Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]([NH2:16])=[O:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[C:5]([C:14]([NH2:16])=[O:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: NC(=O)c1ncc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 97 %

Procedure:
A round bottom flask was charged with 3-nitro-5-(trifluoromethyl)picolinamide (850 mg, 3.62 mmol) and wet 5 wt. % Pd/C (769 mg, 0.362 mmol) and was purged with nitrogen. EtOAc (72300 and then MeOH (72300 were added, and the flask was evacuated and filled with hydrogen. The reaction was stirred at RT under hydrogen atmosphere for 17 h. The mixture was filtered through Celite and washed with EtOAc and MeOH. The filtrate was concentrated to provide 3-amino-5-(trifluoromethyl)picolinamide (720 mg, 3.51 mmol, 97% yield) as a white solid. LC/MS (ESI+) m/z=206.1 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[NH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])=[CH:3][CH:2]=1.[OH:15]P(O)(O)=O>>[C:12]([NH:14][C@H:8]([C:9]([OH:15])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:13])[NH2:11]
Reactant: O=P(O)(O)O
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Product: NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The assay of the D-hydantoinase activity was conducted by incubating a reaction mixture containing 120 mg/dl D-5-benzylhydantoin (BH), 50 mM KPB (pH 8.0) and an enzyme solution at 37° C. for 30 minutes, adding 9 volumes of 1.1 mMCuSO4, 11.1 mM H3PO4, centrifuging at 20,000G for 10 minutes to remove the pellet, and then quantifying the resultant N-carbamylphenylalanine (N—Car—Phe) by HPLC. One unit of the enzyme activity was defined as an enzymatic activity capable of producing 1 μmol of N-carbamylphenylalanine per 1 minute under the condition described above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:29])[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][CH:19]=3)[CH2:13][CH2:12]2)[N:5]=[C:4]([C:30]([O:32]C)=O)[C:3]=1[C:34]#[N:35].[NH3:36]>CO>[NH2:1][C:2]1[C:3]([C:34]#[N:35])=[C:4]([C:30]([NH2:36])=[O:32])[N:5]=[C:6]([C:8]([NH:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:29])[CH:7]=1
Reactant: COC(=O)c1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)cc(N)c1C#N
Reactant: N
Solvent: CO
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound prepared in Example 233 (0.057 g) was suspended in methanol (4 mL) and 7 M ammonia solution in methanol (4 mL) was added. After stirring overnight at room temperature, the reaction was concentrated to provide the title compound (0.053 g) with the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:35]O>>[CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][S:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[O:35])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(SCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[2-(3,4-dimethoxyphenylthio)-ethyl]-methylamine and hydrogen peroxide analogously to Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6].Cl.[NH2:21][C@H:22]([C:27]([NH2:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26].C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][C:10]2([NH:29][C:27](=[O:28])[C@H:22]([CH2:23][CH2:24][S:25][CH3:26])[NH:21]2)[CH2:9][CH2:8]1)=[O:6]
Reactant: COc1ccc(C(=O)N2CCC(=O)CC2)c(OC)c1
Reactant: CSCC[C@H](N)C(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCC3(CC2)NC(=O)[C@H](CCSC)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2,4-dimethoxybenzoyl)piperidin-4-one (1.4 g, 5.1 mmol), (S)-methioninamide hydrochloride (950 mg, 5.1 mmol) and triethylamine (520 mg, 5.1 mmol) in EtOH (40 ml) was heated under reflux for 2.5 h and stirred at RT for a further 16 h. After removal of the solvent, water (25 ml) and CH2Cl2 (25 ml) were added to the residue and it was rendered basic using conc. sodium hydroxide solution. The aqueous phase was extracted with CH2Cl2 (3×20 ml) and the combined organic phases were dried over Na2SO4. After removal of the solvent and drying in vacuo, the product 8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.9 g (95%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]([F:12])([F:22])[F:23])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1OC(F)(F)F
Temperature: 100 °C

Procedure:
2,6-Dichloro-3-nitropyridine (10.0 g, 51.8 mmol) and 2-(trifluoromethoxy)aniline (18.4 g, 104 mmol) were taken up in ethanol (50 mL) and heated to 100° C. for 48 h in a sealed tube. The reaction mixture was cooled in an ice bath, and the resulting precipitate was collected by vacuum filtration to give an intermediate 6-chloro-3-nitro-N-(2-(trifluoromethoxy)phenyl)pyridin-2-amine, which was dissolved in dioxane (65 mL) and H2O (35 mL). Potassium hydroxide (2.90 g, 51.7 mmol) was added and the reaction mixture was heated to 100° C. for 16 h. After cooling, the pH was adjusted to less than 7 with 1 N HCl. The resulting precipitate was collected by vacuum filtration to give the title compound as a bright yellow solid (5.10 g). LCMS m/z=316.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 5.91 (d, J=10.1 Hz, 1H), 7.51 (m, 4H), 8.26 (d, J=10.1 Hz, 1H), 8.50-8.85 (broad s, 1H), 10.78 (broad s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[N:12][NH:13][C:14]=3[CH2:15][CH2:16][CH:17]=2)=[CH:5][CH:4]=1.C1COCC1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:17][CH2:16][CH2:15][C:14]3[NH:13][N:12]=[CH:11][C:10]2=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CCCc3[nH]ncc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2CCCc3[nH]ncc32)cc1
Reaction time: 4 h
Yield: 85.5 %

Procedure:
4-(4-Methoxyphenyl)-6,7-dihydro-1H-indazole (0.141 g, 0.62 mmol) is dissolved in EtOH (10 mL) and THF (4 mL) and 5% Pd/C (0.090 g) is added. The mixture is stirred under hydrogen (40 psi) for 4 hrs. The mixture is filtered through diatomaceous earth and the filtrate is evaporated to dryness. The residue is purified by silica gel chromatography eluting with 98:2 CH2Cl2:MeOH to give the title compound (0.121 g, 85%). ES/MS m/z 229 (M+1).
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[C:18](=[O:29])[CH2:19][O:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[C@H:18]([OH:29])[CH2:19][O:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[CH:8][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CO[C@H](C)c1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
The (S)-Corey-Bakshi-Shibata catalyst (0.012 g, 0.04 mmol) was dissolved in THF (2 mL) and cooled to 0° C. Borane dimethyl sulfide complex (2.0 M in THF, 0.387 mL, 0.77 mmol) was slowly added, followed by 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((R)-1-phenyl-ethoxy)-ethanone (0.172 g, 0.43 mmol) in THF (3.3 mL) over 15 minutes. After stirring for 55 minutes the reaction was submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(CC(F)(F)F)C4)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCN(CC(F)(F)F)C1
Temperature: 120 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-1-(2,2,2-trifluoroethyl)-3-piperidyl]pyrimidin-4-amine, 3a, (0.10 g, 0.18 mmol) in THF was added 1M LiOH (0.90 mL, 0.90 mmol) solution. The reaction mixture was heated in microwave at 120° C. for 10 minutes. The reaction mixture was diluted with brine, extracted with EtOAc, then with 20% isopropanol/CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-10% MeOH:CH2Cl2) to afford the desired product, 1339, as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:10]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C
Yield: 34.8 %

Procedure:
6-Chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-4-ylboronic acid (0.384 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.035 g, 0.050 mmol) were suspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.15 g, 0.871 mmol, 35% yield) as an off-white solid. LCMS R.T.=0.30; [M+H]+=173.11.
Reaction SMILES: [C:1]1([C:10](OC)=[O:11])([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:9][O:8][C:6]([C:1]1([CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:7]
Reactant: COC(=O)C1(C(=O)OC)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COC(=O)C1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of dimethyl cyclopentane-1,1-dicarboxylate (7.1 g, 38.1 mmol) in dichloromethane(75 mL) at −78° C. under an nitrogen atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 51 mL, 76 mmol) dropwise. After 4 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL), then 1N HCl (38 mL) and allowed to warm to room temperature. The mixture was filtered through Celite@ and the organic phase was separated, was dried (MgSO4) and was evaporated in vacuo to yield the title compound which was used without further purification (3.1 g, 52%). MH+157.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:30])[CH2:10][CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([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)[CH:5]=[CH:6][C:7]=1[F:8].N([CH:33]([C:38]([O:40][CH3:41])=[O:39])[C:34]([O:36][CH3:37])=[O:35])=N>>[CH3:37][O:36][C:34]([C:33]1([C:38]([O:40][CH3:41])=[O:39])[CH2:30][C:9]1([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:35]
Reactant: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(F)c(Cl)c1
Reactant: COC(=O)C(N=N)C(=O)OC
Product: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in 2.61 g yield starting from {[3-(3-chloro-4-fluorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsilane (P45, 3.624 g) and from dimethyl diazenylpropanedioate (1.98 g) according to a similar procedure described for Preparation 14.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][CH:7]([O:9][C:10]1[C:15]2[CH2:16][CH2:17][CH2:18][C:19](=[O:21])[NH:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH3:8].C(=O)(O)[O-].[Na+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[N+:1]([C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=2[C:10]=1[O:9][CH:7]([CH3:8])[CH3:6])([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)Oc1cccc2c1CCCC(=O)N2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)Oc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 28.7 %

Procedure:
750 mg of potassium nitrate are added, in portions, to a solution of 1.3 g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 13 ml of trifluoroacetic anhydride brought back to −5° C. The reaction medium is stirred for 5 minutes at −5° C. and then brought back to pH 5 by adding a saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of heptane and of ethyl acetate (80/20 to 50/50). 450 mg of 7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a beige solid. 91 mg of sodium hydride at 50% are added to a solution of 445 mg of 7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 10 ml of DMF. The reaction medium is stirred for 10 minutes at ambient temperature and then 263 mg of iodomethane are added. The reaction medium is stirred for 1 hour at ambient temperature, poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure, so as to give 417 mg of 1-methyl-7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow gum.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl:14][C:15]([F:21])(Br)[C:16]([F:19])([F:18])[Br:17].[CH:22]([O:24]CC)=[CH2:23].[Cl-].[Na+].[BH4-].[Na+].Cl>O.C1COCC1>[Br:17][C:16]([F:19])([F:18])[C:15]([Cl:14])([F:21])[CH2:23][CH2:22][OH:24]
Reactant: C=COCC
Reactant: FC(F)(Br)C(F)(Cl)Br
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: OCCC(F)(Cl)C(F)(F)Br
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of sodium hydrosulfite (34.8 g, 0.2 mol) and sodium bicarbonate (22.0 g, 0.262 mol) in water (400 mL) was treated with 400 mL of THF and the mixture was cooled to 5° C. A mixture of 1,2-dibromo-1-chlorotrifluoroethane (VI) (55.26 g, 0.2 mol) and ethyl vinyl ether (21.6 g, 0.3 mol) was added in one portion to the above mixture with stirring and cooling. The mixture was then stirred at 10°-15° C. for 30 min and then solid sodium chloride was added to saturate the aqueous layer. The aqueous layer was separated and extracted with THF (100 mL). The combined THF extract was diluted with water (100 mL) and treated with sodium borohydride (7.57 g, 0.2 mol) in portions with stirring and cooling (ice-water bath). The mixture was stiffed for 30 min and then acidified 3N HCl by dropwise addition. The aqueous layer was saturated with sodium chloride and the organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was distilled under vacuum to give 37.7 g (78%) of the desired alcohol as a clear oil, bp 98°-100° C./40 mmHg.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:12]([O:14]CC)=[O:13])[C:4]=2[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>C(O)C>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:12]([OH:14])=[O:13])[C:4]=2[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cc1cccc2[nH]c(=O)n(Cc3ccccc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc2[nH]c(=O)n(Cc3ccccc3)c12
Yield: 87 %

Procedure:
Ethyl 2-(2-oxo-3-benzylbenzimidazolyl)acetate (4.19 mmol, 1.3 g) (example 1) is added to potassium hydroxide (13.41 mmol, 0.75 g) in ethanol (10 ml), and the mixture is stirred at reflux for 2 hours. The solvent is evaporated and water (40 ml) is added. The pH is adjusted to 1-2 with concentrated hydrochloric acid. The colorless precipitate is filtered off and dried in vacuo to yield the title compound (87%) (R1=CH2—C(O)—OH, R2=benzyl, n=0).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:37]CN(C(C)C)C(C)C>CC#N>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[N:28]([CH3:37])[N:27]=[N:26][N:25]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(F)C(c1cc(F)cc(-c2nnn[nH]2)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: Cn1nnnc1-c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1

