Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC=CC=1C(C1C=CC(C)=CC=1)=O)#N.[CH3:18][C:19]1[CH:37]=[CH:36][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[O:24])=[CH:21][CH:20]=1.[C:38]1([C:44](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([C:44]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:32]2[C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([CH3:18])=[CH:37][CH:36]=3)=[N:35][N:34]=[N:33]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=O)c2ccccc2-c2nnn[nH]2)cc1
Agent: Cc1ccc(C(=O)c2ccccc2C#N)cc1
Product: Cc1ccc(C(=O)c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-Cyano-4'-methylbenzophenone, prepared as described by G. W. Ebert and R. D. Rieke in J. Organic Chem., 49, 5280-2 (1984), is converted to 5-[2-(4-methylbenzoyl)phenyl]tetrazole by the procedures described in Step 1 of Example 39. Reaction with triphenylmethyl chloride gives N-triphenylmethyl-5-[2-(4-methylbenzoyl)phenyl]tetrazole.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([O:27][C:26]([F:36])([F:37])[F:25])=[CH:29][CH:30]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccc(OC(F)(F)F)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [4-(trifluoromethoxy)benzyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19-1.28 (m, 3H), 1.59 (d, J=13.59 Hz, 4H), 1.67 (s, 1H), 1.86 (s, 3H), 2.23 (s, 3H), 3.79 (s, 1H), 4.56 (d, J=5.04 Hz, 2H), 7.30 (d, J=8.11 Hz, 2H), 7.40-7.45 (m, 2H), 7.57 (d, J=7.23 Hz, 1H), 8.18 (t, J=5.26 Hz, 1H), 12.85 (bs, 1H); MS (ESI) m/z 394.8 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:7][CH:6]=1.[OH-].[Li+].Cl>CO.O>[C:29]1([CH3:32])[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:10][CH:9]=2)(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of {4-[2-(toluene-4-sulfonylamino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester (97 mg, 0.202 mmol) in 1 mL of methanol was added 1 mL of a suspension of lithium hydroxide (42 mg, 1.01 mmol) in 1 mL of water. The resulting mixture was allowed to stir at room temperature until all starting material disappeared. Upon completion, 50 mL of 1N aqueous HCl was added and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with 1N HCl aqueous solution (20 mL), water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 70 mg of {4-[2-(toluene-4-sulfonyl-amino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (1). 1H NMR (CD3OD): δ 7.84 (d, J=1.92 Hz, 1H), 7.58 (d, J=8.27, 1.6 Hz, 2H). 7.32 (dd, J=8.27, 1.6 Hz, 1H), 7.18-7.30 (m, 5H), 6.73 (d, J=8.53 Hz, 1H), 6.57 (d, J=8.53 Hz, 2H), 3.59 (s, 2H), 2.37 (s, 3H). LCMS (ESI−) 464 (M−1).
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH2+:5][CH2:4]1.CCN(C(C)C)C(C)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1>C(#N)C>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:5]1[CH2:6][CH:3]([OH:2])[CH2:4]1)([O-:26])=[O:25]
Reactant: OC1C[NH2+]C1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(CN2CC(O)C2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxyazetidinium chloride (0.68 g, 6.2 mmol) and Hunig's base (2.5 mL, 14.1 mmol) in acetonitrile (10 ml) was added 1-(bromomethyl)-3-nitrobenzene. After the reaction mixture was stirred at room temperature for 18 hours, it was partitioned between ethyl acetate and NaHCO3. The organic layer was washed with brine, dried and concentrated. The crude material was purified by silica gel column chromatography, eluting with 20% ethyl acetate/hexanes to give 0.54 g 1-(3-nitrobenzyl)azetidin-3-ol. MS (DCI(+)) m/e 209 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=3)[NH:13][C:12](=[O:21])[C:11]=1[C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)[CH2:2]2.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:18]=3)[NH:13][C:12](=[O:21])[C:11]=1[C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)[CH2:2]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(N[C@@H]2CN3CCC2CC3)c1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2ccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N[C@@H]4CN5CCC4CC5)c3c2)cc1
Temperature: 90 °C

