Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn(C2CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CC2)c1C(F)(F)F
Yield: 105.4 %

Procedure:
To a solution of 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (140 mg, 0.56 mmol) in CH3OH (2 mL) and water (2 mL) was added LiOH (16 mg, 0.67 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (130 mg, quantitative), which was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].ClC(Cl)(O[C:9](=[O:15])OC(Cl)(Cl)Cl)Cl.[CH3:17][N:18]1[C:26](=[O:27])[NH:25][C:24]2[C:19]1=[N:20][C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N:22][CH:23]=2.N12CCN(CC1)CC2>ClCCl.C(N(CC)CC)C>[CH2:1]([N:3]([CH3:4])[C:9]([N:25]1[C:24]2[C:19](=[N:20][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:22][CH:23]=2)[N:18]([CH3:17])[C:26]1=[O:27])=[O:15])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNC
Reactant: Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)n1c(=O)n(C)c2nc(-c3ccccc3)ncc21
Reaction time: 0.17 h

Procedure:
To a solution of N-ethylmethylamine (78 mg) and triphosgene (209 mg) in dichloromethane (10 ml) was added dropwise triethylamine (365 μl) at room temperature and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of 9-methyl-2-phenyl-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 21> (200 mg) and 1,4-diazabicyclo[2.2.2]octane (220 mg) in dichloromethane (10 ml) and the mixture was stirred for 1 hour. The reaction mixture was washed with water and the organic layer was, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜0/100) to give the title compound 156 mg.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=1)[CH:24]=O>>[Br:20][C:21]1[CH:22]=[C:23]([CH2:24][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:26]=[CH:27][N:28]=1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(Br)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(Br)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-bromoisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 404.91 g/mol.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (1.83 g, 87.1%) as a solid.
Reaction SMILES: [N:1]1([C:8]2[CH:29]=[CH:28][C:11]([CH:12](O)[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].P(Cl)(Cl)(Cl)(Cl)[Cl:31]>C(#N)C>[ClH:31].[ClH:31].[N:1]1([C:8]2[CH:29]=[CH:28][C:11]([CH:12]([Cl:31])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccccc1N1CCN(CC(O)c2ccc(N3CCCNC3=O)cc2)CC1
Solvent: CC#N
Product: Cc1ccccc1N1CCN(CC(Cl)c2ccc(N3CCCNC3=O)cc2)CC1
Product: Cl

Procedure:
7.9 gm (20 millimols) of N-[p-(1-hexahydropyrimidin-2-one-yl)-β-hydroxy-phenethyl]-N'-(o-tolyl)-piperazine (see Example 10) were dissolved in 100 ml of acetonitrile, and while stirring and cooling the solution, 8.34 gm (40 millimols) of phosphorus pentachloride were added thereto. A good yield of N-[p-(1-hexhydropyrimidin-2-one-yl)-β-chlorophenethyl]-N'-(o-tolyl)-piperazine dihydrochloride was obtained. This product was dissolved in 100 ml of methanol, 10 gm of dimethylaniline and a small amount of Raney nickel were added to the solution, and the mixture was hydrogenated at atmospheric pressure, yielding N-[p-(1-hexahydropyrimidin-2-one-yl)-phenethyl]-N'-(o-tolyl)-piperazine, m.p. 127 - 128° C, after working up the reaction mixture in conventional manner.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[Mg].C[O:15][B:16](OC)[O:17]C.Cl>O1CCCC1.C(Br)CBr>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([B:16]([OH:17])[OH:15])=[CH:4][C:3]=1[F:12]
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)c2occc2c1F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OB(O)c1cc(F)c(F)c2ccoc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
Alternatively, a mixture of 0.484 gm (2.08 mMol) 4,5-difluoro-7-bromobenzofuran and 0.065 gm (2.67 mMol) magnesium in 5 mL tetrahydrofuran was heated at reflux. Two drops of 1,2-dibromomethane were added and the mixture heated at reflux for 45 minutes. To this mixture were added 260 μL (2.29 mMol) trimethylborate and heating was continued for an additional 45 minutes. After cooling to room temperature, 2.3 mL 1N hydrochloric acid were added and the mixture stirred for 45 minutes. The mixture was then extracted well with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was slurried in 4 mL hexanes, the solvent removed by decantation, and the residual solid dried under reduced pressure to provide 0.402 gm (97.8%) of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][N:13]2[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14]2)[CH2:11][CH2:10]1.[Br:34]Br>O1CCCC1>[Br:34][CH:18]1[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:14][N:13]([CH2:12][CH:9]2[CH2:10][CH2:11]2)[C:19]1=[O:20]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CC2CC2)CC1c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Br)C(=O)N(CC2CC2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (1 M in THF; 2.13 mL, 2.13 mmol) was added to tert-butyl 4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.489 g, 1.42 mmol) in tetrahydrofuran (5 mL) at −78° C. After 30 min, the enolate solution was transferred dropwise via cannula to a solution of bromine (0.36 mL, 7.10 mmol) in tetrahydrofuran (3 mL) at −78° C. over a period of 5 min. After 15 min, the mixture was quenched with aqueous saturated sodium sulfite and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate, washed with saturated 50 aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. MS 423 (M+1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH:41]1([NH:44][NH2:45])[CH2:43][CH2:42]1.CCN(C(C)C)C(C)C>O.C(Cl)Cl>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:45][NH:44][CH:41]3[CH2:43][CH2:42]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC1CC1
Reaction time: 1 h
Yield: 2.7 %

