Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[C:3]1[Se:7][C:6]2=[C:8]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])[C:9]3[CH:13]=[C:12]([Si](C)(C)C)[Se:11][C:10]=3[C:18]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[C:5]2[CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:35]([CH:30]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][O:28][C:8]1[C:6]2[Se:7][CH:3]=[CH:4][C:5]=2[C:18]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[C:10]2[Se:11][CH:12]=[CH:13][C:9]=12)[CH3:36]
Reactant: CCCCC(CC)COc1c2cc([Si](C)(C)C)[se]c2c(OCC(CC)CCCC)c2cc([Si](C)(C)C)[se]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)COc1c2cc[se]c2c(OCC(CC)CCCC)c2cc[se]c12
Yield: 91.9 %

Procedure:
To a solution of 2,6-bis(trimethysilyl)-4,8-bis(2-ethylhexyloxy)benzo[1,2-b:4,5-b′]diselenophene (11) (0.29 g, 0.423 mmol) in THF (10 mL) was added 1.3 mL of tetrabutylammonium fluoride (1 M solution in THF). The resulted solution was stirred for 3 hours at room temperature water was added (40 mL) then extracted with chloroform (2×40 mL). The extract was dried over MgSO4 (anhydrous), and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:CH2Cl2, 98:2) to give yellow oil (0.21 g, 92%). 1H-NMR(CDCl3): δ 7.90 (d, J=5.9 Hz, 2H), 7.73 (d, J=5.9 Hz, 2H), 4.12 (d, J=5.5 Hz, 4H), 1.80 (m, 2H), 1.35-1.70 (m, 12H), 1.03 (t, J=4.9 Hz, 6H), 0.94 (t, J=4.8 Hz, 6H). MS (EI) Calculated. 540.5 found [M+1]+ 541.5.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH2:40]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[C:41]1[CH:49]=[CH:48][C:47]2[O:46][CH2:45][O:44][C:43]=2[CH:42]=1>>[CH2:40]([N:50]1[CH2:55][CH2:54][N:53]([C:36]([C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([C:23]4[CH:22]=[C:21]([N:15]5[C:14](=[O:39])[C:13]6[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=6)[C:16]5=[O:20])[CH:26]=[CH:25][CH:24]=4)[O:28][C:29]=3[CH:35]=2)=[O:37])[CH2:52][CH2:51]1)[C:41]1[CH:49]=[CH:48][C:47]2[O:46][CH2:45][O:44][C:43]=2[CH:42]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)N5CCN(Cc6ccc7c(c6)OCO7)CC5)cc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and 1-piperonylpiperazine (31 mg, 0.14 mmol) the title compound was obtained (32 mg, 54%). 1H NMR (DMSO) δ 8.33(dd, 1H), 8.25(m, 2H), 8.17(dt, 1H), 8.01(d, 1H), 7.79–7.65(m, 4H), 7.37(d, 1H), 6.77–6.72(m, 2H), 6.64(dd, 1H), 5.88(s, 2H) 3.45(s, 2H), 3.40–3.2(bm, 4H) 2.48–2.22(bm, 4H). MS 629.2 m/z (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH:5]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.N1CCCCC1>O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH:5]=[CH:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C)c(OC)c(C=O)c1C
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: COc1cc(C)c(OC)c(C=CC(=O)O)c1C
Yield: 67.4 %

Procedure:
A mixture of 2,5-dimethoxy-3,6-dimethylbenzaldehyde (5.0 g), malonic acid (3.8 g), pyridine (6 ml) and piperidine (0.3 ml) was refluxed for 25 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and recrystallized from ethanol to obtain 2,5-dimethoxy-3,6-dimethylcinnamic acid (4.1 g) (Compound A-22). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=[C:27]([I:33])[CH:26]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[I:33][C:27]1[CH:26]=[C:25]([CH:22]2[CH:21]3[CH:23]2[CH2:24][CH:19]([OH:18])[CH2:20]3)[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=1
Reactant: CC(C)n1nc(I)cc1C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(I)cc1C1C2CC(O)CC21
Yield: 100.9 %

