Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[CH2:9](Br)[CH:10]=C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8])[CH:9]=[CH2:10]
Reactant: C=CCBr
Reactant: CN1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-methyl-2-pyrrolidinemethanol (5.10 g, 50 mmol, Aldrich Chemical Co.) was dissolved in 50 mL of CHCl3, then 5.25 mL of allyl bromide and 8.34 mL of triethylamine were added. The reaction mixture was stirred at room temperature for 2 hours, then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel to give 63 g of the title product. MS (DCI/NH3) m/e: 142 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 6.05-5.90 (m, 1H), 5.33-5.17 (m, 2H), 3.77-3.68 (m, 1H), 3.58-3.47 (m, 2H), 3.32-3.20 (m, 1H), 3.16-3.05 (m, 1H), 2.90-2.78 (m, 1H), 2.53-2.40 (m, 1H), 2.02-1.73 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17]Cl)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17][O:34][C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)CCl)cs1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)COc2ccc(-c3ccc(Cl)cc3)cc2)cs1
Yield: 17.1 %

Procedure:
By an operation similar to that in Example 2-1 and using 2-{[4-(chloroacetyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (561 mg) obtained in Example 1 and 4′-chlorobiphenyl-4-ol (307 mg), 2-[(4-{[(4′-chlorobiphenyl-4-yl)oxy]acetyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (129 mg) was obtained. Furthermore, by operations similar to those in Example 2-2 and 2-3, the title compound (36 mg) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:13][C:12]([F:14])([F:15])[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: -80 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
3-Methoxy-5-nitrobenzotrifluoride (5 g, 23 mmol) was dissolved in anhydrous methylene chloride (100 mL) and cooled to -80° C. under a nitrogen atmosphere. To this solution was added via dropping funnel a 1M solution of BBr3 in methylene chloride (68 mL, 68 mmol). This solution was allowed to warm to room temperature and stirred for 3 days. Water was slowly added to the mixture and mixed well to quench the excess BBr3. To this mixture ether (500 mL) was added. The organic layer was separated and extracted with 2N NaOH (240 mL). The alkaline extract was neutralized with dilute HCl and extracted with diethyl ether (3×300 mL). The ether extracts were combined, washed with saturated NaCl and dried over anhydrous MgSO4. Evaporation of diethyl ether gave a brownish yellow oil which was chromatographed on a silica column to give 1.6 g (34%) of a yellow solid. 1H-NMR (CDCl3 /CD3OD; 300 MHz) δ 7.38-7.40 (m, 1H), 7.82 (t, 1H, J=2.2 Hz), and 7.95-7.96 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>C1COCC1>[CH:7]1([N:5]2[CH:6]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[N:4]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1cnn(C2CCCC2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnn(C2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of 4-bromo-1-cyclopentyl-1H-pyrazole (9.0 g, 42 mmol) in THF (100 mL) at −78° C. under nitrogen was added a solution of n-BuLi in hexanes (2.5 M, 18.5 mL, 46.2 mmol). The resulting mixture was stirred at −78° C. for 30 min. Dry-ice (solid CO2) was added at −78° C. and the reaction mixture was allowed to slowly warn to RT overnight. The solvent was removed under reduced pressure. Water was added, and the mixture was acidified (pH 3) by the addition of aq. HCl. The aqueous layer was extracted with EtOAc, and the extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized (EtOAc-petroleum ether) to provide 1-cyclopentyl-1H-pyrazole-4-carboxylic acid (3.5 g, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.50 (br s, 1 H), 8.31 (s, 1 H), 7.85 (s, 1 H), 4.78 (m, 1 H), 2.16-1.68 (m, 8 H); MS (ESI) m/z: 181.0 [M+H]+.
