Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][NH:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]([N:12]2[CH2:11][CH:10]([N:8]([C:6](=[O:7])[C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]([F:27])([F:26])[F:25])[CH:4]=3)[CH3:9])[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13]2)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 4-chloro-N-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide instead of {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a white foam. MS m/e: 528.2 [M-BOC]+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH:2]=1.Cl[S:21]([OH:24])(=[O:23])=[O:22].C(=O)=O.CO.[Na+:30].[Cl-]>ClCCl>[Na+:30].[CH:10]([O:9][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([C:14]2[CH:15]=[CH:16][C:17]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:18][CH:19]=2)=[CH:2][CH:3]=1)=[O:13])([CH3:12])[CH3:11]
Reactant: CC(C)OC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)[O-])cc2)cc1
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 92 %

Procedure:
A suspension of isopropyl biphenyl-4-ylcarbamate (256 g, 1 mol) in dichloromethane (2000 ml) was cooled to −10° C. and chlorosulfonic acid (350 g, 200 ml, 3 mol) was added dropwise with stirring within 25 min with gentle cooling using a dry ice-methanol bath. The internal temperature was kept below −4° C. Subsequently, the dry ice-methanol bath was replaced by an ice bath and the mixture was stirred at from 3° C. to 14° C. for 1.5 h. Afterward, chlorosulfonic acid (175 ml, 2.6 mol) was again added at from 2° C. to 3° C., the mixture was stirred again for 30 min and then worked up. To this end, a mixture of ice (5 kg), methylene chloride (1000 ml) and concentrated NaCl solution (1300 ml) was initially charged under vigorous stirring and the reaction mixture was added slowly. The precipitated solid was filtered off with suction and dried at 45° C. under reduced pressure. 329 g (92%) of 4′-isopropoxycarbonylaminobiphenyl-4-sulfonic acid sodium salt were obtained as a white, crystalline powder, m.p.>260° C.,
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[Na].O>C(O)C>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCN1CC(Cc2ccccc2)OC1=O)c1ccccc1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Yield: 0.1 %

Procedure:
5-Benzyl-3-(3-oxo-3-phenylpropyl)-1,3-oxazolidin-2-one (0.31 g, 1 mol) prepared in the above (1) was dissolved in 3 ml of ethanol. To the solution, sodium boron hydride (80 mg, 2 mmol) was added under stirring while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 30 minutes, water was added. The obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.31 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([NH2:14])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:14][CH2:12][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a solution of 2.2 g of 1-benzylisonipecotamide in 50 ml of tetrahydrofuran was added 1.58 g of lithium aluminum hydride at 0° C. and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was cooled to 0° C. After adding water and a 10% aqueous solution of sodium hydroxide, the insoluble matters were filtered off. After distilling off the solvent under reduced pressure, 2.0 g of the title compound was obtained as a brown oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:15][NH:14][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:11])(=[O:10])[NH2:12])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C

Procedure:
1 mmol of 4-Cyano-benzenesulfonamide are dissolved in a mixture of ethanol/water (7:3) and 5 eq of hydroxylamine hydrochloride and 2.5 eq. Na2CO3 added. The suspension is heated to 80° C. for 2 h. After evaporation of the solvent mixture the resulting material is extracted from ethylacetate/water. The product was not further characterized.
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:25])[C:22](Cl)=[O:23])=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:25])[C:22]([O:1][C:2]23[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]2)[CH2:3]3)=[O:23])=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: CC(=O)NC12CC(O)(C1)C2
Product: CC(=O)NC12CC(OC(=O)C(C)c3ccc(CC(C)C)cc3)(C1)C2

Procedure:
The general procedure of Example 1 Step 3 is repeated starting with N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) and using 2-(4-isobutylphenyl)propanoyl chloride in place of the acetyl chloride to produce 3-acetamidobicyclo[1.1.1]pentan-1-yl 2-(4-isobutylphenyl)propanoate (9).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:18]([O:20][CH3:21])=[O:19].CCO.C(#N)C>C(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Agent: O=C=O
Solvent: CC#N
Solvent: CCO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cccc(F)c1
Yield: 36 %