Procedure:
A 100-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g.) and CH2Cl2 (25 mL). DCC (0.29 g, 1.0 eq.) was added and the mixture was cooled to 0° C. for the sequential addition of cyclopropylhydrazine hydrochloride (0.15 g, 1.0 eq.) and DIPEA (0.24 mL, 1.0 eq.). The reaction mixture was stirred for 1 h before being poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound. Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane) afforded 15 mg (yield: 2.6%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-cyclopropylacrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 9.16 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.23-7.26 (d, J=10.4 Hz, 1H), 6.40-6.43 (d, J=10.4 Hz, 1H), 4.97 (s, 1H), 4.63 (s, 1H), 3.18-3.20 (m, 1H), 0.83-0.87 (m, 2H), 0.65-0.69 (m, 2H); LCMS for Chemical Formula: C16H14F6N5O [M+H]+ 406.31 found 406.19 (RT 2.74 min, purity: 98.85%).
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29]C)=[O:28])[CH2:19][CH2:18]1)=[O:16].[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.O>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18]1)=[O:16]
Reactant: CCOCCn1c(C(=O)C2CCN(CCOCC(=O)OC)CC2)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOCCn1c(C(=O)C2CCN(CCOCC(=O)O)CC2)nc2ccccc21
Temperature: 60 °C

Procedure:
Dissolve 1-[[(2-ethoxy)ethyl]-1H-benzimidazol-2-yl][1-(carbomethoxy methoxy ethyl)-4-piperidinyl]methanone (0.9 g, 2.15 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxide monohydroate (932 mg, 8.5 mmol). Seal the flask and warm to 60° C. for 3 hours. Dilute with ethyl acetate/water, acidify and separate the organic phase. Dry (MgSO4), evaporate the solvent in vacuo, and purify by ion-exchange chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(Cl)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1C1=NNC(=O)CC1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-chlorobenzoyl]propionate was cyclised with hydrazine hydrate in a similar manner to the procedure described in Example 2(ii) to give 6-[2(3-t-butylamino-2-hydroxypropoxy)-5-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:30])[C@@H:23]([N:36]4[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]4)[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 78.3 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-17β-hydroxy-5α-androstane is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title compound in a yield of 78.3%, m.p.: 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[C:11]([CH3:23])=[C:12]([C:21]#[N:22])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][OH:19])[C:15]=2[OH:16])=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1.N1C=C[CH:30]=[CH:29][CH:28]=1.[OH2:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[C:11]([CH3:23])=[C:12]([C:21]#[N:22])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][O:19][C:28](=[O:33])[CH:29]=[CH2:30])[C:15]=2[OH:16])=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1
Reactant: c1ccncc1
Reactant: Cc1c(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)n(CCO)c(=O)c1C#N
Reactant: O
Solvent: ClCCl
Product: C=CC(=O)OCCn1c(O)c(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(C)c(C#N)c1=O

Procedure:
Methacryloyl anhydride (17.9 g, 0.116 mol) is added to a stirred mixture of 5-(4-chloro-2-nitrophenylazo)-3-cyano-6-hydroxy-1-(2-hydroxyethyl)-4-methylpyrid-2-one (22 g, 058 mol) and pyridine (25 ml) in methylene chloride (200 ml). The mixture is stirred under reflux for 24 hours, forming a solution after ca. 5 hr. After cooling to 20° C. water (20 ml) is added, with stirring, followed by more water (200 ml) after a further 2 hours. The organic layer is collected and the solvent removed to leave a tarry residue which is stirred at 70° C. for 20 minutes, with aqueous methylated spirits. The resulting brownish yellow solid is collected (21.3 g, 82%). This crude product is passed through silica gel using (methylene chloride:hexane 80:20) as eluant. The solvent is removed and the residue is crystallised from methylene chloride/isopropanol.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.C(O)(=O)C>O>[CH3:1][N:2]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]1=[O:4]
Reactant: CNC(=O)N(CCC(=O)O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)CCN(c2ccc(C(F)(F)F)cc2)C1=O
Yield: 88.7 %