Procedure:
A solution of 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-iodo-1-isopropyl-1H-pyrazole (11.2 g, 19.7 mmol) and triethylamine trihydrofluoride (63 g, 391 mmol) in anhydrous tetrahydrofuran (100 mL) was heated at 70° C. for 6 h. Saturated aqueous sodium bicarbonate solution was added until the solution reached pH=7. The resulting aqueous mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:1 petroleum either/ethyl acetate) afforded crude 6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-ol as a pale yellow oil (6.6 g, 100%). LRMS: [M+H]+ 332.9.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4([C:29](=[O:38])[NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:19][C:18]=3[F:39])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH3:49])[CH2:44][CH2:43]1>CN(C)C=O>[F:39][C:18]1[CH:19]=[C:20]([NH:23][C:24]([C:26]2([C:29]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[O:38])[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:48]([CH3:49])[CH:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:7])[N:11]=[CH:12][N:13]=1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Reactant: CNC1CCN(C)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncn2)CC1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (40 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 1-methyl-4-(methylamino)piperidine (0.045 ml) was added thereto, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (33.7 mg, 79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCC1>CO>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18](/[C:19](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH:11]([CH3:13])[CH3:12])/[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)Oc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.5 %

Procedure:
5-Chloro-2-isopropoxy-benzaldehyde (3 g, 15.1 mmol) and 6-chlorooxindole (2 g, 12.6 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.07 g, 15.1 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16](=[O:28])[C@H:17]([OH:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:28])[C@H:17]([OH:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COC(=O)[C@H](O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 165 mg, 0.84 mmol) and (3S,2R)-3-amino-2-hydroxy-4-phenylbutyric acid methyl ester (Preparation 21, 175 mg, 0.84 mmol) in DMF (10 mL)was added HOBt (125 mg, 0.92 mmol), DIPEA (0.29 mL, 1.68 mmol) and EDCI (177 mg, 0.92 mmol) and the reaction stirred at rt for 72 h. The reaction solvent was removed in vacuo, and the residue partitioned between water (40 mL) and ethyl acetate (3×40 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a yellow solid. δH (CD3OD): 2.97–3.12 (2H, m), 3.67 (1H, s), 4.25 (1H, d), 4.70–4.75 (1H, m), 7.08 (1H, s), 7.15–7.21 (1H, m), 7.25–7.34 (4H, m), 7.65 (1H, s), 8.55 (1H, s); m/z (ES+)=388 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:16][NH:17][C:18]([CH3:31])([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH2:40][OH:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]12([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH2:43]1)[CH2:49]2>>[C:42]12([NH:52][C:27](=[O:28])[CH2:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][C:18]([NH:17][CH2:16][C@@H:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:10]([CH2:40][OH:41])[CH:11]=4)[O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:35])[CH3:34])([CH3:31])[CH3:30])[CH:21]=3)[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:45][CH:44]([CH2:50]3)[CH2:43]1)[CH2:51]2
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Product: CC(C)(Cc1cccc(CC(=O)NC23CC4CC(CC(C4)C2)C3)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Yield: 71 %

Procedure:
The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl propyl}phenyl)acetic acid (preparation 148) and 1-adamantylamine, using a similar method to that of preparation 38, as a yellow oil in 71% yield. 1H NMR (400 MHz, DMSO-d6) δ: 7.52 (3H, m), 7.52-7.24 (4H, m), 7.18-7.08 (2H, m), 7.07-6.98 (2H, m), 6.94 (1H, m), 5.09 (2H, d), 5.01 (1H, t), 4.66-4.61 (1H, m), 4.54 (2H, d), 3.25 (2H, d), 3.15 (1H, d), 2.59-2.43 (2H, m), 1.98-1.92 (3H, m), 1.87 (6H, m), 1.57 (6H, m), 0.96 (6H, dd), 0.79 (9H, d), -0.98 (3H, s), -0.93 (3H, s) ppm; LRMS ESI m/z 712 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (240 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (339 mg, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][NH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2.N1C=CC=CC=1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33].[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:35]([NH:34][CH2:32][CH3:33])=[O:36])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2
Reactant: COCN1c2cc(CNc3cccnc3)ccc2Sc2nccnc21
Reactant: CCN=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCNC(=O)N(Cc1ccc2c(c1)N(COC)c1nccnc1S2)c1cccnc1

