH2:44]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.4 %

Procedure:
A suspension of 1-cyclopropyl-3-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea (47, 3 g, 5.90 mmol, acetate salt), 1-boc-piperazine (1.65 g, 8.85 mmol) and acetic acid (675 μL, 11.80 mmol) in NMP (50 mL) at RT under nitrogen was sonicated for 3 h in order to obtain a solution, then NaBH(OAc)3 (3.95 g, 17.70 mmol) was added. The reaction mixture was stirred at RT for 3 days then quenched by addition of water. The pH was adjusted to 12-13 with 4N NaOH and the suspension was stirred and sonicated for 1 h. The solid was collected by filtration, rinsed with water and air-dried. The residue was purified twice by Biotage (SNAP 50 g KP-Sil cartridge; MeOH/DCM: 1/99 to 10/90 over 20 CV). The desired fractions were collected, concentrated, and co-precipitated with AcOEt with traces of methanol/hexanes to afford the title compound 48 (1.511 g, 2.44 mmol, 41% yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56 (bd, J=2.0 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.87 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bdd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.3 Hz, 1H), 6.57 (bd, J=2.5 Hz, 1H), 3.57 (s, 2H), 4H are hidden by water's peak, 2.59-2.51 (m, 1H), 2.42-2.27 (m, 4H), 1.39 (s, 9H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 619.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>C1COCC1>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1c(F)cccc1F
Solvent: C1CCOC1
Product: CNc1cccc(F)c1[N+](=O)[O-]

Procedure:
Reaction of 2.0 g (2.6 mmol) 2,6-difluoro-nitrobenzene with a 2 molar solution of methylamine in THF analogously to the process for preparing Intermediate 10a. Red solid. Yield: 1.8 g (86%); mass spectroscopy: [M+H]+=171.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13](=[O:21])([O:17][CH:18](Cl)[CH3:19])[O:14][CH2:15][CH3:16].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:13](=[O:21])([O:17][CH:18]([O:11][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])[CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)OC(C)Cl
Reactant: C=C(C)C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(C)OC(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.5 %

Procedure:
Potassium tert. butoxide (3.70 g, 0.033 mol) was added to a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml). Ethyl 1-chloroethyl carbonate (5.08 g, 0.033 mol) from Example 9 above was added to the resulting suspension. 18-crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was left with stirring at room temperature for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 2.50 g (38%) of the title product. (Adjusted for recovered starting material the yield was 75%).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([OH:23])=O)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>CN(C=O)C.C(Cl)Cl>[F:24][C:3]([F:2])([F:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([NH2:28])=[O:23])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (34.6 mg, 0.093 mmol) in DMF (1 mL) was added N,N-triethylamine (31 μL, 0.22 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min to give a 1:1 mixture of starting material and product. The residue was dissolved in CH2Cl2, dried (Na2SO4) and evaporated. The oil was again dissolved in DMF (1 mL) and N,N-triethylamine (15.5 μL, 0.11 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol) were added. The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min at room temperature. The solution was evaporated, dried in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, 3% MeOH in CH2Cl2) to give the title compound (15 mg, 48%) as off-white solid. MS: 337.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1>Cl>[Cl:8][CH2:9][C:10]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
0.236 ml (1.69 mmol) of triethylamine and 0.101 ml (1.27 mmol) of chloroacetyl chloride were added in this order to 200 mg (0.85 mmol) of 7-amino-3-phenyl-2H-isoquinolin-1-one obtained in Example 39. The obtained mixture was stirred at a room temperature for 2 hours. Thereafter, 30 ml of 1 N hydrochloric acid was added to the reaction solution, and the mixture was then extracted with methylene chloride (30 ml×2). The extract was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The precipitated solid was collected by filtration, and the filtrate was then washed with a suitable amount of ether, so as to obtain 229 mg (86%) of 2-chloro-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide in the form of a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-(4-Nitro-benzyl)-piperazin-1-yl carboxylic acid tert-butyl ester (769 mg, 2.4 mmol) and tin chloride dihydrate (2.70 g, 12 mmol) are suspended in ethyl acetate (20 mL) and stirred at room temperature overnight. Then, saturated aqueous solution of sodium bicarbonate (20 mL) is added and vigorously stirred for 1 hour. Solids are removed by filtration and the organic layer of the filtrate is separated and washed with water (20 mL). The organic phase is dried over anhydrous magnesium sulfate and concentrated to give a white solid (620 mg, 89% yield, ES+(m/z) 293 [M+H]).