Procedure:
Trans-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (214 mg, 0.64 mmol) was subjected to chiral preparative HPLC (Column: Chiralcel OJ (250×30), 5 μm particle size, mobile phase: 10% EtOH in CO2 (175 bar), flow rate 150 mL/min) to yield (2S,4S)-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate 77 mg (38.5%), Chiral purity 99.6% ee, Optical rotation [α]D20=+64.9 (acetonitrile, c=1)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(F)nc2c1nc(Cc1cc3c(cc1I)OCO3)n2CCCNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (100 mg, 0.21 mmol) in DMF (3 mL) was added cyclopropanecarbonyl chloride (29 μL, 0.32 mmol) and triethylamine (90 μL, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS71 as a white solid (75 mg, 65%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.32 (s, 1H), 6.77 (s, 1H), 6.02 (s, 2H), 4.24 (s, 2H), 4.16 (t, J=7.3 Hz, 2H), 3.26 (t, J=6.2 Hz, 2H), 1.91-2.01 (m, 2H), 1.50-1.57 (m, 1H), 0.90-0.95 (m, 2H), 0.76-0.82 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H21FIN6O3, 539.0704. found 539.0705.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:9]([CH2:18]O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:23][CH2:18][C:9]1[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:21])([CH3:20])[CH3:1])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOCOc1cc2ccccc2cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[Si](C)(C)CCOCOc1cc2ccccc2cc1CBr
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
400 mg (1.30 mmol) of [3-(2-trimethylsilylethoxy-methoxy)-naphthalen-2-yl]-methanol and 462 mg (1.81 mmol) of carbon tetrabromide were dissolved in 5 ml of absolute acetonitrile and the solution was cooled to 0° C. A solution of 446 mg (1.68 mmol) of triphenylphosphine in 6 ml of absolute acetonitrile was added dropwise thereto at 0° C. within 10 minutes and thereafter the mixture was stirred at 0° C. for a further 30 minutes. Subsequently, the solvent was distilled off under reduced pressure and, for purification, the crude product was chromatographed, without further working up, on silica gel using a 2:3 mixture of methylene chloride and hexane as the eluent. There were obtained 314 mg (65% of theory) of 2-bromomethyl-3-(2-trimethylsilylethoxymethoxy)-naphthalene as a light yellow oil; MS: 366, 368 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.C1(C2CCN(C(C3C=C(OC)C(OC)=C(OC)C=3)=O)CC2)C=CC=CC=1>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: COc1cc(C(=O)N2CCC(c3ccccc3)CC2)cc(OC)c1OC
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5%; 1g), dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. The reaction mixture was filtered and the excess of ethanol was evaporated under reduced pressure. Solid product was recrystallized from hexane to obtain the pure compound 5-aminoindole (55-1). Yield: 92.5%. 1H NMR (500 MHz, CDCl3): δ 7.96 (br, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 6.67 (dd, 1H), 6.37 (s, 1H), 3.50 (s, 2H). MS (ESI) m/z 133.0 (M+H)+
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:13]([Si](C)(C)C)#[CH:14]>>[C:13]([C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)#[CH:14]
Reactant: Nc1cccc2c(Br)cncc12
Reactant: C#C[Si](C)(C)C
Product: C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyltrimethylsilane according to the 2 steps procedure described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[NH2:6]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C(N)=O
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-aminobenzamide (100 g), ethyl bromoacetate (97.74 ml) and potassium carbonate (253.78 g) in N,N-dimethylformamide (400 ml) was stirred at 60° C. for 4.5 hours. After cooling, the reaction mixture was poured into ice-water (2 l) and the resulting crystals were collected by filtration. Thus obtained product was purified by recrystallization from ethanol to give ethyl N-(2-carbamoylphenyl)aminoacetate (123.93 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:26])[CH2:6][N:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[O:8])[CH2:4]1.[CH3:27][S:28][C:29](SC)=[CH:30][N+:31]([O-:33])=[O:32]>C(O)C>[F:16][C:11]1[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:9]([C:7]([N:5]2[CH2:6][C:3]([CH2:2][NH:1]/[C:29](/[S:28][CH3:27])=[CH:30]/[N+:31]([O-:33])=[O:32])([OH:26])[CH2:4]2)=[O:8])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CS/C(=C\[N+](=O)[O-])NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A solution of 3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (0.24 g, 0.5 mmol), prepared using procedures similar to those described in Example 3, and commercially available 1,1-bis(methylthio)-2-nitroethylene (0.083 g, 0.5 mmol) in ethanol (5 mL) was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 0.10 g, (39%) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol. MS (EI) for C20H18F3IN4O4S: 595 (MH+).
Reaction SMILES: C([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:13]1([C@@H:12]2[NH:8][C@H:9]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH2:10][CH2:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reaction time: 0.75 h
Yield: 37.5 %

