Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[CH:9][CH:8]=1)[CH3:5].[CH3:21][O:22][C:23](=[O:36])[CH:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:25]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][C:34](=[O:35])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH:24]([C:23]([O:22][CH3:21])=[O:36])[CH3:25])=[CH:32][CH:31]=2)=[O:15])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)OCCO)cc1
Reactant: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)Oc1ccc(NC(=O)OCCOC(=O)Nc2ccc(OC(C)C(=O)OC)cc2)cc1
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To 2-[4-(2-Hydroxyethoxycarbonylamino)phenoxy]propionic acid methyl ester 33 (5 g, 17.66 mmol) in toluene (50 ml) was added 2-(4-Isocyanato-phenoxy)-propionic acid methyl ester 32 (3.9 g, 17.64 mmol) at room temperature and heated to 60° C. for 30 hours. Toluene was distilled off and water (50 ml) was added. The solids were filtered and dried to give crude 34, which was purified by column chromatography on silica gel using chloroform as eluant to get pure 34 (5.5 g, 61.8%) as a white powder. M.p: 98-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH2:16][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CSC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 8.7 mmol) was solved in 160 ml toluene under inert conditions. To this solution MnO2 (15.0 eq, 130 mmol) was added. The reaction was heated to 70° C. under stirring for 5 h. The mixture was filtered over celite and the filtration agent was washed 3 times with 30 ml toluene and ethylacetate. The combined organic layers were distilled in vacuo. The residue was purified by silica gel chromatography using a DCM/MeOH 95:5 gradient. Yield: 30%
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[CH2:9][C@:10]([OH:19])([CH3:18])[CH2:11][CH2:12][C:13]([F:17])=[C:14]([F:16])[F:15])[C@H:3]1[CH2:20][CH2:21][S:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1.[OH-].[Li+].S([O-])(O)(=O)=O.[K+]>COCCOC.O>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[CH2:9][C@:10]([OH:19])([CH3:18])[CH2:11][CH2:12][C:13]([F:17])=[C:14]([F:15])[F:16])[C@H:3]1[CH2:20][CH2:21][S:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1
Reactant: COC(=O)c1csc(SCC[C@H]2C(=O)CC[C@@H]2/C=C/C[C@@](C)(O)CCC(F)=C(F)F)n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: C[C@@](O)(C/C=C/[C@H]1CCC(=O)[C@@H]1CCSc1nc(C(=O)O)cs1)CCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Compound 16 (152 mg) was dissolved in 1,2-dimethoxyethane (2.0 mL)/water (1.0 mL), and lithium hydroxide (16.0 mg) was added thereto under ice cooling, followed by stirring at room temperature for 2 hr. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine; dried with anhydrous sodium sulfate; and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→methanol:ethyl acetate=1:10) to obtain the title compound (127 mg, amorphous, viscous oil) having the following physical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25]I.[OH-].[K+].Cl>CS(C)=O.C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:10][N:11]([CH3:25])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCC(c1ccc(Cl)c(Cl)c1)N1CCCC1)c1ccccc1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CN(CC(c1ccc(Cl)c(Cl)c1)N1CCCC1)C(=O)c1ccccc1
Temperature: 23 °C
Yield: 40.5 %

Procedure:
A solution of N-[2-(3,4-dichlorophenyl)-2-pyrrolidin-1-yl-ethyl]benzamide (260 mg) in dimethylsulfoxide (1.5 mL) and methyl iodide (230 mg) were added to a solution of KOH (190 mg) in dimethylsulfoxide (0.7 mL). The reaction was stirred at 23° C. for 3/4 hour, was poured into water (10 mL), and extracted with dichloromethane (20 mL). The organic layer was washed (brine), dried and evaporated to a gold oil. Chromatography, with ethyl acetate:hexane (50:50 then 75:25) as the eluent, gave an oil, which was dissolved in diethylether and treated with hydrochloric acid (g)/diethylether to provide the title compound as a white solid (60 mg); mp 199-202° C.; MS: m/z=377(M+1); NMR: 1.98 (m,1), 2.12 (m,2), 2.35 (m,1), 2.54 (s,3,), 2.61 (m,1), 3.35 (m,2), 3.88 (t,1), 4.13 (m,1), 4.63 (m,2), 7.2 (dd,1), 7.26 (s,1), 7.53 (d,1), 7.79 (broad s,1), 8.11 (broad s,1), 13.23 (broad s,1). Analysis Calculated: C, 57.43; H, 5.6; N, 6.7; Found: C, 57.59; H, 5.61; N, 6.35.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[C:24]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C>CS(C)=O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:25]=[C:24]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:23]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCCO
Yield: 67.9 %

Procedure:
1,3-Propanediol (580 mg) was dissolved in dimethyl sulfoxide (15 ml). Sodium hydride (297 mg) and 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]benzenesulfonamide (1.1 g) were added to the solution. The resultant mixture was stirred for 4 hours at 120° C. Ethyl acetate was added to the reaction mixture, followed by successive washing with 0.5N-HCl, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby obtain 802 mg (yield: 68%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Li]C(CC)C.[I:24]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[I:24]
Reactant: II
Reactant: CCCc1ccc(CCc2cccc(F)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1ccc(CCc2ccc(I)c(F)c2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
In a solution of 4.8 g (19.7 mmol) of the 3-fluoro-(2-(4-propylphenyl)ethyl)benzene obtained in the previous step in 25 ml of THF was added dropwise 23 ml of sec-BuLi (1.04 M, cyclohexane solution, corresponding to 23.7 mmol) while being maintained at a temperature lower than −60° C., and they were stirred at the same temperature for 1 hour. Subsequently, a solution of 7.5 g (29.6 mmol) of iodine in 20 ml of THF was added dropwise to the reaction mixture while being maintained at a temperature lower than −60° C., and they were stirred at the same temperature for 1 hour. The reaction solution was poured into 50 ml of a diluted aqueous sodium thiosulfate solution, and extracted with 50 ml of heptane. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under a reduced pressure, the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 6.5 g of a crude 3-fluoro-4-iodo-(2-(4-propylphenyl)ethyl)benzene. This product was used for next reaction without any further purification. (Yield: 90.2%)
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][CH:4]=1)=O.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27].[BH4-].[Na+].O>CN(C=O)C>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:27][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][CH:4]=1
Reactant: NC(=O)c1ccc(Oc2ncc(C=O)c3ccccc23)cc1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCNCc1cnc(Oc2ccc(C(N)=O)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-(4-formylisoquinolin-1-yloxy)benzamide (Preparation 16) (100 mg, 0.34 mmol) in DMF (10 mL) was added 3-methylbutylamine (40 μL, 0.34 mmol) and 4 Å molecular sieves (200 mg). The mixture was stirred at rt for 72 h before adding NaBH4 (65 mg, 1.7 mmol). After 16 h water (1 mL) was added. Solvent was removed in vacuo and the residue purified by column chromatography (NEt3: MeOH:DCM 3:30:500) to give the title compound: RT=2.47 min; m/z (ES+)=364.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:4]2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:4]2[CH:3]=1
Reactant: Cc1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cc1cn2c(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 11.9 mg (7% of theory) of the product are obtained starting from 120 mg (0.36 mmol) of 6-({2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}amino)nicotinonitrile (Example 30A) by coupling with 68.4 mg (0.36 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]1[C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][N:13]([C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:12])[CH2:17]1)[CH3:19])[CH2:33][CH2:34][CH3:35]
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CCCCOC(=O)Cl
Product: CCCCOC(=O)N(C)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid butyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using butyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 510.4 [M]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15](Cl)=[O:16])[CH:8]=2)[CH:3]=1.[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])[CH:8]=2)[CH:3]=1
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Cl)cc2c1
Reactant: CCCCCCCCCCCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1ccc2cc(O)c(C(=O)NCCCCCCCCCCCC)cc2c1
Temperature: 30 °C
Yield: 29 %

Procedure:
A dispersion of 5.4 g of 2-hydroxy-3,6-dichloro carbonylnaphthalene in 20.0 g of dry tetrahydrofuran was added with 14.8 g of n-dodecylamine solution in 30 g of dry tetrahydrofuran and reacted under reflux for 12 hours. To the reaction mixture, 50 g of water was added and the precipitates were collected by filtration, washed with water and thus obtained crystal was washed with 30 g of methanol under reflux. The obtained mixture was cooled to 30° C. and filtrated, washed with methanol and dried to provide 3.3 g of 2-hydroxy-3,6-di-n-dodecylaminocarbonylnaphthalene (decomposition point: 382.9° C.).
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]1[CH2:10][NH:9][CH2:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)[CH3:3].[N+:15]([O-])([O-:17])=[O:16].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[ClH:1].[N+:15]([C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH:4]([CH2:2][CH3:3])[CH2:10][NH:9][CH2:8][C:7]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: CCC1CNCc2ccccc2O1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC1CNCc2cc([N+](=O)[O-])ccc2O1
Reaction time: 0.08 h

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-1,4-benzoxazapine hydrochloride (8.0 g, 37.3 mmol) was dissolved in concentrated sulfuric acid (100 ml) and to this was added potassium nitrate (3.77 g, 37.3 mmol) at 0° C. The mixture was allowed to stir for 5 min., dumped onto ice, neutralized with 50% NaOH, and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil. The oil was dissolved in isopropanol and treated with isopropanol-HCl. The salt was filtered off and dried in vacuo (4.4 g, 46%), m.p. 238-240° C.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[CH3:10]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:10])[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ccnc1Br
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nccc(Cl)c1N
Temperature: 50 °C

Procedure:
Following a modified synthetic procedure reported in WO 2005/016892, a mixture of 2-bromo-4-chloropyridin-3-amine (prepared as described in US2002/0119982) (1.0 eq.), trimethylboroxine (1.05 eq.), K2CO3 (3.5 eq.) and PdCl2(dppf)-CH2Cl2 adduct (0.1 eq.) in 10:1 solution 1,4-dioxane:H2O (0.28M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then irradiated for 1 h at 120° C., using an irradiation power of 100 W. After completion of the reaction, the vial was cooled to 50° C. with air jet cooling before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether affording the titled compound as violet oil. MS (ES) C6H7ClN2 requires: 142, found: 143, 145 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].[O:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14](OC)=[O:15])(=[O:11])=[O:10])[CH2:5][CH2:4]1>CO>[O:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:1][NH2:2])=[O:15])(=[O:11])=[O:10])[CH2:5][CH2:4]1
Reactant: NN
Reactant: COC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Solvent: CO
Product: NNC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Temperature: 70 °C
Yield: 36.9 %

Procedure:
Hydrazine (22.46 mg, 0.701 mmol) was added to the methyl 2-(morpholinosulfonyl)benzoate (100 mg, 0.350 mmol) in methanol and refluxed for 12 h at 70° C. Following cooling, Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the title compound 2-(morpholinosulfonyl)benzohydrazide (40 mg, 0.129 mmol, 36.8% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.86 (m, 1H), 7.66-7.56 (m, 2H), 7.52 (dd, 1H, J=1.2 & 7.6 Hz), 7.40 (m, 1H), 4.09 (m, 2H), 3.70 (m, 4H), 3.15 (m, 4H). ESI-MS: 286.1[M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:23][PH:24]([O-])([O-:28])[O:25][CH2:26][CH3:27].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:24]([CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 68 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 19-b, (10 g, 0.026 mol), ethyl methylphosphite (5.6 g, 0.052 mol) and Et3N (7.88 g, 0.78 mol) in THF (100 ml) was added PdCl2(dppf) (2.2 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the product, 19-c, (6.9 g, 68%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH3-])(=O)C.[Na+]>C(#N)C>[C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1

Procedure:
In an additional embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of a catalyst, ytterbium trifluoromethanesulfonate, and heptane to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). The next step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a acetonitrile produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 1. The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium t-butoxide to afford trans-cyclohexane derivative (10) as a major diastereomer. Reduction of the ester functionality in compound (10), using lithium borohydride yields (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) in good overall yield, which is subsequently purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][NH:27][C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][NH:27][C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 33.7 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 1.0 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 494 mg of 5-amino-phthalazin-1-one. As in Example 3, 775 mg of the imine is reacted by reaction with 24.9 ml of titanium tetrachloride (1 M in dichloromethane) in 46 ml of dichloromethane, and 483 mg of the title compound is obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)=N[C@H](C(OC(C)(C)C)=O)CC2C=CC=C(OC(F)(F)F)C=2[N+]([O-])=O)C=CC=CC=1.C(OC([NH:45][C:46]1[C:54]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([OH:50])=[O:49])=O)(C)(C)C>ClCCl>[NH2:45][C:46]1[C:54]([O:55][C:56]([F:57])([F:58])[F:59])=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([OH:50])=[O:49]
Reactant: CC(C)(C)OC(=O)Nc1c(OC(F)(F)F)cccc1C(=O)O
Agent: CC(C)(C)OC(=O)[C@H](Cc1cccc(OC(F)(F)F)c1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Nc1c(OC(F)(F)F)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl N-(diphenylmethylene)-2-nitro-3-(trifluoromethoxy)-L-phenylalaninate (118) Trifluoroacetic acid (6 mL, 80 mmol) was added to a solution of 2-[(tert-butoxycarbonyl)amino]-3-(trifluoromethoxy)benzoic acid (117) (7.254 g, 22.58 mmol) in dichloromethane (40 mL). The mixture was stirred at RT for 2 h. The volatiles were removed in vacuo to provide 2-amino-3-(trifluoromethoxy)benzoic acid, which was dissolved in trifluoroacetic acid (30 mL). After addition of NaBO3.4H2O (18.3 g, 113 mmol), the mixture was stirred and heated at reflux for 18 h. The reaction mixture was cooled to RT, poured into water and extracted with Et2O. The combined extracts were dried, filtered and concentrated in vacuo to yield 2-nitro-3-(trifluoromethoxy)benzoic acid, which was then dissolved in THF (8.5 mL) and cooled to 0° C. Sodium borohydride (99%, 2.40 g, 62.8 mmol) was added in two portions; after gas evolution had subsided, boron trifluoride dimethyl etherate (98%, 5.89 mL, 62.9 mmol) was added drop-wise at 0° C., and the reaction mixture was stirred for 30 min at 0° C. The reaction was allowed to warm to RT over 18 h, then recooled in an ice bath and treated with saturated aqueous ammonium chloride solution until no additional gas evolution was observed. The mixture was partitioned between EtOAc (30 mL) and water (10 mL), and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide [2-nitro-3-(trifluoromethoxy)phenyl]methanol. This crude residue was dissolved in Et2O (150 mL). The mixture was cooled to 0° C. and phosphorus tribromide (97%, 3.68 mL, 37.9 mmol) was added. The mixture was allowed to warm to RT over 18 h, then poured onto ice water. The layers were separated and the aqueous layer was extracted with Et2O. The combined extracts were washed with water, dried, filtered and concentrated in vacuo to yielding 1-(bromomethyl)-2-nitro-3-(trifluoromethoxy)benzene. This crude residue was converted to the title compound using the general procedure outlined in Example 12 to afford the product as a yellow oil (3.67 g, 32%). LCMS m/z 515.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.20-3.31 (m, 2H), 4.23 (dd, J=8.2, 5.1 Hz, 1H), 6.68 (br d, J=7.2 Hz, 2H), 7.25-7.43 (m, 9H), 7.59-7.62 (m, 2H).