Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][OH:18])=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH2:26][C:27]([NH2:29])=[S:28].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)C>[OH:18][CH2:17][CH:16]([C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:2]2[S:28][C:27](=[NH:26])[NH:29][C:3]2=[O:4])=[CH:9][CH:10]=1
Reactant: COC(=O)C(Br)Cc1ccc(OCC(CO)c2ncccc2C)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccnc1C(CO)COc1ccc(CC2SC(=N)NC2=O)cc1

Procedure:
A mixture of methyl 2-bromo-3-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]phenyl}propionate (4.7 g), thiourea (875 mg), sodium acetate (943 mg) and ethanol (50 ml) was heated under reflux for 3 hours. The mixture was diluted with water, neutralized with aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent to give 5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]-benzyl}-2-imino-4-thiazolidinone in the form of crystals. Yield of 25 g. Recrystallization from chloroform-methanol produced colorless prisms. m.p. 213°-214° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[C:18]([BH3-])#[N:19].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 1-benzyl-4-piperidone (XXV, Chart G, 24.5 mL, 0.1295 mol), N-methylamine hydrochloride (44.75 g, 0.6628 mol) and methanol (50 ml) is stirred for 35 minutes at 20°-25°, at which time additional methanol (10 ml) is added. The mixture is then cooled in an ice bath and a solution of sodium cyanoborohydride (9.1749 g, 0.1460 mol) in methanol (68 ml) is added to the mixture. The mixture is stirred for 5 min and then is allowed to warm to 20°-25°. After 1.25 hr the mixture is concentrated under reduced pressure and saturated aqueous sodium bicarbonate is added. After stirring for 1 hr, the mixture is extracted with dichloromethane and the organic phases are combined, backwashed with saline, dried with magnesium sulfate and concentrated under reduced pressure to give (XXVII). The material is upgraded by forming the dihydrochloride salt and collecting the resulting solids. The dihydrochloride salt is further upgraded by trituration with dichloromethane. The free base (XXVII) is recovered by slurrying the dihydrochloride salt (7.5204 g, 0.02713 mol) in dichloromethane and adding enough saturated sodium bicarbonate to dissolve all the solids and then extracting the aqueous layer exhaustively with dichloromethane to obtain N-(1-benzylpiperidin-4-yl)-N-methylamine (XXVII), MS (m/z) 204; IR (neat) 2942, 2796, 2775, 743 and 2749 cm-1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([N:31]5[CH2:36][CH2:35][S:34][CH2:33][CH2:32]5)=[O:2])=[CH:9][CH:8]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:23])[F:22])[O:18][N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1)N1CCSCC1
Yield: 67 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using thiomorpholine instead of cyclopropanemethylamine, to the title compound (55 mg, 67%) which was obtained as a light yellow solid. MS: m/e=485.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 80 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.95-3.02 (m, 4H), 3.74-3.77 (m, 3H), 4.08-4.14 (m, 4H), 7.01-7.57 (m, 7H), 7.64-7.85 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[N:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58](O)[CH2:57]2>O1CCCC1>[N:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[CH2:57]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reaction time: 96 h
Yield: 56.5 %

Procedure:
A solution of 2-(((benzyloxy)carbonyl)amino)-2-(3-(benzyloxy)phenyl)acetic acid (2.1 g, 5.3 mmol), N,N′-dicyclohexylcarbodiimide (1.20 g, 5.83 mmol), 1-hydroxybenzotriazole hydrate (787 mg, 5.83 mmol) and (R)-quinuclidin-3-ol (1.70 g, 13.5 mmol) in dry tetrahydrofuran (27 mL) was stirred at room temperature for 18 h. Additional (R)-quinuclidin-3-ol (1.70 g, 13.5 mmol) was then added to the mixture and stirred for 4 days. The white slurry was then filtered through a pad of Celite®, rinsed with ethyl acetate (100 mL) and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and saturated sodium carbonate (50 mL). The layers were separated and the aqueous phase back-extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate/10% methanolic ammonia solution in ethyl acetate to afford the title compound (1.5 g, 56%) as a clear thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][C@@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:23]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([N:29]2[CH2:28][CH2:27][C:26]3([CH2:22][N:23]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])[C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25]3)[CH2:31][CH2:30]2)[CH:19]=[C:14]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[N:15]=1
Reactant: Nc1nc(Cl)cc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (19 mg, 0.50 mmol) in dioxane (25 ml) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (175 mg, 0.50 mmol) and sodium bicarbonate (210 mg, 0.25 mmol), and the reaction mixture was heated to 100° C. for 48 h. Then the reaction mixture was cooled to RT, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.S(Br)([Br:27])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][Br:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Br)Br
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: BrCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 15 h
Yield: 55 %

