Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19](C)(C)C)[C:9]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:8]=2[N:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[C:28]([C:26]1[CH:25]=[CH:24][C:9]2[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:23])[CH3:19])[C:6]([CH2:5][OH:4])=[N:7][C:8]=2[CH:27]=1)#[N:29]
Reactant: CC(=O)OCc1nc2cc(C#N)ccc2n1CCCCCCOC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCCCn1c(CO)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 2,2-Dimethyl-propionic acid 6-(2-acetoxymethyl-5-cyano-benzoimidazol-1-yl)-hexyl ester (7.2 g, 18 mmol) and K2CO3 (14 g, 101 mmol) in MeOH (100 mL) was stirred at the ambient temperature for 4 h. The nixture was diluted with EtOAc (100 mL) and filtered. The filtrate was evaporated. The residue was dissolved in EtOAc (300 mL) and washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was left for 2 weeks before being purified by flash chromatography (hexanes:acetone 1:1) to give 4.1 g (72%) of acetic acid 6-(5-cyano-2-hydroxymethyl-benzoimidazol-1-yl)-hexyl ester as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:41]>>[CH2:21]([CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:41])[CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1ccc(F)c(C)c1)CCNCC2
Yield: 87.3 %

Procedure:
The title compound (34 mg) was prepared according to Example 183 using 59 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 19 mg of 4-fluoro-3-methylphenylboronic acid. MS (ESI): exact mass calculated for C19H26FN3, 315.21. found, m/z 316.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.27-7.18 (m, 3H), 4.69-4.65 (m, 1H), 3.93-3.89 (m, 1H), 3.50-3.27 (m, 5H), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.87 (m, 2H), 1.83-1.76 (m, 2H), 0.81-0.68 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]4[NH:28][N:27]=[N:26][N:17]=4)[CH:14]=3)=[CH:12][C:3]1=2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Agent: CCCC[Sn](=O)CCCC
Solvent: C1COCCO1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc21
Yield: 25.6 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3]oxazin-6-yl)benzonitrile (0.77 g, 2.8 mmol), trimethylsilyl azide (0.68 g, 5.6 mmol), and dibutyl tin oxide (0.071 g, 0.28 mmol) in dioxane (20 mL) was heated at reflux under a blanket of nitrogen. Upon completion of the reaction, the dioxane was removed, the organics taken up in ethyl acetate (100 mL), and washed with NaHCO3 (100 mL). The aqueous layer was acidified with 1 N aqueous HCl and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO4, and concentrated. Crystallization from ether (20 mL) gave 4,4-dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]-oxazin-2-one as a light yellow solid (0.23 g, 26%): mp 238-240° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 8.3 (bs, 1H), 8.02 (d, 1H, J=7.66 Hz), 7.9 (d, 1H, J=7.91 Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, J=8.75 Hz), 1.70 (s, 6H); MS (ESI) m/z 320 ([M−H]−, 100%); Anal. Calc. For C17H15N5O2: C, 63.54; H, 4.71; N, 21.79. Found: C, 62.16; H, 4.67; N, 21.31.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:26][CH3:27])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[C:15]([CH3:25])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:28].[F-].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][CH3:12])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[C:15]([CH3:25])[CH:14]=2)[CH2:26][CH3:27])=[CH:6][C:5]=1[CH3:28]
Reactant: CCC(CC)(c1ccc(C#C[Si](C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C
Yield: 98.7 %

Procedure:
To an ambient temperature suspension of 4-[1-Ethyl-1-(3-methyl-4-trimethylsilanylethynyl-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (6.8 g, 16.72 mmol) in acetonitrile/water (180/30 ml) is added cesium fluoride (25.4 g, 167.2 mmol) and stirred for 3d. The reaction mixture is concentrated and partitioned between EtOAc (500 ml) and 1N HCl (200 ml). The aqueous phase is extracted with a second portion of EtOAc (200 ml) and the combined organic phases are washed with brine (200 ml), dried (MgSO4), concentrated and chromatographed (330 g SiO2, 1% EtOAc/Hexanes) to yield the title compound (5.52 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[CH2:19][CH:18]([CH2:20][O:21]C(=O)C)[O:17][C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28].C[O-].[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[CH2:19][CH:18]([CH2:20][OH:21])[O:17][C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28]
Reactant: CC(=O)OCC1Cn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C1OC(CO)Cn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione (46 mg, 0.10 mmol) and 30% sodium methoxide in methanol (39 mg) in dioxane (1.5 mL) was stirred at room temperature for 2 hours. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and Iyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][CH2:13][CH2:14]Cl)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][CH2:13][CH2:14][NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[CH3:11]
Reactant: COc1ccccc1N
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCNc1ccccc1OC
Yield: 40.2 %

