Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>[Pd].CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1

Procedure:
5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (19.85 g, 65.6 mmol), MeOH (200 mL), HOAc (3 mL) and 10% Pd/C Degussa type (400 mg) were charged to a Parr shaker vial and shaken for 3 days at 70 psi hydrogen gas. The resulting material was filtered through Celite® and concentrated. The crude mixture was purified by flash column chromatography (FCC), DCM to 10% MeOH/DCM containing 1% NH4OH, to afford the product. MS (ESI) mass calcd. for C11H20N2O2, 212.29; m/z found, 213.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 3.60-3.55 (m, 2H), 3.38-3.25 (m, 4H), 2.95-2.86 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2ccc(C#N)cc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ccc(C#N)cc2c1-c1ccccc1
Temperature: 100 °C
Yield: 101.1 %

Procedure:
Under nitrogen atmosphere, 1.2 g of 2-cyano-7-methoxy-8-trifluoromethanesulfonyloxynaphthalene, 0.66 g of phenylboronic acid, 0.12 g of tetrakis triphenylphosphine palladium and 1.5 ml of triethyl-amine were suspended in 20 ml of anhydrous N,N-dimethylformamide. The resulting suspension was stirred under heating at 100° C. for 1.5 hours and cooled to room temperature by allowing to stand. A saturated aqueous solution of ammonium chloride was added to the resulting reaction mixture, followed by the extraction with ethyl acetate (50 ml×2). The organic layers were combined, washed with brine, died over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 0.95 g of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:20][CH2:21][CH:22]([OH:33])[CH2:23][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O[N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Si:13]([O:20][CH2:21][CH:22]([O:33][N:35]1[C:36](=[O:45])[C:37]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]2[C:39]1=[O:40])[CH2:23][CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOP(=O)(CCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ON1C(=O)c2ccccc2C1=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Diethyl azodicarboxylate (4.02 ml, 0.0.26 mol) was added to a solution of diethyl [4-(t-butyldimethylsilyloxy)-3-hydroxybutyl]phosphonate (7.9 g, 0.023 mol), N-hydroxyphthalimide (3.79 g, 0.023 mol) and triphenylphosphine (6.70 g, 0.026 mol) in dry tetrahydrofuran (100 ml). The mixture was stirred overnight at ambient temperature under a nitrogen atmosphere. The solvent was removed in vacuo and the residue dissolved in diethyl ether and kept at 4° C. for 24 hours. The mixture was filtered and the filtrate evaporated to dryness. The residue was chromatographed on silica gel (hexane-acetone 3:1 as eluant) to give the title compound as a pale yellow oil (7.9 g, 70%). IR:υmax (film) 2990, 2960, 2940, 2860, 1790, 1740, 1605, 1420, 1370, 1250, 1190, 1160, 1120, 1060, 1030, 970, 880, 840, 790, 700 cm-1. 1H NMR: δH (CDCl3) 0.0 (6H, s, SiMe2), 0.8 (9H, s, SiBut), 1.3 (6H, t, J=7Hz, (OCH2CH3)2), 1.78-2.4 (4H, m, CH2CH2P), 3.6-4.1 (7H, m, OCH2CH+(OCH2CH3)2), 7.65-7.95 (4H, m, aromatic H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH2:18]([N:20]([CH2:28][CH3:29])[CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:27][CH:24]1[CH2:23][CH2:22][CH:21]([N:20]([CH2:28][CH3:29])[CH2:18][CH3:19])[CH2:26][CH2:25]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CCN(CC)C1CCC(N)CC1
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 77.5 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (1.01 g, 3.25 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (660 mg, 3.90 mmol) to afford the desired product (1.12 g, 78%) as a yellow wax: ESI MS m/z 523 [C23H30BrN3O+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][NH2:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Br:1][C:2]1[N:3]2[CH:12]=[N:11][N:10]=[C:4]2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ncc(Br)nc1NN
Product: COc1ncc(Br)n2cnnc12
Temperature: 130 °C

