Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]([CH3:40])([CH3:39])[C:14]([NH:16][C@H:17]([B:26]1[O:30][C@@H:29]2[CH2:31][C@@H:32]3[CH2:35][C@H:34]([C@:28]2([CH3:38])[O:27]1)[C:33]3([CH3:37])[CH3:36])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)=[O:15].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:12][C:13]([CH3:40])([CH3:39])[C:14]([NH:16][C@H:17]([B:26]2[O:30][C@@H:29]3[CH2:31][C@@H:32]4[CH2:35][C@H:34]([C@:28]3([CH3:38])[O:27]2)[C:33]4([CH3:37])[CH3:36])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[O:15])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1cccc(C[C@H](NC(=O)C(C)(C)N)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(C[C@H](NC(=O)C(C)(C)NC(=O)c2ccc(Cl)cc2)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c1
Temperature: 22 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 4-chlorobenzoic acid (0.087 g, 0.553 mmol) in CH2Cl2 were added 2-amino-2-methyl-N-{(1R)-2-(3-methylphenyl)-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}propanamide hydrochloride (0.20 g, 0.503 mmol), HOBt (0.075 g, 0.553 mmol), 4-methylmorpholine (0.204 g, 2.42 mmol) and EDCI (0.106 g, 0.553 mmol). The reaction mixture was allowed to stir at 22° C. After 12 h, the reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (0.210 g, 77%). LC/MS: Rt=2.29 min, ES+537 (Formic Acid method).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:31]=[CH:30][C:20]([CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[CH:13][C:12]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:22][CH2:21][C:20]1[CH:30]=[CH:31][C:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:32]4[CH:33]=[C:34]([Cl:40])[C:35]([OH:39])=[C:36]([Cl:38])[CH:37]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 46.5 %

Procedure:
Following general procedure A-2, tert-butyl 4-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]benzylcarbamate (0.117 mmol) was reacted with TFA (2 mL) to afford the desired product (26 mg, 46% over two steps) a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.44 (s, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.09-7.95 (m, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.24 (s, 2H), 4.28 (s, 2H), 2.88-2.83 (m, 1H), 1.26-1.13 (m, 4H); ESI MS m/z 478 [C26H21Cl2N3O2+H]+; HPLC>99% (AUC), tR=11.99 min.
Reaction SMILES: C(O)C(O)C(O)C(O)C=O.[CH3:11][CH:12]([OH:21])[CH:13]([OH:20])[CH:14]([OH:19])[CH:15](O)[CH:16]=O.O=C[C@@H]([C@@H]([C@H]([C@H](C)O)O)O)O.C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:16][CH:15]1[C:14](=[O:19])[C:13]([OH:20])=[C:12]([CH3:11])[O:21]1
Reactant: CC(O)C(O)C(O)C(O)C=O
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=CC(O)C(O)C(O)CO
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC1=C(O)C(=O)C(C)O1
Yield: 26 %

Procedure:
Several methods of preparation of these compounds involving a pentose or a 6-deoxyhexose are known: U.S. Pat. No. 2,936,308 (Hodge) discloses the reaction of L-rhamnose and piperidine acetate at 75°C. for 18 hours in ethanol and a 26% yield of 2,5-dimethyl-4-hydroxy-2,3-dihydrofuran-3-one was obtained according to Example 2. Although the desired compound was formed in a reasonable yield, it was contaminated with a nitrogen-containing by-product (2,5-dimethyl-4-piperidino-2,3-dihydrofuran3one), which was difficult to remove. The same preparation is disclosed in GB 1,132,600. GB 1,238,942 discloses the reaction between a pentose or 6-deoxy-aldohexose with a dialkylamine to a glycosylamine which further reacts with acid to form the desired compounds. Before isolating the product from the reaction mixture the solvent is removed by distillation under reduced pressure at a temperature below 35° C. The product is then isolated through extraction with an organic solvent followed by purification through column chromatography.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13]C(C2C=CC=CC=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O>C(O)C>[CH2:1]([O:8][CH:9]([CH2:10][OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: OCC(CO)OCc1ccccc1
Yield: 87.4 %

