Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:33][NH:34][CH3:35].C(O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([N:34]([CH3:35])[CH3:33])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CNC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
5-Cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (40 mg, 83 μmol) was dissolved in THF (5 ml), a 33% strength solution of dimethylamine in ethanol (37 μl, 208 μmol; 2.5 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (13.8 mg, 34% of theory).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH2:22][CH2:23][N:24]4[CH2:29][C:30]3([NH:38]C(=O)OC(C)(C)C)[CH2:35][O:34]C(C)(C)[O:32][CH2:31]3)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH3:3].C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:38][C:30]([CH2:29][N:24]1[C:25]2[C:21](=[C:20]([C:17]3[N:16]=[C:15]([C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH3:14])=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=4)[O:19][N:18]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:23]1)([CH2:31][OH:32])[CH2:35][OH:34]
Reactant: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCCC
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1OCCC
Yield: 67 %

Procedure:
When the product of Step E was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 67% yield., as a colourless solid. 1H-NMR (DMSO-d6) 0.95-1.01 (m, 6H); 1.37 (s, 2H); 1.68-1.8 (m, 4H); 2.98 (s, 2H); 3.2-3.3 (m, 6H+H2O); 3.5-3.57 (m, 2H); 3.9-4.05 (m, 4H); 4.55 (broad s, 2H); 6.77 (d, 1H, J=9 Hz); 7.1-7.26 (m, 3H); 7.58 (d, 1H, J=3 Hz); 7.71 (dd, 1H, J=3, 9 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([C:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:35])[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(=O)O)n[nH]1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(=O)N2CCN(C)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
1-Methylpiperazine (126 mg; 1.25 mmol) and (S)-5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazole-3-carboxylic acid (50 mg; 1.25 mmol), HOBt (254 mg; 1.88 mmol), DIPEA (0.33 ml; 1.88 mmol) and EDCl (361 mg; 1.88 mmol) were dissolved in 15 ml of DCM and stirred at RT overnight. 50 ml of DCM was added and washed with 3×15 ml of water. Combined water phases were washed with 2×20 mol of DCM, all organic phases were combined and dried over Na2SO4. Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 75 mg (12%) of the title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 3.90-3.96 (m, 2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61 (d, 1H), 6.66 (d, 1H), 6.95 (s, 1H), 7.48-7.50 (m, 2H), 7.61 (broad s, 1H), 7.68 (d, 1H), 7.76-7.79 (m, 1H), 8.11 (s, 1H), 10.45 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[O:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:29]([O-])([OH:31])=[O:30]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:19])[C:13]3[CH:14]=[C:15]([N+:29]([O-:31])=[O:30])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Yield: 32 %