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-3-hydrazinyl-2-methoxypyrazine (0.5 g crude, ˜1.9 mmol) and triethyl orthoformate (5 mL). The resulting mixture was heated at 130° C. overnight. TLC indicated a complete conversion. Work-up: the reaction mixture was concentrated. The residue was purified by flash column chromatography on silica gel with a 1:50 methanol/dichloromethane, to afford 0.28 g (66% for 2 steps) of the product as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.93 (s, 1H), 7.47 (s, 1H), 4.18 (s, 3H). MS m/z: 229 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](O)=O)=[N:15][CH:16]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:15][CH:16]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1ccc(C(=O)O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
11.3 g. of o-phenylenediamine, 15.1 g. of 5-ethylpicolinic acid and 80 g. of polyphosphoric acid were heated at 180°-190° C. under nitrogen gas current for 3 hours with stirring. The reaction mixture was diluted with 1,000 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate to give 17.1 g. of colorless needles of the product (78% of theory). M.P. 172.5°-173.° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC1C=CC=CC=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][N:16]=1>C(O)CO>[N:1]1([C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17][N:16]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nsc2ccccc12
Reactant: C1CNCCN1
Solvent: Clc1ccccc1
Solvent: OCCO
Product: c1ccc2c(N3CCNCC3)nsc2c1
Yield: 92.3 %

Procedure:
215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g of ethylene glycol were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 169.5 g (1.00 mol) of 3-chloro-1,2-benzisothiazole was added dropwise in the melted state at about 120° C. over 1 hour while stirring, which was thereafter stirred for 2 hours to complete the reaction. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 202.4 g (m.p. 89-90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 3-chloro-1,2-benzisothiazole was 92.4%.
Reaction SMILES: [N+](C1C=CC(C=O)=CC=1)([O-])=O.[CH2:12]([O:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)C=Cc1ccc(N)cc1

Procedure:
The above approach could be used to convert 4-nitrobenzaldehyde (Aldrich) into 3-(4-nitrophenyl)propenoic acid ethyl ester. The latter compound could be reduced (J. Am. Chem. Soc., 1944, 66, 1442) to give 3-(4-aminophenyl)propenoic acid ethyl ester. Reaction of (4-aminophenyl)-propenoic acid ethyl ester with an omega-haloalkyl-isocyanate provides an 4-(omega-haloalkylaminocarbonyl)aminophenyl)propenoic acid ethyl ester (see., Khim. Farm. Zh. 1984, 18(12), 1432–1436). The latter compound can be reacted with sodium hydride to give a 4-(1,3-diaza-2-oxoalicyclylphenyl)propenoic acid ethyl ester (see., Bioorg. Med. Chem. Lett. 1999, 9(5), 749–754), the latter compound could be converted to give a 3-(4-(1,3-diaza-2-oxoalicycl-1-yl)phenyl)propenoic acid ethyl ester by the methods described in Bioorg. Med. Chem. Lett. 1999, 9(5), 749–754. The latter compound could be elaborated by methods described previously, to give a 3-(4-(1,3-diaza-2-oxoalicycl-1-yl)phenyl)-3-amino propanoic acid ethyl ester suitable for subsequent coupling.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:30])([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH2:3][CH2:2]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of tert-butyl 4-piperidin-4-ylpiperazine-1-carboxylate (1.5 g, 5.67 mmol), 4-(trifluoromethoxy)bromobenzene (3.36 g, 13.92 mmol), palladium acetate (25 mg, 0.11 mmol), BINAP (87 mg, 0.14 mmol), and sodium tert-butoxide (1.07 g, 11.14 mmol) in toluene (20 ml) was stirred at 80° C. under a nitrogen atmosphere for 8 hours. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (10 ml) and brine (20 ml) were added, and the mixture was filtered. The organic layer was separated, and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford tert-butyl 4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazine-1-carboxylate (1.01 g, 42%) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][S:37]([CH3:36])(=[O:39])=[O:38])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.77 mmol), N,N-diisopropylethylamine (0.79 g, 6.1 mmol), and dichloromethane (10 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (0.41 g, 3.6 mmol). After 1 hour, warm to ambient temperature and dilute the reaction mixture with dichloromethane. Extract with a 1 M aqueous hydrochloric acid solution and three times with saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.58 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH2:3][Mg]Cl.[C:6]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)(=O)[CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][C:6](=[C:9]1[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2)[CH3:7]
Reactant: COC[Mg]Cl
Reactant: CC(=O)C1c2ccccc2CCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(C)=C1c2ccccc2CCc2ccccc21
Reaction time: 1 h