Procedure:
A suspension of 12.3 g (100 mmol) o-anisidine M10, 11.9 g (110 mmol) chloroethyl ethyl ether M14, 15.2 g (110 mmol) K2CO3 and 9.1 g (55 mmol) KI in 55 ml DMF was heated at 95° C. for 18 hours. DMF was evaporated and the residue was dissolved in 100 ml CHCl3 and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 19.4 g crude oil. The crude oil was purified with a plug packed with 84 g silica gel 100 with CHCl3/cyclohexane (1:1, v/v) as eluant to afford 7.85 g pure product (yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tert-butyl 4-(4-chlorophenylamino)piperidine-1-carboxylate (2.67 g, 8.59 mmol) prepared in Reference Example 131 was dissolved in methylene chloride (20 ml), to which trifluoroacetic acid (15 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. This solution was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 4-(4-chlorophenylamino)piperidine as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)#[N:18].[OH-].[Na+].O>C1(C)C(C)=CC=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:26]2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 25 °C

Procedure:
38.5 ml of a 0.17 M solution of ethyl 4-chloroquinoline-3-carboxylate in xylene, and 0.96 g of p-cyanophenylhydrazine in 30 ml of xylene are mixed and heated at 115° to 120° for 3 hours. The mixture is then cooled to room temperature, and stirred with 20 ml of 1 N aqueous sodium hydroxide and sufficient water to dissolve all solids. The aqueous layer is separated, washed twice with diethyl ether, then treated with an aqueous solution of 1.07 g ammonium chloride, and the resulting precipitate is collected, washed with water and dried to yield the 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 885, 830, 780, 755 and 730 cm-1.
Reaction SMILES: [CH:1]1([S:6][C:7]2[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17]>CC#N>[Cl:17][CH2:13][C:12]1[C:7]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1SC1CCCC1
Solvent: CC#N
Product: ClCc1cccnc1SC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Cyclopentylsulfanyl-pyridin-3-yl)-methanol (0.6 g, 2.87 mmol) obtained in Step B was dissolved in CH3CN (5 mL), and SOCl2(0.42 mL, 5.74 mmol) was added thereto at 0° C. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:41][C:42]1[C:47]([Cl:48])=[CH:46][CH:45]=[CH:44][C:43]=1[N:49]=[C:50]=[O:51]>C1COCC1>[Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:50]([NH:49][C:43]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:48])[C:42]=3[Cl:41])=[O:51])[CH:15]=2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of 3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxy-N-(3-((isobutyl amino)methyl)benzyl)benzene sulfonamide (Compound E of Example 184, 0.04 g, 0.0667 wool, 1.0 eq) in 25 mL of dry THF at 0° C. was added 2,3-dichlorophenyl isocyanate (0.012 g, 0.0667 mmol, 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 min and concentrated. The residue was purified by preparative HPLC to afford the title compound (0.02 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ 0.85-0.87 (d, 6H), 2.0 (m, 1H), 3.09-3.11 (d, 2H), 4.44-4.46 (m, 3H), 4.49 (s, 4H), 7.03-7.05 (d, 2H), 7.13-7.15 (d, 3H), 7.21-7.29 (m, 4H), 7.33-7.35 (m, 1H), 7.43-7.45 (d, 2H), 7.56-7.62 (m, 4H), 7.80 (s, 1H), 8.00 (s, 1H). MS (EP: 788.0 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]=O)=[C:7]([O:15][CH3:16])[N:6]=1.[CH3:17][C:18]([CH3:20])=[O:19]>O>[CH3:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]=[CH:17][C:18](=[O:19])[CH3:20])=[C:7]([O:15][CH3:16])[N:6]=1
Reactant: COc1nc(OC)c(C=O)c(OC)n1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1nc(OC)c(C=CC(C)=O)c(OC)n1