Procedure:
To N,N-dibenzyl-2-aminoethanol (18.47 g) was added hexane (150 ml) and DMF (0.3 ml), and thereto was added dropwise thionyl bromide (15.91 g) at 0° C. The mixture was stirred for 15 hours, and to the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×2) and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane) to give the title compound (12.80 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][Cl:44]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:40][CH2:41][CH2:42][CH2:43][Cl:44])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: ClCCCCBr
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(O)c(C#N)cc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Reaction time: 0.83 h

Procedure:
N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (200 mg), potassium carbonate (65 mg) and 1-bromo-4-chlorobutane (81 μl) were suspended in dimethylformamide (3 ml), and the suspension was heated and stirred for 1 hour and 50 minutes. The reaction solution was poured into saturated saline and extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, it was passed through NH silica (Fuji Silicia Chemical) and washed in ethyl acetate, and the filtrate was concentrated. The obtained solid was washed with ether and dried to obtain 110 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1>CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:3][CH2:2][OH:1])[CH2:26][CH2:27]2)=[CH:7][CH:6]=1
Reactant: C1CO1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CO
Product: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 9 parts of oxirane, 3.24 parts of 1-(4-fluorophenyl-methyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 400 parts of methanol was stirred first overnight at room temperature and further for 4 hours at 50° C. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 15 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2ylamino]-1-piperidineethanol; mp. 138.7° C. (intermediate 93).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Br)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[S:26]([CH3:29])(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:33]4[CH2:32][CH2:31][CH:30]([N:25]([S:26]([CH3:29])(=[O:27])=[O:28])[CH3:24])[CH2:35][CH2:34]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ncc3O2)CC1
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Product: CN(C1CCN(c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)CC1)S(C)(=O)=O

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and N-methyl-N-piperidin-4-ylmethanesulfonamide following a procedure analogous to that described in Example 79. LC (method 10): tR=1.35 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.B(F)(F)F.[CH3:17][CH2:18]OCC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:17][CH3:18])=[O:9])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1

Procedure:
A solution of 10.0 g. p-aminohydrocinnamic acid in 100 ml. of absolute ethanol containing 16 ml. of boron trifluoride etherate is heated to reflux for 48 hours. The solution is then cooled, poured into 5% aqueous sodium carbonate, and extracted with methylene chloride. Evaporation of the organic extracts yields ethyl p-aminohydrocinnamate.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=[O:4].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].Cl>O>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([S:17][CH2:2][C:3]([OH:5])=[O:4])=[CH:15][CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(SCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Sodium chloroacetate (6.29 g, 54 mmol) was added in portions to a solution of 4-t-butylbenzenethiol (9.0 g, 54 mmol) in a 30% (w/v) aqueous solution of sodium hydroxide (10.8 ml, 81 mmol) with stirring at 80° C. When the addition was complete, stirring was continued for an additional 2 hours at 80° C., during which time a thick white precipitate had formed. The reaction mixture was added to water (200 ml) and was acidified to pH 2 by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate. The combined extracts were then extracted with a 10% (w/v) aqueous solution of potassium carbonate. The aqueous extracts were acidified to pH 2 by the addition of 2M hydrochloric acid and again extracted with ethyl acetate. These combined extracts were dried (MgSO4) and the solvent was removed by evaporation to give 2-(4-t-butylphenylthio)acetic acid (B) as a straw coloured oil (9.07 g); which had a satisfactory NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C@@H:31]1[F:43]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][C@H:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32][C@@H:31]3[F:43])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](F)C1
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1