Procedure:
To a stirred suspension of 4-(4-chlorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.15 g, 18.80 mmol) in a mixture of glacial acetic acid (15 mL) and concentrated sulfuric acid (15 mL) was slowly added concentrated nitric acid (3 mL). After 10 minutes the reaction was poured over ice and brine (100 mL) and filtered. Trituration of the solid with ethyl acetate/ether gave 4-(4-chlorophenyl)-4-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one as a tan solid (1.92 g, 32%). 1H NMR (DMSO-d6): δ 11.04 (s, 1H), 8.29 (m, 2H), 7.47 (dd, J=6.6, 2.0 Hz, 2H), 7.32 (dd, J=6.7, 2.1 Hz, 2H), 7.13 (d, J=9.5 Hz, 1H), 2.06 (s, 3H); MS (ESI) m/z [M+H]+(319/321); MS (ESI) m/z [M−H]−(317/319); Anal. calcd for C15H11ClN2O4: C, 56.53; H, 3.48; N, 8.79. Found: C, 55.43; H, 3.37; N, 8.78.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:12]=1[C:13](OC)=[O:14].Cl>C1COCC1>[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:12]=1[C:13](=[O:14])[CH2:2][C:1]#[N:3]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1C(=O)CC#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of acetonitrile (3.24 mL; 61.7 mmol) in dry THF (31 mL) at −78° C. under nitrogen atmosphere was added n-butyllithium 2.5M (15.4 mL; 38.5 mmol) and the reaction mixture was stirred at −78° C. for 30 minutes. Then, a solution of methyl 2-methoxy-4-methylbenzoate (2.78 g; 15.4 mmol) in dry THF (18 mL) was added dropwise and the stirring was continued for 1.5 hour. The reaction mixture was hydrolyzed by adding HCl (1N) and the aqueous layer was extracted several times with ethyl acetate. The organics were combined, dried over magnesium sulphatesulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5 to 80%) in heptane to furnish 2.5 g of the expected 3-(2-methoxy-4-methylphenyl)-3-oxopropanenitrile (86%) as a bright yellow solid.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:34]=[CH:33][C:28]([CH2:29][N:30]=[C:31]=[O:32])=[CH:27][CH:26]=1>O1CCCC1>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][NH:30][C:31]([N:13]2[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:11]3[CH2:12]2)=[O:32])=[CH:33][CH:34]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCCN12
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)N1CCCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To hexahydro-1,1-diphenyl-1H-oxazolo[3,4-a][1,4]diazepin-3-one (60 mg, 0.2 mmol) were added tetrahydrofuran (5 mL) and 4-fluorobenzyl isocyanate (59 mg, 0.39 mmol), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=6:1 to hexane:ethyl acetate=1:4) and powder was formed from diethyl ether to obtain the title compound (73 mg, yield 82%).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:31][CH3:32])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[Cl:18])=[CH:12][CH:11]=1)[CH3:3]>O1CCCC1>[ClH:18].[CH2:31]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:17](\[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)/[Cl:18])=[CH:12][CH:11]=1)[CH3:32]
Reactant: CCN(CC)CCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)CCCCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Combine (E and Z)-1-[4-(4-diethylaminobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene hydrochloride salt (21.5 mol) and tetrahydrofuran (75 L). Heat to reflux. After 1 hour, cool to 30° C. to give a solid. Collect the solid by filtration, rinse with tetrahydrofuran, and dry. Combine the solid with tetrahydrofuran (83.2 L) and heat to reflux. After 18 hour, cool to 50° C. and filter, rinse with tetrahydrofuran, and dry to give (E)-1-[4-(4-diethylaminobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene hydrochloride salt.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C@:30]([OH:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:25]2)=[S:23])[CH2:9][N:10](C)[C:11](OCC[Si](C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](CC)(CC)(CC)CC.[F-]>CC#N>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C@:30]([OH:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:25]2)=[S:23])[CH2:9][NH:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=S)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CNC[C@H](CC1CCCCC1)NC(=S)N1CCC[C@@H]([C@@](O)(CCCCOC)c2ccccc2)C1
Yield: 25.1 %

Procedure:
A solution of (3R)—N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide (35 mg, 52 μmol) and Et4NF (40 mg, 0.26 mmol) in MeCN (1 mL) was heated at 60° C. in a microwave for 10 min. The reaction mixture was submitted directly to prep HPLC to afford (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide (6.4 mg, 23%) and recovered (3R)—N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide (11.2 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:26])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]2[N:11]=1)[CH3:2].[S:27]([Cl:31])(=O)(=[O:29])[OH:28].S(Cl)(Cl)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:31])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:26])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(O)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 300 mg (0.84 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-n-hexyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 23A) and 0.98 g (8.4 mmol) of chlorosulphuric acid. This gives 300 mg (78.7%) of sulphonyl chloride which is directly reacted further.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(N)c2)ccn1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)ccn1
Yield: 52.4 %

Procedure:
To a solution of tert-butyl {4-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (160 mg, 0.51 mmol) and 2,4,5-trichloropyrimidine (98.3 mg, 0.54 mol) in N,N-dimethylformamide (2.3 mL) was added potassium carbonate (212 mg, 1.53 mmol). The resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by trituration with cold EtOAc to give the desired product (123 mg, 36%) as an off-white powder. LCMS for C22H24Cl2N5O2 (M+H)+: m/z=460.1, 462.0.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C1(C)C=CC=CC=1.C([O:22]CC)C>C(Cl)(Cl)Cl.C(#N)C.C(=O)([O-])[O-].[Ag+2]>[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:22]
Reactant: CCOCC
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 46 %

