Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:29]([O:31][C:32](=[O:48])[CH2:33]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:30].[S:49]1[CH:53]=[CH:52][C:51]([CH:54]=O)=[CH:50]1>C1COCC1>[CH2:29]([O:31][C:32](=[O:48])[CH:33]=[CH:54][C:51]1[CH:52]=[CH:53][S:49][CH:50]=1)[CH3:30]
Reactant: O=Cc1ccsc1
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccsc1
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Potassium bis(trimethylsilyl)amide (3.92 g, 19.7 mol) was added to a solution of 18-Crown-6 (9.95 g, 37.6 mmol) and [Bis-(2,2,2 trifluoro-ethoxy)-phosphoryl]-acetic acid ethyl ester (6.54 g, 19.7 mmol) in dry THF (200 mL) at −78° C. After 30 minutes of stirring at this temperature, thiophene-3-carbaldehyde (2.0 g, 19.7 mmol) was added and the reaction was stirred for 3 hours at −780C after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mixture was allowed to come to room temperature and was extracted with ethyl acetate (3×250 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL) and dried with MgSO4 Evaporation of the solvent in vacuo gave the crude product that was purified by silica-gel chromatography using a 0-40% ethylacetate-hexane gradient to afford the subtitle compound (2.7 g, 82.7%). MS calculated for C9H10O2S+H: 183, observed: 183; 1H NMR (300 MHz, CDCl3, ppm) 1.31 (t, J=7 Hz, 3H); 4.22 (q, J=7 Hz, 2H); 5.83 (d, J=13 Hz, 1H); 6.87 (d, J=7 Hz, 1H); 7.24-7.28 (m, 1H); 7.54 (dd, J1=5 Hz, J2=1 Hz, 1H); 8.07 (br d, J=3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O>[CH:24]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1)=[O:25]
Reactant: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F

Procedure:
In a solution of 1.00 g of 4-bromo-2-methyl-N-(2,2,2-trifluoroethyl) benzoic acid amide in 15 ml of tetrahydrofuran under nitrogen atmosphere, 4.7 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at −70° C. with stirring, and then 0.4 ml of N,N-dimethylformamide were added dropwise. After stirring at the same temperature for 30 minutes, 10 ml of 1N hydrochloric acid and then 30 ml of water were added, and extracted with ethyl acetate (30 ml×2). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.80 g of the aimed product as pale yellow crystal.
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:6]2=[O:14]
Reactant: NNC(N)=S
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Agent: Cl
Solvent: O
Product: NC(=S)NN=c1c(=O)c2ccc(O)cc2c1=O

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, thiosemicarbazide hydrochloride, reflux for 2 hours.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][CH:26]1[CH2:31][O:30][CH2:29][CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CCO>[F:11][C:10]([F:13])([F:12])[CH2:9][N:8]([CH2:14][C:15]([F:17])([F:18])[F:16])[C:6]([C:5]1[CH:19]=[CH:20][C:2]([NH:24][CH2:25][CH:26]2[CH2:31][O:30][CH2:29][CH2:28][N:27]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CN
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOCC1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (213 mg, 0.612 mmol) and tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (160 mg, 0.734 mmol) in 10 mL of EtOH containing TEA (0.130 mL, 0.918 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 304 mg (91%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.49 (s, 9H), 3.17 (m, 1H), 3.52 (m, 1H), 3.64 (m, 3H), 3.92 (m, 2H), 4.25 (q, J=8.20 Hz, 6H), 7.57 (d, J=8.59 Hz, 1H), 8.30 (d, J=1.95 Hz, 1H), 8.48 (m, 1H); MS (ESI) 544.75 (MH+).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:31])[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:19]3[CH:18]=[C:17]([CH3:31])[CH:22]=[CH:21][CH:20]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=413.05.
Reaction SMILES: [CH2:1]([C:8]1([CH2:23][CH2:24]OS(C)(=O)=O)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[Na+]>>[CH2:1]([C:8]1([CH2:23][CH2:24][I:30])[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: COC(=O)C1C=CCN2C(=O)C(CCOS(C)(=O)=O)(Cc3ccccc3)C(=O)N12
Agent: [Na+]
Product: COC(=O)C1C=CCN2C(=O)C(CCI)(Cc3ccccc3)C(=O)N12
Yield: 51.2 %