Procedure:
A solution of methoxymethyl magnesiumchloride in dry tetrahydrofuran (prepared from methoxymethyl chloride (16.1 g, 0.2 mol), magnesium turnings (4.8 g, 0.2 mol), mercury chloride (0.25 g) and dry tetrahydrofuran (30 ml)) was cooled on an ice-salt bath to −10° C. A solution of 5-acetyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (21.4 g, 0.09 mol, prepared as described in Belg., 609, 095, 1962) in dry tetrahydrofuran (50 ml) was added drop-wise. When addition was complete the mixture was stirred for 1 h. Saturated ammonium chloride (150 ml) was carefully added and the mixture was extracted with diethyl ether (2×100 ml). The combined extracts were dried (MgSO4) and the solvent was evaporated in vacuo to give a residue which was fractionally distilled. The fraction collected at b.p. 130-140° C./70 Pa was purified by gradient column chromatography on silica gel (80 g) using cyclohexane and then benzene as eluents. The benzene fraction afforded 9.4 g of crude 5-(1-methoxymethylethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[O:22][CH3:31])=[O:14])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2OC)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a suspension of 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide (example 16, 50 mg) in THF (0.5 ml) was added sodium hydride dispersion (60% in mineral oil, 5.4 mg) at 0° C. The mixture was stirred at room temperature for 1 h. Methyl iodide (18.4 mg) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2MeOH 9:1) to give 5-(4-chloro-phenyl)-N-((1R,2R)-2-methoxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide (27 mg) as a colorless oil. MS (ISP) 419.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[S:17][C:18]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:19]=3[N:20]=2)=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[S:17][C:18]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:19]=3[N:20]=2)=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(Nc2nc3cc(F)ccc3s2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)c(Nc2nc3cc(F)ccc3s2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Ethyl (5-chloro-4-(5-fluoro-2-benzothiazolyl)amino-2-fluorophenyl)acetate (298 mg, 0.78 mmol) was dissolved in THF (5 ml). To the resulting solution was added 0.5N NaOH (5.0 ml, 2.50 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured in ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-4-(5-fluoro-2-benzothiazolyl)amino-2-fluorophenyl)acetic acid (237 mg, 86%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:31][C:32]([OH:34])=[O:33])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2C(=O)Nc1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN(c1ccc2c(c1)CCN2C(=O)Nc1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
1.24 g tert.butyl [(3,5-dichloro-phenylsulphonyl)-(1-phenylcarbamoyl-2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 5 ml of trifluoroacetic acid is added with stirring. The mixture is stirred for 2 hours at ambient temperature and then the solvents are eliminated in vacuo. The residue is extracted from diisopropylether and cyclohexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.C1CCN2C(=NCCC2)CC1>CO>[CH3:1][O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC(=O)c1cc2ccc(CO)cc2s1
Reaction time: 48 h

