Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCNCC1)C(F)(F)F

Procedure:
Using 4 g of 10% palladium-on-carbon (50% hydrous) as a catalyst, 11.431 g (39.927 mM) of N-(1-benzyl-piperidin-4-yl)trifluoroacetamide was hydrogenated in 100 ml of methanol at room temperature and atmospheric pressure until the starting compound had disappeared (i.e. for 2 hours). The catalyst in the reaction mixture was filtered off with the aid of celite and washed with methanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure to provide crude N-(piperidin-4-yl)trifluoroacetamide. This crude product was not purified but used as it was in the next reaction. To a solution of the crude N-(piperidin-4-yl)trifluoroacetamide and 6.68 ml (47.9 mM) of triethylamine in tetrahydrofuran (50 ml)-methanol (20 ml) was added 9.59 g (43.9 mM) of di-tert-butyl dicarbonate dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to provide the title compound.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:18]1[C:19](C2C=CC=CC=2)=[C:20]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=2C2C=CC=CC=2)[CH:21]=[CH:22][CH:23]=1>CN1CCCC1=O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([S:14][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([S:24][C:20]4[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=4)[CH:30]=3)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccc(Sc2cccc(Cl)c2-c2ccccc2)c1-c1ccccc1
Reactant: Sc1cccc(Sc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: c1ccc(Sc2cccc(Sc3cccc(Sc4ccccc4)c3)c2)cc1
Temperature: 210 °C

Procedure:
436 g of m-phenylmercapto thiophenol and 78 g of potassium hydroxide were dissolved in 500 ml of N-methyl-2-pyrrolidone, then 376 g of m-chlorophenyl phenylsulfide was added and the resultant mixture was heated to 170° C. After removing the water content, 20 g of cuprous chloride was added and heated to 210° C. and maintained at that temperature for 10 hours while stirring. After the reaction was over, the reaction product was treated by the same procedures as in Example Z-1 and bis(m-phenylmercaptophenyl)sulfide was obtained as a fraction at 255° C.-265° C./5 Torr by vacuum distillation. The product was referred as a comparative oil B and subjected to performance evaluation described above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](Cl)=[S:16])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:16])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: S=C(Cl)N(Cc1ccc(Br)cc1)C1CCCC1
Product: S=C(Nc1ccccc1)N(Cc1ccc(Br)cc1)C1CCCC1
Yield: 0.8 %

Procedure:
Analogously to Example 3, 19 grams (0.2 mole) of aniline were reacted with 34 grams (0.1 mole) of N-4-bromobenzyl-N-cyclopentylthiocarbamoyl-chloride, 0.31 grams of N-4-bromobenzyl-N-cyclopentyl-N'-phenylthiourea were obtained. Yield: 80%. Melting point: 129°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)CCCCCCCNc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1ccccc1Cl)c1cccc(Cl)c1

Procedure:
As described in example 3(b), the reaction is carried out with 10 g (35 mmol) of 8-(3-chlorophenylamino)-caprylic acid methyl ester, 6.2 g (35 mmol) of 2-chlorobenzoic acid chloride, 3.9 g (39 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=O)=[CH:4][C:3]=1[N+:36]([O-])=O>C(O)C.O.Cl.[Fe]>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]2[N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=2)=[CH:4][C:3]=1[NH2:36]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCn1c(-c2ccc(Cl)c(N)c2)nc2ccccc21
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A solution of 42 g of N-(4-chloro-3-nitrobenzoyl)N-n-hexadecyl-2-nitro-aniline in 700 ml of ethanol is allowed to run rapidly into a mixture, which has been heated to 60° C., of 89 g of iron powder in 120 ml of water and 40 ml of concentrated hydrochloric acid, with vigorous stirring. The reaction mixture is then stirred for four hours at the reflux temperature. A further 100 ml of concentrated hydrochloric acid and 200 ml of ethanol are then added and the mixture is filtered hot. About 400 ml of ethanol are then distilled off and the residue is left to crystallise out at 4° C. After filtering and drying, 32 g of the compound are obtained in the form of the hydrochloride with a melting point of 162° to 163° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[NH:6][CH2:5]2>C(OCC)(=O)C>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][NH:6][C:7]2=[O:14])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2c(cc1[N+](=O)[O-])C(=O)NC2
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1N)C(=O)NC2
Reaction time: 12 h
Yield: 78 %