Procedure:
The reaction of mixture of 1.31 g (2.85 mmol) 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole, 0.36 mL (5.70 mmol) methyl iodide, and 1.77 mL (9.97 mmol) DIEA in 8 mL MeCN was heated to reflux for 2.5 h. Then it was concentrated to remove the solvents. Then it was added 20 mL of CH2Cl2 and 5 mL of water and adjust pH=7-8 with aq NaHCO3. The water layer was extracted with CH2Cl2, and the combined organic layer was concentrated. The residue was separated by silica gel chromatography with CH2Cl2/MeOH/NH3 (2M) in MeOH to afford the title compound; 1H-NMR(CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.29(d, 3H, J=22 Hz), 2.37 (t, 1H, J=8 Hz), 2.90 (t, 1H, J=8 Hz), 3.00 (m, 1H), 3.14 (m, 1H), 3.22 (m, 1H), 3.68 (J, 1H, J=6 Hz), 4.19 (s, 3H), 4.26 (s, 1H), 7.12-7.43 (m, 13H); Mass Spectrum: m/e=474 (M+1).
Reaction SMILES: NC1C=C(C)C=CC=1C(N)=[O:5].NC(C1C=CC(C)=CC=1N[C:23]([C:25]1[N:26]=[C:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:35]=2[C:36]([F:39])([F:38])[F:37])[S:28][CH:29]=1)=[O:24])=O>>[F:37][C:36]([F:39])([F:38])[C:35]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:27]1[S:28][CH:29]=[C:25]([C:23]([OH:24])=[O:5])[N:26]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: Cc1ccc(C(N)=O)c(NC(=O)c2csc(-c3cnccc3C(F)(F)F)n2)c1
Product: O=C(O)c1csc(-c2cnccc2C(F)(F)F)n1

Procedure:
Reaction of intermediate III.1 and 2-amino-4-methylbenzamide and subsequent purification by HPLC in analogy to the synthesis of Example 1.1 results in N-[2-(aminocarbonyl)-5-methylphenyl]-2-[4-(trifluoromethyl)-3-pyridinyl]-4-thiazolecarboxamide as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][N:5]2[C:6]3[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O-])=[O:19])=[C:10]3[CH:4]2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[CH2:26][CH2:25][N:5]2[C:6]3[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([CH2:18][OH:19])=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CCN2c3ccccc3Cn3c(c(C(=O)[O-])c4ccccc43)C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN2c3ccccc3Cn3c(c(CO)c4ccccc43)C2C1
Temperature: 25 °C

Procedure:
To a solution of 5.4 g of methyl, 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate in 100 ml tetrahydrofuran is added 1 g of lithium aluminum hydride in small portions over a 10 minute period maintaining the temperature of the reaction below 25°. On completion of the addition the reaction is heated at reflux temperature for 4 hours. On cooling to room temperature the reaction mixture is quenched by the cautious dropwise addition of 0.65 ml of water, then 0.65 ml 15% NaOH solution followed by 1.95 ml water. The reaction mixture is filtered and the filter cake washed thoroughly with 100 ml of methylene chloride. The filtrate is evaporated to dryness under reduced pressure to yield 1,3,4,16b-tetrahydro-2-methyl-16-hydroxymethyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine as an oil which, after crystallization from ether, has mp 184°-189°.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[CH3:50][C:51]([CH3:57])([CH3:56])[CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl>[C:22]1([C@H:10]2[C@H:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[CH2:12][N:8]([C:53](=[O:54])[CH2:52][C:51]([CH3:57])([CH3:56])[CH3:50])[CH2:9]2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44654.2 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and 3,3-dimethylbutanoyl chloride (72 mg, 0.54 μmol) were added and the mixture stirred at roomt for 16 h. The solvent was removed under vacuum and the residue dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes). The resulting solid was recrystallised from methanol to yield 1-[(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-1-yl]-3,3-dimethyl-butan-1-one as a white solid (106 mg, 53%). M.p.=202-204° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.82 (dd, J=7.2 and 1.6 Hz, 1H), 7.56 (dd, J=14.0 and 8.0 Hz, 1H), 7.38 (dd, J=13.6 and 8.0 Hz, 1H), 7.30-7.18 (m, 3H), 7.02 (t, J=8.0 Hz, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 6.77 (m, 1H), 4.21-3.89 (m, 6H), 3.65-3.36 (m, 2H), 2.83 (t, J=5.6 Hz, 2H), 2.21 (s, 2H), 2.04 (m, 2H), 1.04 (s, 9H). LCMS: m/e 440.20 [M+H].