Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(C[N:8]2[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=3[CH3:27])([CH3:13])[C:11]3[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=3[S:9]2(=[O:33])=[O:32])=C(C)ON=1.C([O-])([O-])=O.[K+].[K+].[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br>CN(C=O)C.CCOC(C)=O>[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45][N:8]1[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=2[CH3:27])([CH3:13])[C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[S:9]1(=[O:33])=[O:32]
Reactant: Cc1noc(C)c1CN1C(C)(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2(C)c3ccccc3S(=O)(=O)N2Cc2cccc(F)c2)c2ccccc2n1CC(=O)O
Temperature: 75 °C

Procedure:
The product of example 65, step a) (50 mg, 0.12 mmol) was dissolved in 2 mL DMF and treated with K2CO3 (32 mg, 0.23 mmol) and 3-fluoro-benzylbromide (43 mg, 0.23 mmol). After heating to 75° C. for 2 h, the reaction was cooled, diluted with EtOAc, and washed 3× H2O. The organic solution was concentrated and treated with 3 mL TFA for 2 h at rt. The reaction was concentrated and the title compound was isolated by preparative LCMS to give the title compound. MS: ESI (negative): 477.5 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4](NC2C=CC(CP(=O)(OCC)OCC)=CC=2)[N:3]=1.[F:28][C:29]([F:49])([F:48])[CH2:30][O:31][P:32]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)(=[O:39])[O:33][CH2:34][C:35]([F:38])([F:37])[F:36].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:47][C:44]2[CH:45]=[CH:46][C:41]([CH2:40][P:32](=[O:39])([O:33][CH2:34][C:35]([F:36])([F:37])[F:38])[O:31][CH2:30][C:29]([F:28])([F:48])[F:49])=[CH:42][CH:43]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Nc1ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc1
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: O=P(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)(OCC(F)(F)F)OCC(F)(F)F

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using (4-Aminobenzyl)phosphonic acid bis-(2,2,2-trifluoroethyl) ester (Compound 165B) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine. The desired product was isolated using MDP (ammonium bicarbonate basic buffer pH 9). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 8.81 (s, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.26 (dd, J=8.7, 2.7 Hz, 2H), 4.56-4.72 (m, 4H), 3.51 (d, J=22.2 Hz, 2H). MS (ES+): m/z 532.01/534.02 (100/64) [MH+]. HPLC: tR=1.70 min (TOF, polar—3 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]([OH:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>CCCCCC.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[CH:21]([OH:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Product: CC(O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C

Procedure:
To intermediate 61C (0.1M solution in 10% CH3CN in DCM) add NMO (2 equiv) followed by TPAP (0.05 equiv). Provide sufficient ventilation and take care to watch for exotherm. Stir reaction at rt for 3-5 h. Dilute by half with hexane and allow TPAP to precipitate. Flash filter through silica gel plug (20 fold mass of starting alcohol) and elute with 10% EtOAc/Hex until product is not observed in eluent. Removal of solvents gave the title compound. MS (ES) m/z 344.31 [M+H]30
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[CH3:38][C:36]1[CH:37]=[C:32]([C:31]2[CH:30]=[N:29][N:28]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:25])([F:24])[F:1])[CH:6]=4)=[N:26][C:27]=23)[CH:33]=[C:34]([CH3:39])[N:35]=1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)cc(C)n1
Yield: 52 %

Procedure:
Reaction of 1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (139 mg, 52%). MS (ISP) 535.4 [(M+H)+]; mp 245° C.
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][C@:5]([NH2:16])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:6].[CH3:18][NH:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=S>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:20]1[N:19]([CH3:18])[C:3](=[O:17])[CH2:4][C@@:5]([CH3:6])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C[C@](C)(N)c1cccc([N+](=O)[O-])c1
Product: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as white solid. MS (ESI): m/z=361.4 [M−H]−.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@H:6]2[CH2:8][C@@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[OH:1][C@H:2]1[CH2:7][C@H:6]2[CH2:8][C@@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH:11]=[CH:10]2
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312