Procedure:
A solution of 370 g of 5-benzyloxy-2-phenyl-1,3-dioxane and 35 ml of concentrated sulfuric acid in a medium of 750 ml of water and 1.2 l of ethanol was refluxed for 2 hours. The ethanol was then removed by evaporation under reduced pressure, and by-product benzaldehyde was removed by steam distillation. The aqueous mixture was saturated with potassium carbonate, and the product was extracted from the aqueous medium with ether. The ethereal solution was dried (MgSO4) and evaporated under reduced pressure to give solid product, which upon recrystallization from a benzane/ligroine system gave 218 g of 2-benzyloxy-1,3-propanediol, m.p. 38°-39° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][NH:22][CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2].C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH3:32])[CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2]
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(c3)CNCC4)C2=O)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 322.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.29 g, 0.71 mmol) in 10 mL of CH2Cl2 is added 0.27 mL of 37% aqueous formaldehyde. The solution is stirred at room temperature for 1 hour. After this time, sodium triacetoxyborohydride (0.05 g, 0.22 mmol) is added and the resulting mixture is stirred for 18 hours. The reaction mixture is diluted with CH2Cl2 and washed with saturated NaHCO3 solution. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 2-methyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.16 g, 0.71 mmol) as a solid. The crude methylated material is then converted to the title compound as described in EXAMPLE 24, Part C. The imidate intermediate is formed over a period of 18 hours at room temperature. The amidine formation occurred upon heating at reflux for 2 hours. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH:16]4[CH2:18][CH2:17]4)=[N:13][NH:12][C:11]=3[C:10](=[O:19])[N:9]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[C:14]([CH:16]4[CH2:18][CH2:17]4)=[N:13][N:12]([CH3:31])[C:11]=3[C:10](=[O:19])[N:9]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(N2C(=O)c3[nH]nc(C4CC4)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12
Reactant: CI
Product: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3C)C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 112.5 using 4-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 129.1) and MeI at RT for 30 min. The crude product was purified by preparative achiral SFC (column NH2, gradient 19-24% in 6 min_total 11 min). tR: 0.95 min (LC-MS 2); ESI-MS: 433.2 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm-0.10-0.07 (m, 1H) 0.50-0.78 (m, 3H) 1.59-1.76 (m, 1H) 1.92 (s, 3H) 3.36 (s, 3H) 3.92 (s, 3H) 6.09 (s, 1H) 7.27 (d, J=8.4 Hz, 2H) 7.32-7.45 (m, 3H) 7.68 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](O)=O)[CH3:2].N1CCCCC1.C=O.Cl>O.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCCOc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: C=C(CCCCOc1ccccc1)C(=O)OCC
Yield: 74.1 %

Procedure:
66.45 g of 4-phenoxybutylmalonic acid ethyl ester, 45 ml of pyridine, 3 ml of piperidine and 9.9 g of paraformaldehyde are stirred together at 50° C. for 4 hours. After cooling, 400 ml of water are added to the reaction mixture which is then acidified with half-concentrated hydrochloric acid, while cooling with ice. The reaction mixture is then extracted 3 times with 200 ml of diethyl ether each time, the combined organic phases are concentrated and distilled in vacuo. 43.6 g 2-methylene-6-phenoxyhexanoic acid ethyl ester are obtained as a colorless liquid of b.p. 140° C. under 0.06 mm Hg (9 Pa).
Reaction SMILES: C(O[C:4](=[NH:14])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])C.N>CO>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([CH:10]=1)[CH:4]=[NH:14]
Reactant: CCOC(=N)c1cc(Cl)ccc1OC
Agent: N
Solvent: CO
Product: COc1ccc(Cl)cc1C=N
Yield: 129 %

Procedure:
A mixture of 5-chloro-2-methoxy-benzimidic acid ethyl ester (1.0 g, 4.0 mmol) and a solution of ammonia in methanol (7.0 M, 50 ml) was stirred for 48 hours. Evaporation of volatiles under reduced pressure provided 5-chloro-2-methoxy-benzylideneamine (0.875 g, 99% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[OH-].[K+].Cl.O>CO.O>[O:32]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)SC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccc(OCc2ccccc2)cc1)SC1=NS(=O)(=O)c2ccccc21
Yield: 40 %