Procedure:
Prepared from 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.123 g, 0.25 mmol, prepared according to Example 7, Step B), and ±(3S*,4S*)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (0.164 g, 0.750 mmol, prepared according to the procedure described in WO 2006/087543) according to the procedure described for Example 143, Step A. LRMS (APCI+): m/z 581 (M+1) detected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].O>CCOCC>[F:18][C:19]([F:26])([F:25])[C:20]([C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1)=[O:21]
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
5.00 g (20.57 mmol) of 3-bromo-5-fluorobenzotrifluoride were stirred in 60 ml of dry ether and admixed dropwise at −78° C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of ten-butyllithium solution [cf. also trifluoroacylation: H. K. Nair. D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993): G. J. Pork et al. J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at −78° C., for 45 minutes and then added dropwise, with the aid of a syringe, in portions at −78° C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at −78° C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40° C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[OH:6][C:7]1[C:12]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:18]=3[C:19]([CH3:22])([CH3:21])[O:20][C:11]=2[CH:10]=[C:9]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1.C(N(CC)CC)C>CN(C)C=O>[OH:6][C:7]1[C:12]2[C:13]3[CH2:14][N:15]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:16][CH2:17][C:18]=3[C:19]([CH3:21])([CH3:22])[O:20][C:11]=2[CH:10]=[C:9]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(N)=O)CC1
Reaction time: 17 h

Procedure:
A solution of 1.03 g (0.011 mole) of 2-chloroacetamide in 8 ml of dimethylformamide was added dropwise to a stirred solution of 3.57 g (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 12 ml of dimethylformamide and 1.11 g (0.011 mole) of triethylamine. After stirring for 17 hours, the mixture was diluted with 20 ml. of water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from acetonitrile, m.p. 165°-168°.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2ccc(Cl)cc2)cc1OC

Procedure:
As described under 1.2, 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 12.2 g (0.055 mol) of 4-chlorobenzenesulfonic acid chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 15.9 g (84%) of α-(4-chlorophenyl-sulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 145.5-148.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 350 nm (ε=11660) that extends to 437 nm. Elemental analysis: C16H13ClN2O5S (380.80)
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH3:17])[C:14](S)=[N:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:16]([N:15]1[CH:14]=[N:13][N:12]=[C:11]1[CH2:10][OH:9])[CH3:17]
Reactant: CCn1c(S)nnc1CO
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCn1cnnc1CO
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a mixture of 90% nitric acid (15 ml) and water (22 ml) was added sodium nitrite (0.06 g) and then 3-hydroxymethyl-5-mercapto-4-ethyl-4H-1,2,4-triazole (7.5 g) was slowly added for 0.5 hours at 45° C. After allowing the mixture to be cooled to room temperature, sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixture was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 2:1), to give 4-ethyl-3-hydroxymethyl-4H-1,2,4-triazole (4.60 g) as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([N+:15]([O-])=O)[CH:5]=1.[H][H]>CO.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH2:15])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(-c2ncco2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)cc(-c2ncco2)c1

Procedure:
A solution of 11.7 g (47.1 mmol) of 3-nitro-5-oxazol-2-yl-benzoic acid methyl ester in 1 l of MeOH and 200 ml of THF is stirred under an atmosphere of hydrogen in the presence of 0.6 g of Pd/C (10%) until the hydrogen up-take ceases. The mixture is filtered over high-flow, and the filtrate is washed with THF and evaporated to yield the product.
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17](CCCCN3C(=O)C4C=CC=CC=4S3(=O)=O)[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1.Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]1[C:46](=[O:47])[C:45]2[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=2[S:43]1(=[O:53])=[O:52]>>[ClH:1].[Cl:1][C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]3[C:46](=[O:47])[C:45]4[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=4[S:43]3(=[O:53])=[O:52])[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCCBr
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Agent: Cl
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
This compound was prepared analogous to the method described for 2-(4-(4-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)-butyl)-1,2-benzisothiazole-3(2H)-one-1,1-dioxide, dihydrochloride (Example 3) using intermediate 2a (2.00 g, 6.9 mmol) and 2(5-bromopentyl)-1,2-benzisothiazole-3(2H)-one-1,1-dioxide (2.52 g, 7.6 mmol). Yield 1.40 g, m.p. 193°-5° C.