Procedure:
1 g of 17β-hydroxy-14β,15β-methylen-androst-4-en-3-one (production, Example 2) is refluxed with 1.2 g of chloranil in 50 ml of tert-butanol for 30 minutes. It is allowed to cool and evaporated to the dry state. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethyl acetate 10:1). For further purification, it is recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[N:6]([CH3:11])[C:7](=[O:10])[CH2:8]Br)(=[O:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[C:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][N:16]=[N+:17]=[N-:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1N(C)C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1N(C)C(=O)CN=[N+]=[N-]
Yield: 51.6 %

Procedure:
2.05 g (7.59 mmol) of 2′-acetyl-2-bromo-N-methylacetanilide and 2 g (30.77 mmol) of sodium azide were stirred in 20 ml of dimethylformamide at room temperature for 4 hours. The resulting mixture was diluted with water and extracted with diethyl ether. The organic phase was washed twice with water, dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol 5:3 for the elution. There was obtained 910 mg of 2′-acetyl-2-azido-N-methylacetanilide as a colorless gum. MS: m/e 233 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].C([Li])CCC.CN(C)[CH:16]=[O:17].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:3][C:4]1[S:5][C:6]([CH:16]=[O:17])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
To a solution of 2-ethoxythiophene (355 mg, 2.77 mmol) in 14 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (1.22 mL, 2.5 M in hexanes) dropwise over 5 minutes. After stirring at −78° C. for 20 minutes, dimethylformamide (1.07 mL, 13.9 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 60 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (2×75 mL), washed with 1 N hydrochloric acid (2×40 mL), water (40 mL) and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-7% ethyl acetate in hexanes) to give 5-ethoxy-2-thiophenecarbaldehyde (216 mg, 49%). Used without further characterization.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].O>C(O)C>[C:13]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:20][CH:16]([CH3:17])[CH2:18][CH3:19])=[N:3][C:4]=1[CH3:15])#[N:14]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C#N)c(C)nc1NC(C)CC

Procedure:
22.4 g of 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (1 mol) of Example 1(b) are treated in 100 ml of ethanol with 15 g sec. butylamine at reflux temperature with stirring. After the addition of the amine is completed, the solution is poured into 200 ml of cold water, and the amino compound is filtered off. Yield 22 g (84%); m.p. 55°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:22]#[N:23])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
3-Nitro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (89.7 g, 272 mmol), zinc cyanide (19.2 g, 163 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 g) were suspended in N,N-dimethylformamide (2500 ml). The reaction mixture was stirred for 3 hours at 100° C. under an inert atmosphere. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give 4-cyano-3-nitro-benzoic acid methyl ester (34.0 g, 60.7% yield). 1H-NMR (400 MHz, CDCl3): 8.92 (s, 1H), 8.48 (d, 1H), 8.04 (d, 1H), 4.03 (s, 3H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=S)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C(Cl)CCl>CC#N>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:9][C:10]=3[N:15]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Oc2ccncc2)cc1N
Solvent: ClCCCl
Solvent: CC#N
Product: FC(F)(F)c1cc(Nc2nc3cc(Oc4ccncc4)ccc3[nH]2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(pyridin-4-yloxy)-benzene-1,2-diamine (0.273 g, 1.36 mmol) in 20 mL CH3CN was added 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (prepared similarly to the procedure described in Preparation III, 0.322 g, 1.36 mmol). The reaction was stirred 18 h at RT. The reaction was diluted with 25 mL CH3CN, and then EDC (0.39 g, 2.03 mmol) was added. The reaction was heated at 80° C. for 2.5 h. The reaction was cooled to RT and concentrated in vacuo. The crude mix was dissolved into EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane-EtOAc gradient. The partially pure compound was triturated with CH2Cl2 to yield the title compound. MS (MH+)=405.1; Calc'd 404.78 for C19H12ClF3N4O.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][Al](C)C.Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH3:20][C:18]1([OH:19])[C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][NH:10][C:9]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: C[Al](C)C
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Agent: Cl
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC1(O)c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Temperature: 90 °C