Procedure:
An aqueous solution of 2% sodium hydroxide (15 ml) was added to a stirred suspension of 2,4,6-trimethoxypyrimidine-5-carboxaldehyde (8 g) in acetone (15 ml) and water (15 ml). The mixture was stirred and refluxed for 4 hours, a precipitate slowly forming during this period. The suspension was diluted with water (100 ml) and extracted with chloroform (2×100 ml). The organic layer was washed with water, dried over magnesium sulphate and the solvent was removed by evaporation under reduced pressure to give 1-(2,4,6-trimethoxy-5-pyrimidyl)but-1-en-3-one as a pale yellow solid (8.0 g), mp 98°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=399.1, tR (minutes, Method G)=2.61
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:11][S:12]([O-])(=[O:14])=[O:13]>C(Cl)(Cl)Cl>[Cl:11][S:12]([C:5]1[C:6]2[C:7](=[N:8][O:9][N:10]=2)[C:2]([F:1])=[CH:3][CH:4]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)([O-])Cl
Reactant: Fc1cccc2nonc12
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(F)c2nonc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.0 g of 7-fluoro-2,1,3-benzoxadiazole were dissolved in 10 ml of chloroform and then 11.0 ml of chlorosulfonate at 0° C. were dripped into the solution. After reacting at room temperature for one hour, the solution was stirred and reacted for an additional two hours. Next, the reaction solution was transferred to 200 g of ice water, and extracted with chloroform very quickly. The extract was then water washed and dried with magnesium sulfate before filtering. The filtrate was then reduced pressure concentrated. The remaining extract was subjected to silica gel column chromatography (chloroform as mobile phase; 2 cm×60 cm) in 5 ml fractions. The respective fractions were analyzed using thin layer chromatography (silica gel, chloroform). The fraction having an Rf value of about 0.5 was then collected and reduced pressure concentrated. 4.0 g of a pale brown needle-shaped crystalline substance with a melting point of between 64° and 66° C. were obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C@H:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C>[C@H:31]1([NH:41][C:6]([C:3]2[CH2:2][O:1][CH2:5][CH:4]=2)=[O:8])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccoc1
Reactant: N[C@@H]1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCc2ccccc21)C1=CCOC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.78 mmol) and EDCI.HCl (196 mg, 1.03 mmol) in CH2Cl2 (8 mL) and DMF (1.5 mL) at 0° C., was added (R)-1,2,3,4-tetrahydronaphthalen-1-amine (160 μL, 1.06 mmol). The reaction was stirred at rt for 24 h, after which CH2Cl2 was added. The resulting solution was washed with saturated NaHCO3, H2O, brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOH/H2O afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,5-dihydrofuran-3-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J=7.75 Hz), 6.59 (dd, 1H, J=1.90, 0.86 Hz), 7.13 (m, 1H), 7.19 (m, 2H), 7.32 (m, 1H), 7.43 (t, 1H, J=1.73 Hz), 7.93 (m, 1H). MS (M+H, 242).
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[Br:18])(=O)C>CO.O>[Br:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][OH:6]
Reactant: CC(=O)OCc1ccc2ccccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Potassium hydroxide (25.3 g, 0.45 mol) was added to a solution of 1-bromo-2-naphthalenemethanol acetate (105 g, 0.38 mol) in methanol (300 mL) at room temperature. The resulting yellow solution was stirred at room temperature for 3 hours, then diluted with water and a precipitate was formed. The mixture was extracted with ether (2×300 mL), and the combined organic layers were washed with water (250 mL), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The pure product was obtained as a light yellow solid (86.8 g, 96%).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-:18])(=O)=O)=CC=1.[C:20]([O:25][CH3:26])(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>O1CCCC1>[CH3:23][C:22]1[C:21]([C:20]([O:25][CH3:26])=[O:24])=[CH:16][NH:17][CH:18]=1
Reactant: C/C=C/C(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1C
Yield: 42 %