Procedure:
In a manner analogous to that described in Example 7(E), from 5.9 g of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-methanesulfonyloxyethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 4.2 g of sodium iodide there were obtained 3.25 g (51%) of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 90°-92° C. (from diethyl ether).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][S-:29].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([S:29][CH3:28])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)cc2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)cc2n1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
2-Chloro-6-(4-(cyclopropylmethyl)piperazin-1-ylmethyl)-4-morpholin-4-ylthieno[3,2-d]pyrimidine (0.2 g, 0.49 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100° C. with stirring. After 2 hours the contents of the tube were diluted with EtOAc then washed with saturated aqueous NaHCO3 (×2) followed by brine and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford 6-(4-(cyclopropylmethyl)piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pale yellow solid (0.2 g, 97%). LCMS (Method D): RT=2.04 min, [M+H]+ 419
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([Cl:26])=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].CI.[C:30](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:20]=[N:21][C:22]([Cl:26])=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[CH3:30])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a solution of [(R)-4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (prepared as described above in example 2-1, 1st step) (740 mg, 1.55 mmol) in acetonitrile (15 mL) was added methyl iodide (655 mg, 4.65 mmol) and potassium carbonate (641 mg, 4.65 mmol). The reaction mixture was stirred at 65° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-4-[(5-bromo-6-chloro-pyridine-3-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (680 mg, 89%) as a yellow solid. Ms cald. for C17H20BrClN4O4S 490, obsd. (ESI+) [(M+H)+] 491.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[F:8][C:9]([F:32])([F:31])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:29]\O)/[C:25]([O:27][CH3:28])=[O:26])[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:31][C:9]([F:8])([F:32])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:29]\[O:6][CH3:7])/[C:25]([O:27][CH3:28])=[O:26])[CH:13]=[CH:12][CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)/C(=C/O)c1ccccc1COc1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dimethyl sulphate (0.65 ml, 6.9 mmol) was added dropwise to a mixture of (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (2.12 g, 6 mmol) and anhydrous potassium carbonate (1.2 g, 8.7 mmol) in dry DMF (10 ml). After stirring at room temperature for 6 hours, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and concentrated to give a crude product which was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (Compound No.177 in Table I of EP-A-0278595); (1.01 g, 46%) as a cream solid; mp 73-74° C.; 1H NMR (270 MHz)δ: 3.68(3H,s), 3.82(3H,s), 5.34(2H,s), 6.87(1H,d), 7.15-7.70(6H,m), 7.55(1H,s) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:29]1[CH2:34][C@H:33]([CH3:35])[NH:32][C@H:31]([CH3:36])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[CH:16]([N:29]1[CH2:30][C@@H:31]([CH3:36])[N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[C@@H:33]([CH3:35])[CH2:34]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1CCCN1C(=O)c2ccccc2C1=O

Procedure:
N-(3-Bromopropyl)phthalimide (2.50 g, 9.33 mmol) is added to a stirred solution of benzhydryl-3,5-cis-dimethylpiperazine (2.61 g, 9.33 mmol) and diisopropylethylamine (1.81 g, 14.0 mmol) in N,N-dimethylacetamide (25 mL). The resultant mixture is heated at 120° C. for 48 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 0-1%, 2-[3-(4-benzhydryl-2,6-cis-dimethylpiperazin-1-yl)-propyl]-isoindole-1,3-dione is obtained as a brown oil (1.98 g, 45% yield).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[CH2:31][S:32][CH2:33][C:34]([F:37])([F:36])[F:35])[CH:7]=1)C.[OH-].[Li+]>CO.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[C:16]([CH2:31][S:32][CH2:33][C:34]([F:37])([F:35])[F:36])[CH:17]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSCC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)c2ccc(Cl)cc2)cc1CSCC(F)(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To {3-[4-(4-chloro-benzoylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.47 mmol) in MeOH and H2O was added 1N aqueous lithium hydroxide. The reaction was stirred overnight at 65° C., and then acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[CH:29][CH:28]=[CH:27]4)=[CH:22][CH:21]=3)[N:18]=[C:17]([C:31]([F:34])([F:33])[F:32])[CH:16]=2)=[CH:11][CH:10]=1)(=O)C.Cl>C1COCC1.CO>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([N:19]3[C:15]([C:12]4[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][OH:6])=[CH:10][CH:11]=4)=[CH:16][C:17]([C:31]([F:33])([F:32])[F:34])=[N:18]3)=[CH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(-n3cccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(-n3cccc3)cc2)cc1
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1M NaOH (436 μl) was added to a solution of 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate (128 mg) in THF (1.5 ml) and MeOH (0.3 ml) under ice bath cooling. The mixture was stirred at 0° C.˜ambient temperature for 2 hours. The mixture was neutralized with 1M HCl (436 μl), and was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=50%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanol (96.5 mg) as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39]2)(=[O:37])=[O:36])[C:25]([Cl:44])=[CH:24][N:23]=1>>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39]2)(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: C[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](C)C3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-((S)-3-methyl-pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.061 g, 47%). MP: 79-89° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.36 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.93 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.56-7.49 (m, 2H), 7.25-7.20 (m, 2H), 6.64 (s, 1H), 3.87 (s, 3H), 3.43 (dd, J=9.6 Hz and 7.1 Hz, 1H), 3.40-3.33 (m, 1H), 3.30-3.22 (m, 3H), 3.14 (s, 3H), 2.98 (s, 3H), 2.91-2.86 (m, 2H), 2.79 (dd, J=9.5 Hz and 7.5 Hz, 1H), 2.74-2.63 (m, 6H), 2.25-2.10 (m, 1H), 1.95-1.87 (m, 1H), 1.43-1.33 (m, 1H), 0.86 (d, J=6.8 Hz, 3H). MS: 628.21 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([OH:32])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of 57 mg (0.11 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step B) in DCM (359 μL) was added trifluoroacetic acid (415 μL, 5.38 mmol) at 0° C. After being stirred at 25 C. for 2 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure three times. Separation of the crude product by reversed phase HPLC (45 to 70% AcCN/H2O in 30 min, 3 time runs, tR=18.52 min) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:23][OH:24])[C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=1)([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:25](Br)[CH3:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O>[CH2:25]([O:24][N:23]=[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][Si:2]([CH3:10])([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)=[CH:14][CH:15]=1)[C:20](=[O:22])[CH3:21])[CH3:26]
Reactant: CC(=O)C(=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCON=C(C(C)=O)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
13.8 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propane-1,2-dione-1-oxime, 4 ml of ethyl bromide and 9 g of potassium carbonate are stirred in 150 ml of dimethylformamide for 2 hours at room temperature. 200 ml of diethyl ether are added to the reaction mixture, which is then washed with water and saturated sodium chloride solution; the organic phase is dried and the solvent is evaporated off to yield the title product in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[CH2:7][C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][CH2:18][S:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:38]>>[CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[C:7](=[O:38])[C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][CH2:18][S:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1ccc(S(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: COc1ccc(S(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=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-[3-(3,4-dimethoxy-phenylsulfinyl)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].S(Cl)(Cl)=O.[CH3:19]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1