Procedure:
5-Methyl-6-nitro-2,3-dihydro-isoindol-1-one (100.00 mg, 0.52 mmol) was taken up in ethyl acetate in a Paar vessel and flushed with argon. Palladium on carbon (25 mg) was added and the argon atmosphere was replaced with hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen was then replaced with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure to yield 65.8 mg of the desired amine. C9H10N2O MS m/e=163.2 (M+H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: NN1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(NN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (27.8 g, 0.14 mole) in CH2Cl2 (350 mL) at 0° C. was added a solution of 4-aminomorpholine (10.2 g, 0.1 mole) and triethylaminie (10.2 g, 0.1 mole) in CH2Cl2 (40 mL) via addition finnel over 1 h. A white ppt formed during the addition. After the addition was complete, the ice bath was removed and the reaction was stirred an additional 1 h. The solid was collected by filtration, re-suspended in Et2O and filtered to give the desired product as a white solid (15 g, 62% yield).
Reaction SMILES: Br[C:2]1([C:12]([O:14][CH3:15])=[O:13])[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[OH:11][C:10]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH:4]=[CH:3][C:2]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1(Br)CCc2sccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2sccc2c1O
Temperature: 100 °C
Yield: 31.8 %

Procedure:
A solution containing methyl 5-bromo-4-oxo-4,5,6,7-tetrahydro-1-benzothiophene-5-carboxylate (Preparation 12, 1.18 g) and lithium carbonate (1.81 g) in anhydrous DMF (10 mL) is heated at 100° C. overnight. After cooling, the solids are removed by filtration and the filtrate is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown solid. This crude product is chromatographed on a. Biotage column eluting with 0-20% ethyl acetate in heptane (250 mL each 10%) to give 270 mg (32%) of the title compound as a white solid. Physical characteristics: Mp 94-95° C.; MS (ESI−) m/z 207.0 (M−H)−. Anal. found: C, 57.26; H, 3.88; N, 0.17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:23][C:24]([C:26]1[O:27][C:28](Br)=[CH:29][C:30]=1[CH3:31])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[O:27][C:28]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:15])=[CH:29][C:30]=1[CH3:31])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1cc(Br)oc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)oc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-5-bromo-3-methylfuran-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 22% yield: mp 191-192° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (t, J=6.2 Hz, 1H), 8.23 (d, J=7.9 Hz, 1H), 7.49-7.20 (m, 10H), 6.78 (s, 1H), 6.25 (dd, J=7.9, 2.7 Hz, 1H), 6.06 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.43 (d, J=6.2 Hz, 2H), 2.33 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.4, 160.7, 158.3, 143.7, 139.6, 137.1, 135.4, 134.5, 128.4, 128.3, 128.2, 128.0, 127.2, 126.7, 105.6, 101.8, 97.6, 69.9, 41.5, 11.0; MS (ES+) m/z 415.3 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([O:3][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCc3cccnc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An oily suspension (50% by weight; 1.2 g) of sodium hydride is added in small portions at a temperature in the region of 0° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.2 g) in anhydrous dimethylformamide (100 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. and a 1.4M solution (16 cc) of 3-chloromethylpyridine in toluene is then added. The reaction mixture is heated with stirring to a temperature of 70° C. for 1 hour, then cooled to a temperature in the region of 10° C., poured into distilled water (600 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 1N aqueous hydrochloric acid solution (30 cc) is added to the residue obtained. After removal of a solid by filtration, the filtrate is alkalinized with 10N aqueous sodium hydroxide solution to a pH in the region of 11, and extracted with dichloromethane (3×150 cc). The organic phases are combined, washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-[(3-pyridyl)methoxy]-1-isoindolinone (3.7 g), m.p. 175° C., is obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][CH2:25][OH:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:26][CH2:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCCc1ccccc1
Product: N=C(OCCc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-phenylethanol, there is obtained 2-phenylethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 342 (18), 237 (71), 194 (100), 105 (18);
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:30]=1[CH2:31]Br>C1COCC1>[C:13]([NH:21][CH:22]([CH2:31][C:30]1[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:37])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOC(=O)CNC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry THF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid.
Reaction SMILES: C(OC[O:6][C:7](=[O:31])[C:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([O:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=1)(=O)C.[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([O:38][CH2:39][O:31][C:7](=[O:6])[C:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([O:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=1)=[O:37]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(C)=O)cc1OC(=O)OCC
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(=O)C(C)(C)C)cc1OC(=O)OCC