Reaction SMILES: C([O:8][C:9]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)=[O:10])C1C=CC=CC=1>[Pd].CO.O1CCCC1>[C:9]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)([OH:10])=[O:8]
Reactant: COC(=O)c1ccc(OCC(=O)OCc2ccccc2)c(-n2cccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OCC(=O)O)c(-n2cccc2)c1
Yield: 60 %

Procedure:
10% Palladium on carbon (0.5 g) was added to a solution of methyl 4-benzyloxycarbonylmethoxy3-(pyrrol-1-yl)benzoate (5.0 g) in methanol (50 ml) and tetrahydrofuran (20 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and filtrate was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 8 with potassium carbonate. The separated aqueous layer was adjusted to pH 2 with 6N-hydrochloric acid and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 4-carboxymethoxy3-(pyrrol-1-yl)benzoate (2.26 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:18])(=[O:3])[CH3:2].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36]N=C([O-])C(Cl)(Cl)Cl)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:36][CH2:35][C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[C:6]1=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Reactant: COc1ccc(CCN=C([O-])C(Cl)(Cl)Cl)cc1OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
To a chilled (0° C.) solution of (3R)-1-((1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-yl acetate (15.0 g, 58.7 mmol) in anhydrous dichloromethane (100 mL) was added tetrafluoroboric acid diethyl ether complex (3.2 mL). The resultant reaction mixture was stirred at 0° C. for 20 minutes before adding a solution of 2-(3-benzyloxy-4-methoxy-phenyl)-ethyl-2,2,2-trichloroacetimidate (24.8 g, 61.6 mmol, 1.05 equiv.) in dichloromethane (100 mL) via an addition funnel over 30 minutes. The reaction mixture was stirred at 0° C. until the reaction was judged complete by HPLC analysis. The reaction mixture was quenched with water (250 mL). The organic layer was separated from the aqueous layer and subsequently washed with dilute NaHCO3 (5% wt solution, 2×100 mL), and water (5×100 mL). The organic layer was dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to ˜100 mL solution. The solution was cooled at −20° C. for 24 hours and the precipitate (trichloroacetamide) was removed by filtration. The filtrate was further concentrated to a volume of ˜40 mL. This process was repeated three times until the bulk of the by-product (trichloroacetamide) was removed. After the third filtration, the filtrate was concentrated in vacuo to give (1R,2R)-1-{2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-yl acetate as a pale yellow syrup (25 g, 86% yield).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13]#[N:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:17][CH2:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>>[CH3:20][N:19]1[CH2:21][CH2:22][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH:9]=2)([C:13]#[N:14])[CH2:17][CH2:18]1
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1csc(-c2ccccc2)n1
Agent: Cl
Product: CN1CCC(C#N)(c2csc(-c3ccccc3)n2)CC1
Yield: 25 %

Procedure:
This compound was synthesized from (2-phenyl-thiazol-4-yl)-acetonitrile and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 step 1b (135 mg, yield 25%). 1H NMR (300 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.45-7.43 (m, 3H), 7.30 (s, 1H), 3.00-2.96 (m, 2H), 2.53-2.40 (m, 7H), 2.25-2.20 (m, 2H). MS (ESI) m/z: Calculated for C16H17N3S: 283.11. found: 284.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14](=O)[CH3:15])=[CH:9][CH:10]=2)[CH:5]=1)(=O)[CH3:2].[NH2:17][C:18]1[C:19]([CH:28]=O)=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2.[OH-].[K+]>C(O)C>[N:17]1[C:18]2[C:19](=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:28]=[CH:2][C:1]=1[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[CH:15]=[CH:28][C:19]4[C:18](=[C:27]5[C:22](=[CH:21][CH:20]=4)[CH:23]=[CH:24][CH:25]=[N:26]5)[N:17]=3)=[CH:9][CH:10]=2)[CH:5]=1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: CC(=O)c1ccc2ccc(C(C)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1cnc2c(c1)ccc1ccc(-c3ccc4ccc(-c5ccc6ccc7cccnc7c6n5)cc4c3)nc12
Yield: 42.1 %

Procedure:
54.0 g of 2,7-dihydroxynaphthalene was dissolved in a mixture of 680 ml of dichloromethane and 136 ml of pyridine, and to this, 228 g of trifluoromethanesulfonic anhydride (produced by TOKYO CHEMICAL INDUSTRY CO., LTD.) was added dropwise at 0° C. After the resulting mixture was reacted at 5° C. for 2 hours and then at room temperature for one day, a reactant was treated by a normal method to obtain 143 g of 2,7-bis(trifluoromethane sulfonyloxy)naphthalene. 143 g of this 2,7-bis(trifluoromethane sulfonyloxy)naphthalene was mixed with 216 ml of n-butyl vinyl ether, 113 ml of triethylamine, 2.78 g of 1,3-bis(diphenylphosphino)propane, 0.76 g of palladium acetate and 680 ml of dimethylformamide and the resulting mixture was reacted at 70 to 85° C. for two days. The reactant was treated by a normal method to obtain 40 g of 2,7-diacetylnaphthalene. 4.62 g of this 2,7-diacetylnaphthalene was reacted with 7.87 g of 8-amino-7-quinoline carboaldehyde and 7.9 g of potassium hydroxide in 220 ml of ethanol at 60° C. and a reactant was treated by a normal method to obtain 4.44 g of 2,7-di(1,10-phenanthroline-2-yl)naphthalene. 5.48 g of this 2,7-di(1,10-phenanthroline-2-yl)naphthalene was reacted with 22.6 ml of phenyl lithium (2.0 M cyclohexane-ether solution) in 200 ml of toluene at room temperature for 2 days and a reactant was treated by a normal method. The obtained product was reacted with 100 g of manganese dioxide in 400 ml of dichloromethane at room temperature for 2.5 hours and a reactant was treated by a normal method to obtain 0.93 g of E-57.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][CH:22]=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17][CH2:22][CH2:21][Cl:20])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: O=CCCl
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Solvent: ClCCl
Product: ClCCN[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of (trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropanamine (4.2 g, 13.24 mmol) in DCM (42 mL) 4° A molecular sieves was added followed by chloroacetaldehyde (1.0 g, 13.24 mmol), stirred at RT for 1 h. After completion of reaction, monitored by TLC, the reaction mixture was cooled to −10° C. and Na(CN)BH3 (0.99 mg, 15.88 mmol) was added and stirred at RT for 2 h. After completion, the reaction mixture was quenched with NH4Cl (5%) and filtered through a pad of celite. The filtrate was extracted with DCM (2×150 mL) combined extracts were washed with water (50 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography by using EtOAc: Pet ether to get (trans)-2-(4-(4-bromobenzyloxy)phenyl)-N-(2-chloroethyl)cyclopropanamine (4 g, 80%)
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[CH:26]1([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH:26]1([N:29]2[CH2:34][CH2:33][CH:32]([NH:21][C:17]3[C:18]([NH2:20])=[N:19][C:14]([C:7]4[C:8]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[N:5]([CH2:4][C:3]5[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=5[F:1])[N:6]=4)=[N:15][CH:16]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C1CCN(C2CC2)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 182 mg (1.312 mmol) of 1-cyclopropyl-4-piperidinone were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-cyclopropyl-4-piperidinone, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added and the mixture was stirred vigorously for 10 min. Subsequently, the mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 165 mg of the title compound were obtained (60% of theory).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]=1[CH3:32])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:11]2[NH:12][C:13]3[C:18]([C:9](=[O:8])[C:10]=2[CH3:32])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:30][CH:29]=1
Reactant: Cc1c(C=CCCCOc2ccc(F)cc2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CCCCCOc2ccc(F)cc2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
4-(Benzyloxy)-2-[5-(4-fluorophenoxy)pent-1-en-1-yl]-3-methylquinoline (E/Z mixture, 810 mg) was dissolved in ethanol-THF (1:1, 20 mL), and 10% palladium-activated carbon (200 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2-[5-(4-fluorophenoxy)pentyl]-3-methylquinolin-4(1H)-one (572 mg).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:29]1(C(OC(C)(C)C)=O)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[N:7]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCNCC5)n4)n[nH]c3cn2)cn1