Procedure:
To a stirred solution of methyl 4-[N-Boc-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.28 g, 3.11 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (10 ml) at rt, and the resulting mixture was stirred for 45 min. The mixture was concentrated in vacuo and poured into aq.NaHCO3, then extracted with CHCl3. The organic layer was washed with water, drying over anhydrous Na2SO4, and concentrated in vacuo to give methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinyl methoxy]benzate (363 mg, quant.) as yellowish oil. The product was used for next reactions without further purification. 1H-NMR (CDCl3) δ 1.71–1.83 (m, 2 H), 2.03–2.10 (m, 1 H), 2.15–2.24 (m, 1 H), 3.68–3.74 (m, 1 H), 3.89 (s, 3 H), 4.01–4.09 (m, 2 H), 4.28 (t, J=7.2 Hz, 1 H), 6.95 (d, J=8.8 Hz, 2 H), 7.22–7.27 (m, 1 H), 7.33 (t, J=8.0 Hz, 2 H), 7.42 (d, J=7.6 Hz, 2 H), 8.00 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 312 (M++H) 353 (M++CH3CN).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:13](OCC)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.CCCCCCC>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)cn1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A dry vessel under nitrogen at room temperature was charged with 5-bromo-4-(trifluoromethyl)pyridin-2-amine B1 (200 g, 830 mmol) and ethyl acetate (200 ml). The reaction mixture was cooled to 0° C. To the solution was added N,N-dimethylpyridin-4-amine (1.01 g, 8.29 mmol). Heptane (400 ml) was added and the mixture was cooled to 0° C. Acetic anhydride (109.6 ml, 1162 mmol) was added over a period of 60 min. The reaction mixture was warmed to 50° C. within 60 min. The reaction mixture was stirred at 50° C. for 18 h. Solvent (330 g) was removed by distillation (540-250 mbar, 50° C.) until a residue of ˜300 ml was obtained. The reaction mixture was allowed to cool to 20° C. Heptane (800 ml) was added and the mixture was stirred for 30 min. The precipitate was collected by filtration. The filter cake was washed with heptane (100 ml). The product was dried in a tray dryer for 16 h at 40° C., <20 mbar to yield 212 g (90%) B2 as sligthly brown solid.
Reaction SMILES: [ClH:1].[C:2]1([CH2:14][NH2:15])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=1.[H][H]>CO.[Pd]>[ClH:1].[CH:2]1([CH2:14][NH2:15])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3]1
Reactant: [H][H]
Reactant: NCC1=Cc2cccc3cccc1c23
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1Cc2cccc3cccc1c23
Yield: 83 %

Procedure:
The N-[(1-acenaphthylenyl)methyl]amine hydrochloride, A as prepared in Example A above (1.8 g, 8.3 mmol) was dissolved in methanol (100 ml) and 5% Pd/C (0.2 g) added. The mixture was stirred at room temperature, under 51 psi of hydrogen, for 2.5 hours (hydrogen uptake: AP=6.8 psi, calculated 7.1). The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was treated with ether (150 ml) and filtered to collect precipitate. The solid was dried at 45° C., in vacuo, overnight, to give 1.5 g (83%) of a white N-[(1,2-dihydro-1-acenaphthylenyl)methyl]amine hydrochloride salt, mp >250° C. Anal (C13H13N.HCl.0.15H2O), calc: C=71.20, H=6.48, N=6.30, Cl=15.54; found: C=70.14, H=6.51; N=6.42; Cl=16.11.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)[C:20]1=[O:36]>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)[C:20]1=[O:36])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCCCCCCCc1ccc2c(c1)CC(Br)C2=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)CC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a stirring solution of 60% NaH (1.194 g, 29.85 mmol) in DMF (5 mL) was added diethyl acetamidomalonate (6.484 g, 29.85 mmol) via cannula at 0° C. The solution was allowed to stir for 3 hours for anion to form. A solution of 3 (3.22 g, 9.95 mmol) in DMF (10 mL) was then added to then transferred to anion solution at 0° C. and left to stir over night at room temp. The reaction mixture was then poured over ice and extracted with EtOAc. The organic layer was washed with brine, dried with NaSO4 and concentrated. The product was then purified with silica gel chromatography eluding with 70% hexanes-30% EtOAc. The reaction provided 4 (2.842 g, 6.184 mmol, 65%).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:7].O.NN>C(O)C>[NH2:17][CH2:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:46])([F:1])[F:45])[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=2)[C@H:9]([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)[CH2:10]1)=[O:15]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Yield: 55.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethylcarbonyl)piperazine (250 mg), hydrazine hydrate (50 mg) in ethanol (5 ml) was heated under reflux for 2 hours. The resulting precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was washed with aqueous 1N sodium hydroxide solution and then purified by column chromatography on a silica gel eluting with a mixture of ethyl acetate and methanol (4:1) to afford (2R)-4-(2-aminoacetyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (110 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:19]1(=[O:26])[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([CH:20]1[C:21](=[O:25])[CH2:22][CH2:23][CH2:24][C:19]1=[O:26])=[O:5]
Reactant: Cn1nnn(-c2c(Cl)ccc(C(=O)Cl)c2Cl)c1=O
Reactant: O=C1CCCC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)C3C(=O)CCCC3=O)c2Cl)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.1 %

Procedure:
A dichloromethane solution of the crude 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl chloride (1.10 g) was added drop by drop to the solution of 1,3-cyclohexanedione (0.44 g) and triethylamine (0.43 g) in dichloromethane (8 ml) at 5° C. and the mixture was stirred at room temperature for 6 hours. After completion of the reaction it was extracted with dichloromethane (150 ml), washed with diluted hydrochloric acid and aqueous solution of sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the dichloromethane, was dissolved in acetonitrile (7 ml), added with triethylamine (0.43 g) and acetonecyanohydrin (18 mg) and stirred at room temperature for 8 hours. After the solvent was distilled off, the residue was acidified by addition of diluted hydrochloric acid and extracted with ethyl acetate (150 ml). The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective 2-[2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl]cyclohexan-1,3-dione (0.70 g, 51% yield from 2,4-dichloro-3-(4,5-dihydro4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid) was obtained. mp 138-140° C.