Procedure:
To a solution (100 mL) of potassium t-butoxide (23.0 g) in tetrahydrofuran was added dropwise a solution (50 mL) of p-toluenesulfonylmethyl isocyanide (25.0 g) and methyl crotonate (12.3 mL) in tetrahydrofuran with stirring under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (7.6 g, 42%) as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:14]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3 hydroxy 4-(p-toluenesulfonyloxy)butylamine hydrochloride (8.8 g) in methanol 90 ml), sodium carbonate (3.3 g) was added and the mixture was stirred at room temperature for 8 hours. Then, the mixture was filtered, and the filtrate was evaporated under reduced pressure to obtain crude 3 pyrrolidinol. One tenth of the crude 3-pyrrolidinol was dissolved in methylene chloride. To the solution, triethylamine (432 μl ) was added, and after cooling to 0° C., benzoyl chloride (360 μl ) was added. After stirring for 2 hours, the mixture was evaporated under reduced pressure and purified by silica gel column chromatography (Wako Gel C200, an eluent: ethyl acetate/methanol (volume ratio of 95/5) to obtain pure N-benzoyl-3-pyrrolidinol (438 mg). Yield, 85 %.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:28]4[C:29]([CH3:31])=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Product: Cc1nc(Cl)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 19 %

Procedure:
4-[4-(6-Chloro-2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared in 19% yield as a white powder using Method A described for the preparation of Example 92 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 6-chloro-2-methyl-pyridin-3-ol (Intermediate 3; 28 mg, 0.19 mmol). 1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 1.96-2.06 (m, 2H), 2.20-2.35 (m, 2H), 2.42 (s, 3H), 2.92-3.05 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.02 (m, 1H), 7.27-7.30 (m, 1H), 7.48 (d, 1H, J=8.4 Hz), 8.15 (s, 1H), 8.47 (s, 1H). Mass spectrum (ES) MH+=445. HRMS Calcd. for C21H26ClN6O3 (MH+): 445.1750. Found: 445.1750.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](Cl)=[O:19])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18]([NH:1][C:2]1[C:7]([S:8](=[O:9])(=[O:10])[NH2:11])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1)=[O:19])[CH3:14]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ncc(Br)cc1S(N)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)Nc1ncc(Br)cc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
2-Amino-5-bromo-pyridine-3-sulfonic acid amide (2.5 g, 9.9 mmol) was dissolved in 1,4-dioxane (50 mL). Chlorocarbonyl-acetic acid ethyl ester (1.9 mL, 14.85 mmol) was added and the mixture was heated at 90° C. while stirring for 2 h. Upon cooling to 25° C., the mixture was poured into half-saturated aqueous sodium bicarbonate solution (250 mL). A solid precipitated and was collected by vacuum filtration, rinsed with water (50 mL) and dried in vacuo to afford the desired product, N-(5-bromo-3-sulfamoyl-pyridin-2-yl)-malonamic acid ethyl ester (2.5 g, 6.82 mmol, 69%), as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (3H, t, J=7.0 Hz), 3.67 (2H, s), 4.10 (2H, q, J=7.3 Hz), 7.78 (2H, bs), 8.33 (1H, d, J=2.3 Hz), 8.70 (1H, d, J=2.4 Hz), 9.85 (1H, bs).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>[OH-].[Na+]>[CH2:17]([O:16][C:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (122.56 mmol) of 2(S)-indolinecarboxylic acid in 2N NaOH (62 ml) is cooled in an ice/water bath and the solution is stirred using a powerful magnetic stirrer. 20.0 ml (140.09 mmol) of benzyl chloroformate and 68 ml of 2N NaOH are added thereto alternately in about 10 portions over 60 minutes. The temperature of the reaction mixture is maintained between 0° and 5° C. by controlling the rate of addition of the reactants. 50 ml of NaOH are then added and the mixture is maintained at room temperature for 30 minutes. The alkaline solution is washed with ether (4×150 ml) and is then acidified by addition of 5N HCl (80 ml, pH<2). A crystalline mass precipitates after leaving overnight at room temperature. It is filtered off and washed with distilled water (500 ml). After drying over P2O5, the desired product is obtained.