Procedure:
A solution of 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (9.45 g, 40.0 mmol) and DBU (6.00 mL, 40.1 mmol) in anhydrous MeOH (200 mL) was allowed to stir for 2 d. After concentration, the residue was dissolved in EtOAc (800 mL) and washed with 1N HCl, water, saturated NaHCO3 and brine. The organic layer was dried, filtered and the filtrate was concentrated and dried to give 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid methyl ester as off white solid. 1H NMR (CDCl3, 200 MHz) δ 8.03 (d, J=0.6 Hz, 1H), 7.90-7.80 (m, 2H), 7.39 (dd, J=8.0, 1.4 Hz, 1H), 4.83 (s, 2H), 3.94 (s, 3H), 1.98 (brs, 1H). MS (EI): cal'd 223.0 (MH+), exp 223.1 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[OH:12].[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[C:27]([CH3:35])=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].[Cl-].[NH4+]>CN(C)C=O>[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:12][C:5]4[CH:6]=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:4]=4[F:3])=[C:28]3[C:27]([CH3:35])=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14]
Reactant: Cc1nn(C2CCN(C(=O)OC(C)C)CC2)c2ncnc(Cl)c12
Reactant: Oc1cc(F)c(F)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nn(C2CCN(C(=O)OC(C)C)CC2)c2ncnc(Oc3cc(F)c(F)cc3F)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 7 mg, 0.18 mmol) was added to a solution of 2,4,5-trifluorophenol (18 mg, 0.12 mmol) in dimethylformamide (1 mL) and the mixture was stirred at room temperature for 15 min. A solution of 4-(4-chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid isopropyl ester (Intermediate 21; 40 mg, 0.12 mmol) in dimethylformamide (1 mL) was added, and the reaction mixture was heated at 100° C. for 2 h. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layer was washed with water (3 times) and brine, dried (sodium sulfate), filtered, evaporated and purified on a flash silica column (20 mm×3″) eluting with 25-33% ethyl acetate/hexanes to give 4-[3-methyl-4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (37 mg, 70%) as a white foam. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.93-2.02 (m, 4H), 2.62 (s, 3H), 2.96-3.09 (m, 2H), 3.32 (s, 3H), 4.04-4.12 (m, 2H), 4.74-4.83 (m, 1H), 4.89-4.96 (m, 1H), 7.81-7.90 (m, 2H), 8.48 (s, 1H). Mass spectrum (ES) MH+=450.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>O1CCCC1>[F:31][C:9]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[N:6][O:7][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COCOc1cc(-c2ccccc2)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1noc(-c2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
3-Methoxymethoxy-5-phenylisoxazole (2.05 g) was dissolved in anhydrous tetrahydrofuran (30 ml), and the solution was cooled to -78° C. Butyllithium (1.68M hexane solution, 7.1 ml) was added dropwise thereto, and the resulting mixture was stirred at the same temperature for 15 minutes. Then, N-fluorobenzenesulfonimide (3.15 g) was added to the reaction mixture, followed by stirring of the resulting mixture at the same temperature for 15 minutes. The cooling bath was removed and the temperature of the resulting mixture was raised to room temperature. The reaction mixture was poured into ice-cold water (200 ml) and extracted with ether (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (1.78 g, 80%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=1.C[O:24][C:25]([C:27]1[S:28][C:29]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[CH:30][C:31]=1[N:32]=[CH:33]N(C)C)=O>>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:29]2[S:28][C:27]3[C:25](=[O:24])[N:1]([CH2:2][C:3]4[N:8]=[C:7]([O:9][CH:10]5[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]5)[CH:6]=[CH:5][CH:4]=4)[CH:33]=[N:32][C:31]=3[CH:30]=2)=[CH:42][CH:41]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CN)n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1

Procedure:
Prepared from tert-butyl 4-{[6-(aminomethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (629 mg, 2.05 mmol) and 5-(4-chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (662 mg, 2.05 mmol) according to the procedure in Example 14c. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 10-100% EtOAc in heptane yielded the title compound as a colorless solid. Yield: 679 mg (60%). 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.60 (m, 2H), 7.53 (t, 1H, J=7.7 Hz), 7.46 (s, 1H), 7.39 (m, 2H), 6.95 (d, 1H, J=7.2 Hz), 6.60 (d, 1H, J=8.2 Hz), 5.18 (s, 2H), 4.96 (m, 1H), 3.66 (m, 2H), 3.09 (m, 2H), 1.78 (m, 2H), 1.56 (m, 2H), 1.41 (s, 9H).