Procedure:
The crude product from Step A was dissolved in a MeOH/H2O mixture (2:1, 4 ml). 0.7 g KOH was added to the solution and heated at reflux for 1.5 h. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2; ethyl acetate). The yield was 40%.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:23])[CH2:9][C:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:11].[BH4-].[Na+].CCOC(C)=O>CCO>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH:10]([OH:11])[CH2:9][CH:8]([OH:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: CCCCCCC[C@H](O)CC(=O)CCc1ccc(O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCC(O)CC(O)CCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [8]-gingerol (0.1 g) in EtOH (15 mL) was added dropwise a solution of NaBH4 (0.02 g in 1 mL H2O). The mixture was stirred at room temperature for 3 hrs. After acidification, EtOAc was added and organic layer was washed with water twice. Evaporation of solvent left a white solid which was purified by gradient chromatography to afford the title compound as a colourless liquid in quantitative yield.
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].C1C[O:25]CC1>P([O-])([O-])([O-])=O>[N+:18]([C:6]1[CH:7]=[C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:25])([O-:20])=[O:19]
Reactant: C1CCOC1
Reactant: CN(C)/C=C/c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Yield: 52 %

Procedure:
To a solution of crude (E)-N,N-dimethyl-2-(2-nitro-4-(perfluoroethyl)phenyl)ethenamine (12.2 g, 39.2 mmol) in THF (300 mL) and pH 7.2 phosphate buffer (300 mL) was added NaIO4 (29.3 g, 137.2 mmol). After 2.5 hours an aliquot (˜0.3 mL) was removed, filtered and dried. The proton NMR of this sample indicated that the reaction was complete. The solids were removed and the filter cake was washed with EtOAc. The filtrate was washed with brine (2×100 mL), dried and concentrated. The concentrate was purified via flash chromatography (100% hexane to 5% EtOAc) to provide 2-nitro-4-(perfluoroethyl)benzaldehyde (5.4 g, 52%).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:30][C@H:31]1[CH2:36][NH:35][CH2:34][C@@H:33]([CH3:37])[NH:32]1>CS(C)=O>[CH3:30][C@H:31]1[NH:32][C@@H:33]([CH3:37])[CH2:34][N:35]([C:2]2[N:3]([CH2:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:7]=[C:6]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)[N:5]=3)[CH2:36]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CCOC2)C[C@H](C)N1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol), cis-2,6-dimethylpiperazine (82 mg, 0.72 mmol), and dimethyl sulfoxide (800 μl) was stirred at 150° C. for 1.5 hours. The reaction mixture was cooled and then partitioned with ethyl acetate and water and the organic layer was washed twice with saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give the title compound (64 mg, 57%) as a light brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2].[Br:10]Br>C(OCC)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([Br:10])[CH:7]=[O:8])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)CCC=O
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C=O
Reaction time: 1.25 h
Yield: 66.5 %

Procedure:
To a 0-5° C. mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3.9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%).
Reaction SMILES: Cl.[CH2:2]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[CH2:2]([N:9]1[C:25]2[CH:24]([CH2:23][C:21]([OH:22])=[O:20])[CH2:29][CH2:28][CH2:27][C:26]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccccc1)c1ccc(F)cc1
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccccc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(benzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O:32][C:33](=[O:47])[C:34]([O:44][CH2:45][CH3:46])([CH3:43])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)C.O>CS(C)=O.O1CCCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:39]2[CH:38]=[CH:37][C:36]([CH2:35][C:34]([O:44][CH2:45][CH3:46])([CH3:43])[C:33]([OH:47])=[O:32])=[CH:41][CH:40]=2)=[CH:15][CH:16]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(C)(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
Sodium hydroxide (0.105 g; 2.63 mmole) was pulverized and dissolved in DMSO (8 ml). To 4 ml of this solution 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.515 g; 1.316 mmole) and 2-ethoxy-3-(4-hydroxyphenyl)2-methyl propanoic acid ethyl ester (0.331 g; 1.316 mmole) were added and the mixture was stirred at room temperature over night. The remaining volume (4 ml) of the sodium hydroxide solution and water (1 ml) were added. A precipitate was formed which was dissolved by addition of tetrahydrofuran (1 ml). The mixture was allowed to stand over night and was then evaporated. The residue was redissolved in dichloromethane and water and the phases were separated. The water phase was extracted once more with dichloromethane, acidified with hydrochloric acid (1 M), extracted several times with ethyl acetate and diethyl ether. The organic phases were combined, dried with magnesium sulfate and evaporated. Purification of the crude product by flash chromatography and preparative HPLC gave 0.103 g (17.1% yield) of 3-[4-{2-(4[-tert-butoxycarbonylamino]phenyl)ethoxy}phenyl]-2-ethoxy-2-methyl-propanoic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([O:12]C)=[CH:10][CH:11]=1)[CH3:3].[C-]#N.[Na+].O.CC(C)=O>CS(C)=O>[CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 182.5 °C