Procedure:
A vial was charged with the hydrochloride salt of 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6-bromoquinolin-2(1H)-one (1.0 equivalent) and 4-methoxyphenyl boronic acid (1.3 equivalents). To this solution was added DME and 2 M aqueous Na2CO3 (10%). The mixture was degassed by bubbling argon through the solution for 5 minutes. Pd(dppf)2Cl2.CH2Cl2 (0.2 equivalents) was then added to the degassed solution. The mixture was heated at 90° C. for 16 hours, and the top organic layer was separated and filtered. The solvent was removed, and the residue was purified by reverse phase HPLC affording the desired product. MS m/z 492.6 (M+H).
Reaction SMILES: [C:1](=[O:34])(OC1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH3:35][N:36]1[CH:40]=[C:39]([S:41]([NH2:44])(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]>>[Cl:24][C:17]1[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:34])[NH:44][S:41]([C:39]4[N:38]=[C:37]([CH3:45])[N:36]([CH3:35])[CH:40]=4)(=[O:42])=[O:43])=[CH:6][CH:7]=3)[C:15]=2[CH:16]=1
Reactant: Cc1nc(S(N)(=O)=O)cn1C
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cn(C)c(C)n2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 1,2-dimethyl-1H-imidazol-4-ylsulfonamide.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[F:22][C:23]1([F:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:22][C:23]1([F:29])[CH2:27][CH2:26][CH:25]([NH:28][C:13](=[O:14])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:24]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: NC1CCC(F)(F)C1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NC1CCC(F)(F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 39.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL), 3,3-difluorocyclopentanamine (11.2 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a brown oil (8 mg, 39.4%). 1H NMR (500 MHz, CD3OD) δ 0.93 (d, J=6.83 Hz, 3 H) 1.04 (dd, J=6.35, 2.93 Hz, 3 H) 1.62-1.80 (m, 1 H) 1.87-2.02 (m, 1 H) 2.14-2.28 (m, 2 H) 2.35-2.58 (m, 2 H) 3.35 (s, 1 H) 4.22-4.35 (m, 1 H) 4.94-5.10 (m, 2 H) 5.45 (dd, J=18.79, 5.13 Hz, 1 H) 7.86 (s, 1 H) 8.17 (d, J=2.93 Hz, 1 H). [M+H] calc'd for C19H21F3N4O2, 395; found, 395.4.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[P:7]([O:14][C@H:15]1[CH2:19][O:18][C@@H:17]2[C@H:20]([O:23][N+:24]([O-:26])=[O:25])[CH2:21][O:22][C@H:16]12)([O:12][CH3:13])([O:9][CH2:10]Cl)=[O:8].[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[N:56]=[N:55][N:54]=3)=[CH:43][CH:42]=2)[C:33]([C:37]([OH:39])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[N:56]=[N:55][N:54]=3)=[CH:45][CH:46]=2)[C:33]([C:37]([O:39][CH2:10][O:9][P:7]([O:12][CH3:13])([O:14][C@H:15]2[CH2:19][O:18][C@@H:17]3[C@H:20]([O:23][N+:24]([O-:26])=[O:25])[CH2:21][O:22][C@H:16]23)=[O:8])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COP(=O)(OCCl)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OCOP(=O)(OC)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (29.3 mg, 0,090 mmol) was added to a stirred, room temperature mixture of chloromethyl methyl (3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl phosphate (30 mg, 0.090 mmol) and 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 61.1 mg, 0.090 mmol) in N,N-dimethylformamide and the mixture was stirred at room temperature for overnight. The reaction was cooled, quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered and concentrated in vacua. Chromatography over silica, eluting with 40-100% ethyl acetate/hexane afforded the separated diastereomers.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[CH3:11][N:2]([CH3:1])[C:3](=[O:10])[CH:4]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:13]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)C(=O)Cc1ccsc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)N(C)C)c1ccsc1
Temperature: 25 °C

Procedure:
To a solution of acetamide from Step 1 (510 mg) in THF (15 mL) at -78° C. was added LDA (mono THF, 1.5M, cyclohexane, 250 μL) followed by MeI (700 μL) after 30 min. The mixture was warmed to r.t., quenched with a saturated NH4Cl sol. and then extracted with Et2O. The organic phase was washed with H2O, brine, dried (MgSO4) and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (60:40)) to afford the title compound as a oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10](Br)[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2C=1C(C#N)=C[NH:29]2)C1C=CC=CC=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[C:3]([O:2][CH3:1])[CH:11]=1)[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: COc1cc(Br)cc2[nH]ccc12
Product: CCOC(=O)C=C(c1cc(OC)c2cc[nH]c2c1)c1ccccn1