Procedure:
Precursors of Example 28 starting from 4-chloro-3-methylsulfonylbenzoic acid via 4-N-hydrazino-3-methylsulfonylbenzoic acid (m.p. 243°-245° C.) and its hydrogenolytic N-N cleavage with Raney nickel catalyst in methanol/aq. NH3 under normal pressure at room temperature to give 4-amino-3-methylsulfonylbenzoic acid (m.p. 258°-262° C.) and subsequent reaction with thionyl chloride and methanol to give methyl 4-amino-3-methylsulfonylbenzoate (m.p. 146° C.).
Reaction SMILES: FC(F)(F)[C:3]([N:5]([CH:23]([CH3:25])[CH3:24])[C:6]1[CH:19]=[C:18]2[O:20][CH2:21][O:22][C:17]2=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:28]>O1CCCC1>[CH:23]([N:5]1[C:6]2[C:7](=[CH:16][C:17]3[O:22][CH2:21][O:20][C:18]=3[CH:19]=2)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:28][C:3]1=[O:4])([CH3:25])[CH3:24]
Reactant: CC(C)N(C(=O)C(F)(F)F)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: N
Solvent: C1CCOC1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
A mixture of 1.0 g. of 2-(N-trifluoroacetylisopropylamino)-4,5-methylenedioxybenzophenone (prepared as in Example C) and 50 ml. of tetrahydrofuran saturated with anhydrous ammonia is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue recrystallized from isopropanol to give 1-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)-quinazolinone, m.p. 189°-190°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[N:13]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH:12][NH2:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(C(=O)O)c1
Reaction time: 1 h
Yield: 284 %

Procedure:
Part A: 5-(Furan-2-yl)-3-trifluoromethyl-1-(2-carboxyl-4-methoxyphenyl)-1H-pyrazole: 3-Methoxy-6-aminobenzoic acid (23 g, 138 mmol) in conc. HCl (300 mL) was cooled to 0° C. and NaNO2 (11.4 g, 165 mmol) in H2O (50 mL) was added dropwise while the temperature of the reaction was maintained below 10° C. The reaction was stirred at or below 10° C. for 1 h, then SnCl2.H2O (92.3 g, 413 mmol) in conc. HCl (125 mL) was added dropwise. The reaction was allowed to thaw to ambient temperature and stirred for 3 h. The precipitate was filtered and air-dried then heated in a vacuum oven for 18 h. There was obtained 71.4 g of 3-methoxy-6-hydrazinobenzoic acid entrained with tin (II) salts.