Procedure:
5.0 g Venlafaxine was dissolved in 50 ml dimethylsulfoxide at 25-30° C. Sodium cyanide 9.0 g was added and reaction mass was heated to 180-185° C. for 4 hours. The reaction mass was cooled and 25 ml water was added. The resulting solution was extracted with 2×50 ml ethyl acetate, combined organic layer was dried over anhydrous sodium sulfate, followed by distillation to give residue. The residue was treated with 25 ml acetone then cooled to 0-5° C. to give O-desmethylvenlafaxine.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[CH3:2].[ClH:49]>C(O)C.C(OCC)C>[ClH:49].[ClH:49].[ClH:49].[ClH:49].[NH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2]
Reactant: CCN(CCCN(CCCCCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCNCCCNCCCCCCCCNCCCN

Procedure:
Dissolve 2.5 g (0.0036 mol) of the product of Step A in 5 ml of ethanol and treat with 60 ml of 2N HCl in diethyl ether stirring overnights. Filter the mixture and dry the residue to yield 1.35 g of the title compound, mp>300° C. Elemental analysis: Calculated, C-43.54, H-9.82, N-12.69, Cl-32.13; Found, C-43.43, H-9.60, 9.55; N-12.60, 12.62; Cl-32.30.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])\[CH3:16]>ClCCl.[Cl-].[Na+].O>[Cl:1][CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])\[CH3:16]
Reactant: C/C(=C\CO)c1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: C/C(=C\CCl)c1cccc(C#N)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-chlorosuccinimide (9.8 g, 73.1 mmol) in dichloromethane (25 ml) at −10° C. was added dropwise over 15 minutes dimethylsulfide (5.4 ml, 73.1 mmol). The mixture was stirred at −10° C. for 30 min, then a solution of 3-[(E)-3-hydroxy-1-methyl-1-propenyl]benzonitrile (from Preparation 33, 11.9 g, 69.6 nlmol) in dichloromethane (20 ml) was added dropwise over 15 minutes at −10° C. The mixture was stirred at 0° C. for 1 h, and was then poured onto saturated brine (50 ml). The layers were separated, and the aqueous layer was extracted with diethyl ether (2×50 ml). The extracts were combined, washed with water (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude pale yellow oil (13.1 g, 100%) was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([CH3:33])[S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29](=[CH2:32])[CH2:30][CH3:31])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+](=[CH2:37])=[N-]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]4([CH2:32][CH3:37])[CH2:31][CH2:30]4)[CH:20]=3)(=[O:18])=[O:17])[CH3:33])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=C(CC)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C2(CC)CC2)c1
Yield: 83 %

Procedure:
Starting with ((R)-4-{methyl-[3-(1-methylene-propyl)-5-trifluoromethyl-benzenesulfonyl]-amino}-4,5,6,7-tetra-hydro-indazol-1-yl)-acetic acid ethyl ester and a solution of diazomethane in diethyl ether using the method analogous to the one described above for 2nd step of example 14-1, ((R)-4-{[3-(1-ethyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (82 mg, 83%) was obtained as a white solid. MS cald. for C24H30F3N3O4S 513, obsd. (ESI+) [(M+H)+] 514.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:42][CH2:43][CH:44](CO)[OH:45]>>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:44]([OH:45])[CH2:43][OH:42])=[O:26])=[CH:29][CH:30]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(15-carbomethoxypentadecylamino)benzoate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 4 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate.