Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8](C3CCC(=O)CC3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(OC(N1CCCCC1)=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)N1CCCCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
In a similar manner to the previous Example, 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (0.4 g from 1.0 g of 40% pure material) and 1-ethoxycarbonyl-piperidine (158 mg) were reacted together in the presence of sodium triacetoxyborohydride (296 mg) in dichloromethane (15 ml) containing glacial acetic acid (60 mg) to give after workup and chromatography cis-7-(4-N-ethoxycarbonyl)piperazin-1-ylcyclohexyl)-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N-ethoxycarbonyl)-piperazin-1-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:30]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution comprising 10 g (33.7 mmol) of 1,4-dibenzyl-2-hydroxymethylpiperazine (prepared in accordance with the process described by Jucker and Rissi in Helv. Chem. Acta, 1962, 45, 2383-2402) in 9.5 ml (2.8 equivalents; 94.4 mmol) of triethylamine and 95 ml of dichloromethane (CH2Cl2) is placed in a 500 ml ground-necked conical flask on which is fitted an addition funnel, and is cooled in an ice bath. After dropwise addition of 6.4 g (1.25 equivalents; 42 mmol) of phenyl chlorocarbonate dissolved in 95 ml of CH2Cl2, the mixture is stirred at 0° C. for one hour and then at room temperature for 10 hours. At the end of the reaction, the solution is washed once with saturated sodium bicarbonate (NaHCO3), solution and then with water until a neutral pH is obtained, and it is dried over magnesium sulfate (MgSO4). After filtration on paper and evaporation of the CH2Cl2, the residue is chromatographed on a column of silica gel, using dichloromethane as eluent. 8 g of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine are thus obtained in the form of a viscous product. Yield: 57%. Rf=0.52 (2/98 v/v MeOH/CH2Cl2,).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][CH2:22][CH3:23])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:2]2[CH:3]=[C:4]([NH:21][CH2:22][CH3:23])[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:25][CH2:26]1
Reactant: CCNc1cc(Cl)nn2c(C(=O)Nc3ccncc3F)cnc12
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 120 °C

Procedure:
A mixture of 82A (62.7 mg, 0.187 mmol), trans-cyclohexane-1,4-diamine (214 mg, 1.873 mmol) and DIEA (0.033 mL, 0.187 mmol) in NMP (1 mL) was heated in a microwave reactor at 120° C. for 50 minutes. The resulting mixture was diluted with water and made basic with saturated aqueous NaHCO3. The resulting solid was collected by filtration and dried under vacuum to give 6-((trans)-4-aminocyclohexylamino)-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as an off white solid (66.1 mg). HPLC Rt=2.122 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=413.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.CN(OC)[C:14]([C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)=[O:15]>CCOCC>[O:9]1[CH:10]=[CH:11][C:7]([C:14]([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)=[O:15])=[CH:8]1
Reactant: CON(C)C(=O)c1ccoc1
Reactant: Brc1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccoc1)c1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a solution of n-butyllithium (2.5M, 28 mL, 0.07 mol) in 150 mL of ether at -78 ° C. was added a solution of 3-bromofuran (10 g, 0.0628 mol) in 30 mL of ether over a 20 min period and the mixture was stirred at -78° C. for 20 min. To the above mixture was added 3-(N-methyl-N-methoxycarbamoyl)furan (9.16 g, 0.059 mol) in 30 mL of ether over a 15 min period and the mixture was stirred at room temperature for 1/2 h. The reaction mixture was quenched with 200 mL of ammonium chloride solution, 500 mL of methylene chloride was added and the mixture was stirred. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was triturated with 100 mL of hexane/TBME (9:1). The solid product was filtered and washed with TBME to afford 7.5 g (78.3%) of di-(3-furyl)ketone.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:23]=[CH:22][C:9]([O:10][C:11]2[CH:12]=[C:13]([C:17]#[C:18][CH:19](O)[CH3:20])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1>>[Br:2][CH:19]([C:18]#[C:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:22]=[CH:23][C:6]([F:5])=[CH:7][CH:8]=2)[CH:12]=1)[CH3:20]
Reactant: BrP(Br)Br
Reactant: CC(O)C#Cc1cccc(Oc2ccc(F)cc2)c1
Product: CC(Br)C#Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
The solution of 4-[3-(4-fluorophenoxy)phenyl]-3-butyn-2-ol in methyl t-butyl ether prepared in step 1 was cooled to 0°-10° C. and PBr3 (7.6 kg) was added slowly to maintain the reaction temperature under 15° C. The reaction mixture was agitated for 2 hours and then was quenched by the addition of chilled distilled water (25 kg). The layers were separated and the organic phase was diltuted with methyl t-butyl ether, washed with distilled water and 5% aqueous NaHCO3, and concentrated in vacuo to give 2-bromo-4-[3-(4-fluorophenoxy)phenyl]-3-butyne.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]2[C@H:19]3[C@H:24]([CH2:25][CH2:26][C:17]=2[CH:16]=1)[NH:23][CH2:22][CH2:21][CH2:20]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@H:19]([C:18]5[CH:27]=[CH:28][C:15]([O:14][CH3:13])=[CH:16][C:17]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc2c(c1)CC[C@H]1[C@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 71 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 71% of theory; LC (method 1): tR=2.61 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH3:32][CH2:33][C:34](Cl)=[S:35].[OH-].[Na+]>CC(C)=O>[CH3:32][CH2:33][C:34]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[S:35]
Reactant: CCC(=S)Cl
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(C(CCNC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20° ) solution of 10.4 g. (0.026 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml. of 3% sodium bicarbonate and 220 ml. of acetone is added dropwise a solution of 3.66 g. (0.029 mol.) of methylthioacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>CCO.C1COCC1.O.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[O:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[N:15][CH:14]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1)C(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Temperature: 80 °C
Yield: 86 %

Procedure:
Methyl 3-methyl-2-(5-(4-nitrophenyl)oxazole-2-carboxamido)butanoate (step E product, 700 mg) was dissolved in a solvent mixture of EtOH (7 ml), THF (2.8 ml), and water (2.8 ml). Ammonium chloride (323 mg) and iron (264 mg) were then added and the reaction mixture was refluxed at 80° C. for 3 hours. It was then cooled, filtered through celite and the solvent was removed under reduced pressure to get dark brown residue. The residue was dissolved in water and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated to get dark brown residue which was purified by silica gel column chromatography in 2.5:7.5 EtOAc:CHCl3 to get yellow solid which was crystallized in DCM/Pet ether to yield 550 mg (86%) yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 8.83 (d, 1H), 7.55 (s, 1H), 7.48 (d, 2H), 6.66 (d, 2H), 5.63 (bs, 2H), 4.28 (m, 1H), 3.67 (s, 3H), 1.98 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[C:9]([Cl:13])=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]=1[CH3:14])[CH:2]=[CH2:3].[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[ClH:13].[CH2:1]([C:4]1[C:8]2[C:9]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]=1[CH3:14])[CH:2]=[CH2:3]
Reactant: c1ccc2c(c1)CCNC2
Reactant: C=CCc1c(C)[nH]c2ccnc(Cl)c12
Product: C=CCc1c(C)[nH]c2ccnc(N3CCc4ccccc4C3)c12
Product: Cl
Yield: 77.4 %

Procedure:
In accordance with the same procedures as Examples 1 and 2, except for using 3-allyl-4-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridine prepared in Preparation 4 and 1,2,3,4-tetrahydroisoquinoline, the titled compound was obtained as a pale yellow solid. (Yield: 77.4%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:23])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C=O
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (19.53 g, 0.0639 mol) in dry MeOH (300 mL) under an argon atmosphere at room temperature was treated with paraformaldehyde (5.76 g, 0.1918 mol) and sodium methoxide (17.27 g, 0.3197 mol). The reaction mixture heated at 50° C., stirred overnight then cooled to room temperature. Sodium borohydride (7.26 g, 0.1918 mmol) was added portionwise and the reaction mixture was then re-heated to 50° C. and stirred for 2 days. The reaction mixture was cooled to rt and stirred for a further 24 h, then concentrated and re-dissolved in DCM (200 mL). Saturated aq. NaHCO3 solution (200 mL) was added portionwise with stirring and on completion of addition the mixture was stirred at room temperature for a further 0.5 h. The DCM phase was separated, washed with brine, dried (MgSO4) and concentrated to give a yellow oil which was purified by column chromatography. Elution with 0%, 10% and then 20% EtOAc/hexane yielded the title compound as a yellow oil which crystallised on standing (16.7 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9][CH3:10])=[O:8].[N:11]([O-])=[O:12].[Na+].C(O)(=O)C>O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([N:11]=[O:12])[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=N[O-]
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1[C@@H](O)CCN1N=O
Reaction time: 4 h

Procedure:
To a solution of (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate (16 g, 0.110 moles) in water (60 mL) was added NaNO2 (16 g, 0.220 moles) in water (30 mL) followed by the addition of glacial acetic acid (9.43 mL, 0.165 moles) at 0° C. and the reaction mixture was stirred for 4 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to get the title compound which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.N1C=CC=CC=1C([OH:28])C.[CH2:29]1[CH2:39][CH2:38][N:37]2C(=N[CH2:34][CH2:35][CH2:36]2)C[CH2:30]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([O:28][CH2:34][CH2:35][C:36]2[CH:30]=[CH:29][CH:39]=[CH:38][N:37]=2)[N:3]=1
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Reactant: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccccc1F

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, (2-pyridyl)ethanol and DBU in DME. ES-MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-aminobenzoate (5.02 g) in N,N-dimethylacetamide (DMA, 50 ml) was added dropwise pentanoyl chloride (4.0 ml), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was stirred for 1 hr. The mixture was partitioned and extracted by adding ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give ethyl 3-(N-pentanoyl)aminobenzoate (7.55 g). To a solution of the obtained amide compound in DMA (100 ml) was added potassium tert-butoxide (4.09 g), and the mixture was stirred for 30 min. To the reaction mixture was added [4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methylbromide (18.6 g), and the mixture was stirred at 50° C. for 3 hrs. The reaction mixture was added to ethyl acetate-water and, after partitioning and extraction, the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate:3-2 v/v) to give the object compound (20.6 g, yield 93.6%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]1[CH:11]=[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:9]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]1=[S:32](=[O:34])=[O:33].Cl>O.C(O)C>[CH2:25]([NH:24][C:8]1[C:7](=[S:32](=[O:34])=[O:33])[CH:6]([CH:11]=[C:10]([N:12]2[CH:13]=[CH:14][CH:15]=[CH:16]2)[C:9]=1[S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:5]([OH:35])=[O:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(NCc2ccccc2)C1=S(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(NCc2ccccc2)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A solution of 0.083 g of NaOH in 30 ml of water is added to a solution of 1.0 g of 3-benzylamino-4-phenylthio-5-pyrrol-1-yl-sulfonyl-benzoic acid methyl ester in 70 ml of ethanol, and the mixture is stirred first for 4 hours at room temperature and then for 1 hour at 40° C. to complete the reaction. After stripping off the ethanol under reduced pressure, the aqueous phase is acidified with dilute hydrochloric acid and the product is filtered off and recrystallized from ethyl acetate. 3-Benzylamino-4-phenylthio-5-pyrrol-1-yl-sulfonylbenzoic acid of melting point 218°-220° C. is obtained. Yield: 60%.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH:21][C@@H](C3C=CC=CC=3)C)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1>[OH-].[Pd+2].[OH-].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH2:21])=[O:14])[CH2:8]2)=[CH:30][CH:31]=1
Reactant: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 20 h
Yield: 96.4 %

Procedure:
[(S)-3-(4-Fluoro-benzyl)-piperidin-1-yl]-[(3S,4R)-3-((R)-1-phenyl-ethylamino)-tetrahydro-pyran-4-yl]-methanone (1.10 g, 2.6 mmol), palladium hydroxide (20 weight % on carbon, dry basis; 440 mg) and ethanol (40 mL) were combined in a pressure bottle and shaken under a hydrogen atmosphere (55-60 psig) for 20 h. The mixture was filtered through Celite, and the solids were washed thoroughly with ethanol. The filtrate was concentrated to give the product as a glassy foam (803 mg, 96%), used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[N:12][OH:13])[NH2:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(N)=NO)cc1
Yield: 20 %

Procedure:
13.32 g (0.1 mol) 4-methoxybenzonitrile, 20.85 g (0.3 mol) of hydroxylamine hydrochloride and 41.40 g (0.3 mol) potassium carbonate was added to 400 mL absolute ethanol and refluxed 21 hours. The product was filtered and recrystallized from methanol to give 3.12 g (0.02 mol) of 4-methoxybenzamide oxime.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(N(C(C)C)C(C)C)C>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: Clc1ncccn1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncccn2)cc1F
Temperature: 80 °C
Yield: 71.1 %

Procedure:
A mixture of 2.08 g (4 mmol)(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 0.687 g (6 mmol) 2-chloropyrimidine and 1.16 ml (6.8 mmol) N-ethyldiisopropylamine was heated for 3 h at 80° C. The reaction was cooled and partitioned between H2O/Et2O (3×300). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (CH2Cl2/EtOAc 97.5:2.5) gave 1.7 g (71%) (2S,4R)-2-[2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 598 (MH+).
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F-:12].[K+].O>CC#N>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([F:12])(=[O:9])=[O:8]
Reactant: [F-]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1S(=O)(=O)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/1; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H](O)CC1CCC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
A mixture of 1.05 g (7.3 mmol) of 2-(S)-hydroxy-3-(cyclobutyl)propanoic acid (from Step D), 40 mL (10.0 mmol) of TEA and 1.20 mL (10.0 mmol) of benzyl bromide in 8 mL of DMF was stirred at rt for 2 h. The mixture was partitioned between 200 mL of ether and 100 mL of H2O and the layers were separated. The organic layer was washed with 100 mL of 2.0 N HCl, 100 mL of sat'd NaHCO3, 2×100 mL of H2O, 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 60 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 1.20 g (70%) of the title compound: 1H NMR (500 MHz) δ1.58-1.70 (m, 2H), 1.72-1.82 (m, 2H), 1.84-1.92 (m, 2H), 1.98-2.10 (m, 2H), 2.46-2.58 (m, 1H), 2.63 (br s, 1H), 4.15 (dd, J=7.5, 3.0), 7.33-7.40 (m, 5H).