Procedure:
3-(4-Methoxy-1H-indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLXXIV was prepared from 4-methoxy-6-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl este using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Zr+4:5].[C:6]1([B:12]([C:19]2[CH:23]=[CH:22][CH2:21][C:20]=2[Si](C)(C)C)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[Cl-:1].[C:6]1([B:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2([Zr+3:5])[CH:23]=[CH:22][CH:21]=[CH:20]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)C1=C(B(c2ccccc2)c2ccccc2)C=CC1
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: [Zr+3]C1(B(c2ccccc2)c2ccccc2)C=CC=C1
Temperature: -20 °C
Reaction time: 24 h

Procedure:
24.8 g (106.5 mmol) of zirconium tetrachloride and 150 ml of toluene were placed under argon in a 0.5 l two-neck flask. The white suspension was cooled to −20° C. and a solution of 30.68 g (101.4 mmol) of diphenylboranyltrimethylsilylcyclopentadiene in 150 ml of toluene was added. The brown suspension was stirred at room temperature for 24 hours and filtered through a D3 frit. The filtrate was evaporated to dryness under reduced pressure. The brown residue was stirred a number of times with n-hexane, giving a brown powder. This was dried to constant weight under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[C:11](OCC)=[CH:10][S:9][CH:8]=1)=[O:5]>O>[F:19][C:16]1[CH:17]=[CH:18][C:2]2[NH:1][C:11]3=[CH:10][S:9][CH:8]=[C:7]3[NH:6][C:4](=[O:5])[C:3]=2[CH:15]=1
Reactant: CCOc1cscc1NC(=O)c1cc(F)ccc1N
Solvent: O
Product: O=C1Nc2cscc2Nc2ccc(F)cc21

Procedure:
A 5.7 g. portion of 2-amino-N-(4-ethoxy-3-thienyl)-5-fluorobenzamide and 60 g. of polyphosphoric acid are stirred and heated at 120°-128° C. for one hour, cooled and poured into ice and water. The solid is recovered by filtration, washed with water, sodium carbonate solution, sodium bicarbonate solution and then water and dried at 60° C. overnight, giving 7-fluoro-4H-thieno[3,4-b][1,4]benzodiazepin-9(10H)-one.
Reaction SMILES: [Se](=O)=O.[OH2:4].[CH3:5][N:6]([C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:12])[CH3:11])=[O:8]>O1CCOCC1>[CH3:5][N:6]([C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:4])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:11])[CH3:12])=[O:8]
Reactant: CCOC(=O)Cc1csc(N(C)C(=O)OC(C)(C)CC)n1
Reactant: O
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1csc(N(C)C(=O)OC(C)(C)CC)n1
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
A mixture of selenium dioxide (0.452 g.), dioxane (9 ml.) and water (0.36 ml.) was refluxed in bath at 110° C., and to the solution was added a solution of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]acetate (1.07 g.) and dioxane (9 ml.), and the mixture was stirred for 4.5 hours at the same temperature. After the reaction, the reaction mixture was filtered, and dioxane was distilled off from the filtrate under reduced pressure. To the residue were added water and ethyl acetate with stirring, and then ethyl acetate layer was separated. The ethyl acetate layer was dried over magnesium sulfate and then concentrated to give oil of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate (0.45 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(Cl)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 174.1-176.1° C. 1H NMR (acetone-d6/300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.29 (d, 1H, J=7.5 Hz), 7.17 (d, 1H, J=2.0 Hz), 7.08 (d, 1H, J=8.3 Hz), 6.73 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz) FABLRMS m/z 403 (M−H). ESHRMS m/z 402.9752 (M−H, Calc'd 402.9729). Anal. Calc'd for C17H9Cl2F3O4: C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.18; H, 2.00; Cl, 17.26.
Reaction SMILES: C([O:8][C:9]1[C:41]([O:42][CH3:43])=[CH:40][C:12]2[C:13](=[O:39])[N:14]3[CH2:38][CH2:37][CH2:36][C@H:15]3[C@H:16]([O:25][CH:26]3[C:31]([OH:32])=[C:30]([OH:33])[C:29]([OH:34])=[C:28]([OH:35])[O:27]3)[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CCCCCC>[OH:8][C:9]1[C:41]([O:42][CH3:43])=[CH:40][C:12]2[C:13](=[O:39])[N:14]3[CH2:38][CH2:37][CH2:36][C@H:15]3[C@H:16]([O:25][CH:26]3[C:31]([OH:32])=[C:30]([OH:33])[C:29]([OH:34])=[C:28]([OH:35])[O:27]3)[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N(C(=O)OC(C)(C)C)[C@@H](OC1OC(O)=C(O)C(O)=C1O)[C@@H]1CCCN1C2=O
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)N(C(=O)OC(C)(C)C)[C@@H](OC1OC(O)=C(O)C(O)=C1O)[C@@H]1CCCN1C2=O
Yield: 89.3 %