Procedure:
Following the procedure for preparation of compound 101, and substituting bromomethyl acetate with iodomethyl pivalate, provided the title compound. 1H NMR (CD3OD, 400 MHz): 1.24 (s, 9H), 1.34 (t, 6H), 1.44 (s, 3H), 3.08 (dd, 2H), 4.29 (q, 4H), 5.88 (dd, 2H), 7.19–7.25 (m, 3H). MS (ESI) m/z 485.32 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-:53]=[N+:54]=[N-:55].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39][N:53]=[N+:54]=[N-:55])[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][CH:51]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)CN=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A slurry of 5'-O-(4,4'-dimethoxytrityl)-3'-p-toluensulfonyloxymethylthymidine (0.40 g; 0.55 mmol) and NaN3 (0.11 g; 1.65 mmol) in anhydrous DMF (3 ml) was heated at 50° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml), and washed with water (3×40 ml), then with 10% NaHCO3 (3×40 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica (EtOAc-Hexanes, 1:1) to yield 0.30 g (92%) of 5'-O-(4,4'-dimethoxytrityl)-3'- C-azidomethylthymidine as a colorless powder.
Reaction SMILES: B.[F:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6](O)=[O:7])[C:4]=1[C:12](O)=[O:13]>O1CCCC1>[F:2][C:3]1[C:4]([CH2:12][OH:13])=[C:5]([CH2:6][OH:7])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(F)c1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCc1cccc(F)c1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a stirred solution of borane.tetrahydrofuran complex (50 mL of 1.5 M solution in tetrahydrofuran/diethyl ether) cooled to 0° C. under argon was added a solution of 3-fluorophthalic acid (4.51 g; 24.0 mmol) in tetrahydrofuran (40 mL) dropwise over a 15 minute period. At the end of the addition, the mixture was allowed to stir for 2 h at 0° C. The mixture was allowed to warm to room temperature and then refluxed for 20 h. The mixture was allowed to cool to room temperature, quenched with methanol (30 mL) and concentrated in vacuo. The residue was taken up into ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution. The aqueous layer was further extracted with ethyl acetate (2×125 mL) and the combined extracts were washed with brine solution. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo to give 3.73 g (99%) of 3-fluoro-1,2-di-(hydroxymethyl) benzene as a white solid: ES-LRMS calcd for C8H8FO2 (M+−1) 155, found 155.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)[CH3:14]>CO>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
A mixture of 2-chloro-4-fluorobenzoic acid (6.5 g, 37 mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (14.0 mL, 111 mmol), stirred 24 h at room temperature and evaporated. The residue was dissolved in dichloromethane, washed with sodium bicarbonate, dried (sodium sulfate) and evaporated to provide 2-chloro-4-fluoro-benzoic acid methyl ester (7.01 g, 99% yield) as a pale yellow oil. 1H-NMR (CDCl3, 500 MHz) 7.93 (m, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 3.95 (s, 3H) ppm; MS (FIA) 189.1 (M+H); HPLC (Method A) 3.37 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].Cl[C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[O:15]=[C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:16])[N:6]1[O:5][CH2:4][CH2:3][NH:2][C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19]
Reactant: CC(C)(C)OC(=O)NC(=O)Cl
Reactant: NCCON1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.40 g, 1.65 mmol, EP 1674452 A1, 2006), tert-butyl (chlorocarbonyl)carbamate 82 (1.70 g crude. US 2005/187277 A1) in DCM (10 mL) was added triethylamine (0.69 mL, 4.95 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 83 (0.56 g, 96%) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C@H:5]([OH:7])[CH3:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.O>CN(C)C=O>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][O:7][C@H:5]([CH3:6])[C:4]([F:9])([F:8])[F:3])[CH:13]=1
Reactant: Clc1cccc(CBr)c1
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cccc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (77 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of (R)-1,1,1-trifluoropropan-2-ol (213 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and the mixture was stirred for 15 minutes. Then, a solution of 1-bromomethyl-3-chlorobenzene (311 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred at room temperature for 2.5 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (307 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[CH:37][CH:36]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
1-[1-(4-Chloro-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]-pyrimidine was prepared according to General Procedure H by the reaction 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-chlorobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.90-1.96 (m, 2H), 2.16-2.25 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.54 (s, 2H), 4.77-4.82 (m, 1H), 7.36-7.42 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=498.