Procedure:
3-Phenylindeno[1,2-c]pyrazol-4-(1H)-one (2.4 g) was suspended in toluene (40 ml) under nitrogen and trimethyl aluminium (2.2 ml of a 2M solution in heptane) was added at 20° C. with stirring. The mixture was heated at 90° C. for 16 hours, then cooled to ambient temperature and poured on to crushed ice (approx. 600 ml) containing concentrated hydrochloric acid (30 ml). The precipitated solid was collected by filtration and recrystallized from ethyl acetate with hot filtering to give 4-methyl-3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-4-ol, m.p.154-155° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@:4]([N:17]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH3:18])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[N:5]=[C:6]=[O:7].Cl>O1CCOCC1.O>[CH3:18][N:17]([C@@:4]([C:3]([OH:24])=[O:2])([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[N:5]=[C:6]=[O:7])[CH2:19][CH:20]([OH:23])[CH2:21][OH:22]
Reactant: COC(=O)[C@](Cc1ccc(OC)cc1)(N=C=O)N(C)CC(O)CO
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C[C@](N=C=O)(C(=O)O)N(C)CC(O)CO)cc1

Procedure:
The resultant compound from Example 115 (114 mg, 0.355 mmol) in dioxane (4 ml) and water (2 ml) at 0° C. was treated with LiOH monohydrate (42.0 mg, 1 mmol). After 90 min 2M HCl (0.6 ml, 1.2 mmol) was added and the mixture was evaporated to a form which was used without further purification; DCI-MS: (M+H)+ =327.
Reaction SMILES: [CH2:1]([C:3]1[CH:35]=[CH:34][C:6]2[CH:7]([C:17]3[C:18](=[S:33])[NH:19][C:20](=[O:32])[N:21]([CH2:23][C:24]4[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>>[CH2:1]([C:3]1[CH:35]=[CH:34][C:6]2[CH:7]([C:17]3[C:18](=[S:33])[NH:19][C:20](=[O:32])[N:21]([CH2:23][C:24]4[O:28][C:27]([C:29]([NH:36][C:37]5[NH:41][N:40]=[N:39][N:38]=5)=[O:31])=[CH:26][CH:25]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=S
Reactant: Nc1nnn[nH]1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)Nc3nnn[nH]3)o2)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of example 31(0.93 g) and amino tetrazole (0.3 g) according to the method of example 10 step (i). Purification was by precipitation from ethyl acetate-iso-hexane. Yield 0.426 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[F:17])=[CH:5][C:4]([CH3:18])=[N:3]1.[I:19]N1C(=O)CCC1=O.O>C(#N)C>[F:17][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:16])[C:8]=1[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[C:5]=1[I:19])[C:12]#[N:13]
Reactant: Cc1cc(Oc2c(F)cc(C#N)cc2F)n(C)n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1I

Procedure:
A solution of 4-[(1,3-dimethyl-1H-pyrazol-5-yl)oxy]-3,5-difluorobenzonitrile (i.e. the product of Step A) (1.38 g, 5.5 mmol) in acetonitrile (20 mL) was stirred at ambient temperature, and N-iodosuccinimide (1.35 g, 6.0 mmol) was added in one portion. The reaction mixture was heated at reflux for 2 h, cooled, and then poured into water (40 mL). The resulting mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with water (20 mL) and saturated aqueous NaHCO3 solution (20 mL), dried over MgSO4, and concentrated under reduced pressure to give the title compound as a tan solid (2.1 g).
Reaction SMILES: C([NH:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH:19]=[CH2:20])[CH:7]=1)(C)(C)C.[ClH:21]>CO>[ClH:21].[NH2:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH:19]=[CH2:20])[CH:7]=1
Reactant: C=Cc1cc(NC(C)(C)C)c([N+](=O)[O-])cc1C(=O)OC
Agent: Cl
Solvent: CO
Product: C=Cc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C