Procedure:
A catalytic amount of 10% palladium on carbon (380 mg) was added to a solution of THP protected compound 13 (3.8 g, 7 mmol) in absolute alcohol (30 mL). The reaction mixture was hydrogenated for 3 h at 35 Psi. When the reaction was complete as indicated by TLC (SiO2, 50% EtOAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 14 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: [α]20D=+84° (c=0.48, CHCl31H NMR (CDCl3, 400 MHz): δ 1.35 (s, 18H, Boc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.18 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, 8H, 3-H, 11a-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (m, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H), 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H); 13C NMR (CDCl3, 400 MHz): δ 19.9, 20.7, 23.1, 23.2, 25.1, 25.3, 28.0, 28.1, 28.9, 29.1, 30.8, 31.2, 46.3, 56.13, 56.19, 60.0, 60.2, 63.4, 64.5, 81.0, 81.1, 87.9, 91.1, 95.8, 100.7, 109.6, 110.0, 116.4, 117.0, 125.5, 125.9, 130.2, 130.5, 145.7, 145.8, 147.4, 147.5, 154.9, 155.3, 167.4, 167.6; IR (neat): 3266, 2947, 1703, 1631, 1612, 1514, 1468, 1411, 1368, 1331, 1275, 1201, 1163, 1116, 1023 cm−1; MS (FAB) m/z (relative intensity) 471 ([M+Na]+., 15), 449 (M+., 99), 246 (100), 347 (25).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[C:18]([N:23]=[C:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1>O>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:3]1=[N:2][C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])=[O:25]
Reactant: CN1CCCC1=N
Reactant: Cc1ccccc1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccccc1NC(=O)N=C1CCCN1C

Procedure:
A 6.73 g. (0.05 mole) sample of 2-imino-1-methylpyrrolidine HCl is treated with 50 ml. of benzene and 2 ml. of water. With stirring, 10 ml. of 50% sodium hydroxide is added. After stirring about one minute, the benzene layer is decanted onto anhydrous K 2 CO 3 and the extraction repeated twice with 50 ml. portions of benzene. The dried, combined extracts are filtered from the drying agent and the filtrate is treated with 6.66 g. (0.05 mole) of o-tolylisocyanate. After stirring overnight, the mixture is filtered from a small amount of insoluble material and the solvent removed in vacuo. Recrystallization from ethyl acetate and finally from ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-o-tolyl urea, m.p. = 91°- 93° C.
Reaction SMILES: C([NH:3][CH:4]([CH3:17])[CH2:5][C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=O.Cl.O>CCOCC>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:6]2([CH2:5][CH:4]([NH2:3])[CH3:17])[CH2:9][CH2:8][CH2:7]2)=[CH:15][CH:14]=1
Reactant: CC(CC1(c2ccc(Cl)cc2)CCC1)NC=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(N)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
N-formyl-2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (11.06 g) prepared as described above was heated under reflux for six hours with a mixture of concentrated hydrochloric acid (34 ml), water (34 ml) and diethyleneglycoldimethyl ether (40 ml). The mixture was cooled, washed with ether and basified with aqueous sodium hydroxide. The basified solution was extracted into ether, washed with water, dried, evaporated and distilled to give 2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (b.p. 119°-121° C. at 0.8 mm Hg). The amine (2.65 g) was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid added to pH 2. Ether (110 ml) was added and crystals of 2-[1-(4-chlorophenyl) cyclobutyl]-1-methylethylamine hydrochloride (m.p. 184°-185° C.) were collected. (Formula I R1, R2 =H; R3, R4 =H; R5 =4-Cl; R6 =H; R7 =Me and R8 =H.)
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=2)[NH:32][CH:31]=1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH:15][C:39]([C:35]2[CH:34]=[C:33]3[C:38]([C:30]([Cl:29])=[CH:31][NH:32]3)=[CH:37][CH:36]=2)=[O:40])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc3c(Cl)c[nH]c3c2)cc1
Yield: 72.2 %

Procedure:
Using the procedure described in Example 9, Part C, 4-t-butyldimethylsilyloxy-N2-(4-t-butylbenzoyl)-1,2-benzenediamine (750 mg, 1.9 mmol) and 3-chloroindole-6-carboxylic acid (372 mg, 1.9 mmol) yielded 790 mg (72%) of the title compound.