Procedure:
To a mixture of pentanoracid 7 (600 mg; 1.2 mmol), silver carbonate (440 mg; 1.6 mmol) in a mixture of chloroform (10 ml) and acetonitrile (7 ml), benzyl bromacetate (260 μl; 1.6 mmol) was added and the reaction mixture was stirred for 28 hours at room temperature. The course of the reaction was monitored by TLC (toluene/diethyl ether 6:1). The reaction mixture was then filtered through diatomaceous earth and the filtrate was worked-up and the product was purified by analogical procedure as in the preparation of 21-oxoacid benzyl glycolate. The obtained crude pentanoracid benzyl glycolate (358 mg; 46%) having m.p. 156-157° C. (methanol), [α]D=+57° (c=0.31) was used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:22]C(=O)C)[C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:22])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a solution of acetic acid (4-bromo-phenyl)-(4-trifluoromethyl-phenylcarbamoyl)-methyl ester (5.7 g, 13.7 mmol) in THF (20 mL) was added LiOH monohydrate (0.863 g, 20.5 mmol) in water (12 mL) dropwise at room temperature. After stirring an additional hour at room temperature, the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to obtain white solid (5.04 g, 98.8%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:5]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C1COCC1.Cl>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:3][C:4]2[N:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:5]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
To a suspension of NaH (152 mg, 3.8 mmol, 60% dispersion in mineral oil) in anhydrous THF (2 mL) at room temperature was slowly added a solution of 2-amino-4-(trifluoromethyl)-6-(2,2,2-trifluoroethoxy)pyrimidine (0.50 g, 1.9 mmol) in anhydrous THF (2 mL) and the resulting mixture was stirred 20 min. To the mixture was added 4-trifluoromethylphenyl isocyanate (326 μL, 2.28 mmol) and the resulting mixture was allowed to stir at room temperature. After 18 h of stirring the reaction mixture was diluted with 2 N HCl (30 mL). The acidic mixture was extracted with ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated. The resulting residue was mixed with ethyl acetate (30 mL), diluted with hexane (100 mL) and allowed to stand at room temperature. After 18 h the insoluble material was filtered and dried in a vacuum oven (50° C.) to afford 102 as a white solid (379 mg, 44% yield): m.p. 197-199° C.; 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 10.71 (s, 1H), 7.72 (app s, 4H), 7.35 (s, 1H), 5.25-5.16 (q, 2H, J=8.9 Hz); ESI/MS 448 (M+H), 447 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][OH:35])[CH:27]=4)[CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][S:42]([O:35][CH2:34][CH2:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH2:13][CH2:12][CH2:11][N:10]4[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:2]=3[CH3:1])[CH:21]=[N:22]2)[CH:27]=1)(=[O:44])=[O:43]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCOS(C)(=O)=O)c5)c4)cccc32)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 4-(2,3-dimethylphenoxy)-1-(5-(1-(3-(2-hydroxyethoxy)benzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.07 g, 0.13 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.019 g, 0.17 mmol) and triethylamine (0.029 mL, 0.21 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and then quenched with saturated NaHCO3. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried and concentrated to afford the title compound (80 mg, 100%). LCMS, [M+H]+=618.4.
Reaction SMILES: ClC1C=CC=CC=1CC(O)=O.[Br:12]C1C=CC2C3SC(C(OC)=O)=CC=3CCOC=2C=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[C:41]3[S:42][C:43]([C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])=[CH:44][C:40]=3[CH2:39][CH2:38][O:37][C:36]=2[CH:55]=1.C(O)(=O)C>C(OCC)(=O)C.[Cu](Br)Br>[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[C:41]3[S:42][C:43]([C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])=[CH:44][C:40]=3[CH2:39][CH2:38][O:37][C:36]=2[CH:55]=1.[Br:12][CH:46]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:45]([C:43]1[S:42][C:41]2[C:35]3[CH:34]=[CH:33][C:32]([Br:31])=[CH:55][C:36]=3[O:37][CH2:38][CH2:39][C:40]=2[CH:44]=1)=[O:54]
Reactant: COC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: Br[Cu]Br
Agent: O=C(Cc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: O=C(O)Cc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)C(Br)c1ccccc1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-(8-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone (1.0 g, 2.3 mmol) was prepared by reaction of 2-chlorophenylacetic acid with methyl 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate. A solution of 1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone in ethyl acetate (60 mL) was treated with copper(II) bromide (1.3 g, 5.8 mmol) in one portion in 100 mL rb flask. Acetic acid (2 mL) was added, and the flask sealed and heated at 85° C. After 8 hr, the reaction was removed from heat and allowed to stand overnight. The reaction mixture was concentrated to dryness, diluted with 100 mL diethyl ether and filtered through celite (ether wash). The eluent was re-filtered through the same celite pad, and concentration gave 2-bromo-1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone as a crude solid used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([S:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][N:27]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:28]=4)[C:12]=3[C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([S:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccc(Cl)cc2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(Cl)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
A mixture of methyl 6-(4-chlorophenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxylate (330 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 6 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 267 mg (58%) of methyl 6-(4-chlorophenyl)-8-(methylthio)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][CH:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccc(F)cc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 4-fluorobenzoyl chloride.