Yield: 61 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 1-piperazinecarboxylate were reacted. The product was deprotected to give 234 as a white solid (61% over two steps). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 3.63 (s, 4H), 2.94 (s, 4H); two protons not seen. LC/MS: m/z 361.1 [M+1]
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of 54 g (0.5 mol) of benzyl alcohol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methanesulfonyl chloride. The temperature of the reaction mixture during the addition is ca. 10°. The reaction mixture is then stirred for 1.5 hours at 10°. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% HCl, saturated KHCO3, saturated NaCl and dried (MgSO4). Solvent is removed in vacuo to yield the benzyl methanesulfonate as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53](Cl)=[O:54].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=3)=[O:54])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added pyridine-2-carbonyl chloride (0.089 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 708 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:48])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(SCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(S(=O)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[[1-[3-methoxy4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]benzoate (264 mg, 0.482 mmol) in CH2Cl2 (5.2 mL) was added m-CPBA (118.8 mg, 0.482 mmol) at 0° C., and the mixture was stirred at room temp for 1 hr. The mixture was diluted with CHCl3, and quenched with sat. Na2S2O3. The separated organic layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2 pyrrolidinyl]methylsulfinyl]benzoate as a crude amorphous solid. To a stirred solution of this crude compound in THF (4 mL) and H2O (1mL) was added LiOH (34.6 mg, 1.45 mmol), and the stirring was continued overnight at room temp. The mixture was diluted with CHCl3, washed with 1 N HCl, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-CHCl3-MeOH to afford 193.2 mg (73%) 24 as a white crystalline powder. IR (KBr) 3338, 2956, 1708, 1529, 1299, 1207, 1155 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.70–2.06 (m, 4H), 2.24 (s, 3H), 2.90 (dd, J=8.3, 13.2 Hz, 1H), 3.02–3.08 (m, 1H), 3.16–3.25 (m, 1H), 3.41–3.60 (m, 3H), 3.84 (s, 3H), 4.40 (br s, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.94 (d, J=7.3 Hz, 1H), 7.11–7.17 (m, 2H), 7.75–7.81 (m, 3H), 7.98–8.05 (m, 1H), 8.10 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.56 (s, 1H); MS (FAB) m/z 550 (M++1), 572 (M++Na); Anal. Calcd for C29H31N3O6S.3/2H2O: C, 60.40; H, 5.94; N. 7.29. Found: C, 60.15; H, 5.82; N, 6.90.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@H:21]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@H:20]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C@@H:19]([CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[O:18][C:9]1([OH:17])[CH2:10][P:11]([O:15][CH3:16])([O:13][CH3:14])=[O:12].[BH4-].[Na+]>C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([C@H:21]([C@@H:20]([C@@H:19]([CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[OH:18])[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[C@@H:9]([OH:17])[CH2:10][P:11]([O:13][CH3:14])([O:15][CH3:16])=[O:12]
Reactant: COP(=O)(CC1(O)O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: COP(=O)(C[C@H](O)[C@H](OC1CCCCO1)[C@@H](OC1CCCCO1)[C@H](OC1CCCCO1)[C@H](O)COC1CCCCO1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 3,4,5,7-tetra-O-(tetrahydropyranyl)-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (26.6 g) in diethyl ether (300 ml) was added sodium borohydride (3.0 g). The mixture was stirred overnight at room temperature. Insolubles were filtered off and washed with diethyl ether. The filtrate and the washings were combined, washed with 10%(W/V) sodium chloride solution, and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was chromatographed on a column of silica gel (1 l) with tolueneacetone (1:1). The eluate was concentrated under reduced pressure and dried under reduced pressure to give a mixture (18.8 g) of 3,4,5,7-tetra-O-(tetrahydropyranyl)-1-deoxy-1-(dimethoxyphosphoryl)-D-glycero-D-gulo-heptitol and 1,3,4,5-tetra-O-(tetrahydropyranyl)-7-deoxy-7-(dimethoxyphosphoryl-D-glycero-L-gulo-heptitol.