Procedure:
At first, 4 g (0.014 moles) of N-(methylcarbamoyl)-N-(4-trifluoromethylphenyl)-β-alanine was added to a solution consisting of 45 ml of 6N-hydrochloric acid and 15 ml of acetic acid, and the mixture was refluxed with heating for 2 hours. After completion of the reaction, 50 ml of water was added thereto. The deposited crystals were recovered by filtration with suction and recrystallized from ethyl acetate-n-hexane, 3.38 g of the desired compound was obtained as colorless needle crystals having a melting point of 115°-117° C. (yield: 90.1%).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][C:17]=1[CH3:26])[CH3:14].[CH3:27][NH2:28]>CO>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([NH:28][CH3:27])=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)=[CH:18][C:17]=1[CH3:26])[CH3:12]
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1cc(C)c(CN(C)C)o1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamine [prepared in Step C] and the resultant 3-{2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-b 1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is produced.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].ClCCl>>[F:33][C:32]([F:35])([F:34])[C:30]([O-:36])=[O:31].[CH2:1]([NH:8][C:9]([CH:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][NH2+:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)NCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1[NH2+]CCCC1c1ccccc1
Product: O=C([O-])C(F)(F)F
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of tert-butyl 2-[(benzylamino)carbonyl]-3-phenylpiperidine-1-carboxylate (1.44 g, 3.65 mmol) in 1:1 TFA/dichloromethane (10 ml) was allowed to stir for 3 h. The reaction was concentrated in vacuo, and the residue was dissolved in acetonitrile/water and lyophilized to yield 2-[(benzylamino)carbonyl]-3-phenylpiperidinium trifluoroacetate (91%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.[CH2:11]([O:18][C:19]([NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](O)=[O:30])[CH2:25][CH2:24]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N=C=NCCCN(C)C)C.Cl.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:20])[NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](=[O:30])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:25][CH2:24]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-chloropyrazin-2-yl)methanamine hydrochloride (5 g, 21.38 mmol), (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (6.23 g, 21.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (4.51 g, 23.52 mmol), 1-hydroxy-7-azabenzotriazole (1.455 g, 10.69 mmol), and triethyl amine (4.76 ml, 34.2 mmol) in dichloromethane (60 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane with gradient 0.5 to 5% of methanol) to yield benzyl((trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl)methylcarbamate (8.79 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@H:13](O)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:64]([C@@H:13]1[C@@H:11]2[C@@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[N+:65]=[N-:66]
Reactant: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reaction time: 16 h

Procedure:
(3aR,4R,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (3.00 g, 13.81 mmol, Example 706, Step 1) and triphenylphosphine (4.35 g, 16.57 mmol) were combined in toluene (69 mL). Diisopropyl azodicarboxylate (3.49 g, 17.26 mmol) was added dropwise via addition funnel to the reaction solution at 5° C. Diphenylphosphoryl azide (4.56 g, 16.57 mmol) was then added to the reaction solution. The reaction was allowed to proceed at room temperature for 16 hours and then quenched with saturated aqueous sodium bicarbonate (100 mL). The resulting layers were separated and the product containing phase was extracted with 1.2 M hydrochloric acid (2×40 mL). The acid layer was extracted with ethyl acetate (50 mL) and then basified with 1.9 M potassium hydroxide (68 mL). The aqueous solution was extracted with methyl tert-butyl ether (2×50 mL). The methyl tert-butyl ether was removed under reduced pressure by co-distillation with ethanol and then filtered to provide (3aR,4S,6aS)-4-azido-2-benzyloctahydrocyclopenta-[c]pyrrole in ethanol.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[OH:15][C:16]1[CH:20]=[C:19]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[N:18]([C:32]2[C:37]([Cl:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:33]=2[Cl:40])[N:17]=1.O>ClC(Cl)C(Cl)Cl.CO>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:20]1[C:16]([OH:15])=[N:17][N:18]([C:32]2[C:33]([Cl:40])=[CH:34][C:35]([Cl:39])=[CH:36][C:37]=2[Cl:38])[C:19]=1[N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])=[O:9]
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1Cl)c1c(O)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum trichloride (2.34 g, 17.6 mmol) was added to a solution of 2-chlorobenzoyl chloride in 60 mL of 1,1,2,2-tetrachloroethane and the resulting mixture was stirred for 30 minutes at room temperature. Then 2.87 g of the compound of Step B was added all at once and the reaction mixture was refluxed overnight. The cooled mixture was poured into water and the aqueous phase was extracted three times with ethyl acetate. The organic extracts were dried with brine and magnesium sulfate and evaporated to give a red oil which was taken up in methanol and crystallized to give the title compound, 2.97 g (77%), m.p. 245 -246° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[NH:23][CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]ccc4c3O2)cc1

Procedure:
A mixture of 3.75 g (9.2mmole) of [(2R)-7-nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate and 3.0 g of platinum oxide in 50 mL of ethyl acetate was treated with 45 psi of hydrogen on a Parr hydrogenation apparatus for 6 hours. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on silica gel with first 10% hexane/methylene chloride, then 1% methanol/methylene chloride and finally 2% methanol/methylene chloride to give 1.50 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 145° C.