Procedure:
To a mixture of 3.74 g of methyl 4-(tert-butylamino)-5-nitro-2-vinylbenzoate and 37.4 mL of methanol was added 21.7 mL of 6 M hydrochloric acid, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature and the precipitated solid was collected by filtration. The obtained solid was dried at 40° C. for 2 hours under reduced pressure to obtain 2.56 g of methyl 4-amino-5-nitro-2-vinylbenzoate monohydrochloride as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(CC)C.[CH2:14]([O:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH3:17].Cl>C(OCC)(=O)C.C1COCC1.C1CCCCC1.CCCCCC>[CH2:14]([O:18][CH:19]1[CH2:20][CH2:21][C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[F:8])([OH:25])[CH2:23][CH2:24]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOC1CCC(=O)CC1
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCOC1CCC(O)(c2cccc(F)c2F)CC1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
1,2-Difluorobenzene (21) (57.0 g) and THF (1000 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 500.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. Then, 4-butoxycyclohexanone (22) (85.1 g) in a THF (200 ml) solution was added dropwise thereto in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. The reaction mixture obtained was poured into a vessel containing an aqueous 1N-HCl solution (500 ml) and ethyl acetate (500 ml), and mixed. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 130.1 g of 4-butoxy-(2,3-difluorophenyl)cyclohexanol (23). The obtained compound (23) was a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]2[NH:10][C:11](=[O:19])[C:12]3[CH:18]=[CH:17][CH:16]=[N:15][C:13]=3[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH2:20](I)[CH3:21]>CN(C=O)C>[CH2:20]([O:19][C:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[N:15][C:13]=2[NH:14][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:3])[C:9]=2[N:10]=1)[CH3:21]
Reactant: CCI
Reactant: Cc1cccc2c1NC(=O)c1cccnc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1=Nc2c(C)cccc2Nc2ncccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
Sodium hydride (80% oil dispersion, 0.13 g, 5.5 mmol) was added at room temperature to a suspension of 6,11-dihydro-7-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (1.12 g, 5.0 mmol) in DMF (20 mL) under argon. The reaction mixture was heated at 60° C. for 1 h and then was cooled in an ice-bath before the addition of ethyl iodide (0.86 g, 5.5 mmol). Stirring was continued at room temperature overnight, followed by warming to 60° C. for 1 h. The solution was concentrated in vacuo to near dryness, the residue was poured over ice-water, and the resulting solid was collected, washed with water, and dried. Purification by chromatography (elution with 1% MeOH/CH2Cl2) afforded 0.23 g (18%) of the title compound, which crystallized as yellow needles from petroleum ether (30°-60° C.): m.p. 135°-136° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].[C:11]1([C@@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[F:8][C:7]([F:10])([F:9])[CH2:6][CH:2]([CH3:1])[C:3]([NH:19][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18])=[O:4]
Reactant: CC(CC(F)(F)F)C(=O)O
Reactant: C[C@H](N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-methyl-4,4,4-trifluorobutanoic acid (10.0 g, 0.064 mole) in dichloromethane (150 mL) was treated with 4-(N,N-dimethylamino)-pyridine (7.8 g, 0.064 mole), and the mixture was stirred for 15 min. A solution containing (S)-1-phenylethylamine (7.8 g, 0.064 mole) in dichloromethane (50 mL) was added, the mixture was stirred for a further 15 min, and then a solution of dicyclohexylcarbodiimide (15.9 g, 0.077 mole) in dichloromethane (100 mL) was added. Stirring was continued for 15 hours, then the precipitated dicyclohexylurea was removed by filtration, and the filtrate was concentrated to an oil under reduced pressure. The oil was partitioned between 2N hydrochloric acid (100 mL) and ether (100 mL), and the two phase mixture was filtered to remove a further quantity of dicyclohexylurea. The layers were separated; and the ether fraction was washed with 2N hydrochloric acid (100 mL), 2N aqueous sodium hydroxide solution (100 mL) and saturated brine (100 mL); dried (MgSO4); and evaporated to an oil, which solidified on standing. The solid, which comprised a mixture of the two diastereomeric butyramides was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[NH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[NH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=c1[nH]nnn1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-n2nn[nH]c2=O)c1

Procedure:
A mixture of 1-(3-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one (130 mg, 0.63 mmol) and palladium on charcoal (Aldrich Cat. No. 330108; 13 mg) in MeOH (10 mL) was hydrogenated at 20 psi for 3 hr. The mixture was then filtered through celite and the filter cake washed with MeOH (×3). The filtrate was concentrated under vacuum to leave the product, which was used directly in the next step (yield assumed quantitative=111 mg).