Procedure:
341 mg of 10-methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 5 ml of toluene. After adding 3 ml of pyridine and 1.9 ml of ethyl isocyanate, the reaction mixture was heated under reflux for 3 days. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted repeatedly with ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with toluene/acetone) to thereby give 350 mg of the title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=2[C:40]2[C:41]([N+:51]([O-])=O)=[N:42][N:43](C3CCCCO3)[CH:44]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:51][C:41]1[C:40]([C:31]2[CH:32]=[C:33]([C:36]([F:37])([F:39])[F:38])[CH:34]=[CH:35][C:30]=2[O:29][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]3[S:13][CH:14]=[N:15][N:16]=3)(=[O:10])=[O:9])=[C:5]([F:28])[CH:4]=2)=[CH:44][NH:43][N:42]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1n[nH]cc1-c1cc(C(F)(F)F)ccc1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl
Temperature: 80 °C

Procedure:
To a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 867, 3.20 g, 4.00 mmol) in ethanol (200 mL) was added saturated aqueous ammonium chloride solution (50 mL) and iron (5.66 g, 101 mmol). The reaction solution was heated at 80° C. for 15 minutes. The solution was cooled, filtered and adjusted to pH=9 with saturated aqueous sodium bicarbonate solution. The mixture was filtered and then concentrated to remove most of the ethanol. The resulting slurry was extracted with dichloromethane (3×). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. This provided the aminopyrazole as a yellow foam. To this was added an HCl (g) saturated methanol solution (200 mL) and the mixture heated at 60° C. for two hours. The reaction solution was cooled, concentrated, and purified by automated flash column chromatography using a 0-10% methanol/dichloromethane gradient. Additional purification by prep HPLC provided the TFA salt. The resulting white solid was redissolved in a HCl (g) saturated methanol solution and concentrated (3×) in order to isolate the HCl salt of the title compound (1.20 g, 53%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[F:42][C:43]([F:48])([F:47])[CH2:44][CH2:45]I>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:45][CH2:44][C:43]([F:48])([F:47])[F:42])[C:23]([O:25][CH3:26])=[O:24]
Reactant: FC(F)(F)CCI
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 26.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 1,1,1-trifluoro-3-iodopropane (0.117 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.061 g (25%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=O>C(O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2](/[N:1]=[CH:12]/[C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc(C(=O)OCc2ccccc2)c1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2cccc(C(=O)OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-aminobenzoate (7.94 g, 52.5 mmol) in ethanol (100 mL) was added benzyl 3-formylbenzoate in ethanol (50 mL) and the resulting mixture was stirred at room temperature for 2 h. The white solid precipitated was collected by filtration and washed with ethanol, dried in vacuo (50° C.) to give 15.6 g of (E)-benzyl 3-((4-(methoxycarbonyl)phenylimino)methyl)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:14]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (2.29 g, 10 mmol) in methylene chloride (30 mL) was added 25% ammonium hydroxide (10 mL) at room temperature and the mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was redissolved in ethyl acetate (50 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The resulting solid was recrystallized from ether-hexane to give the title compound (1.429 g, 68.2% yield).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19]>CC(C)=O>[O:19]=[C:9]1[N:8]([CH2:7][CH2:6][CH:2]=[O:1])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCC1OCCO1
Solvent: CC(C)=O
Product: O=CCCn1c(=O)[nH]c2ccccc2c1=O
Yield: 95.9 %

Procedure:
A solution of 3-(2-[1,3]dioxolan-2-yl-ethyl)-1H-quinazoline-2,4-dione (0.11 g, 0.43 mmol) 10% sulfuric acid (10 mL) and Acetone (10 mL) was stirred at ambient temperature for 24 hours. Concentration yielded 3-[2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]propionaldehyde (0.09 g, 95%) as an off-white solid. 1H NMR CDCl3 δ9.85 (s, 1H), 8.10-8.06 (m,1H), 7.63-7.57 (m, 1H), 7.24-7.19 (m, 1H), 7.13-7.07 (m, 1H), 4.44-4.40 (m, 2H), 2.85 (dt, 2H, J1,2=2 Hz, J1,3=7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]([F:31])([F:43])[F:44])=[CH:39][CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(C)C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(F)(F)F)cc3)ccc2n1-c1ccc(N(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-dimethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 16) and 4-trifluoromethoxyphenylboronic acid (50 mg, 0.74 mmol). Yield 120 mg (57%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[Br:29][C:30]1[CH:31]=[C:32]([NH2:37])[C:33]([NH2:36])=[CH:34][CH:35]=1>CN(C=O)C.N1C=CC=CC=1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]2[NH:36][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:37][C:32]=2[CH:31]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To the mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2 g, 8.7 mmol) in DMF (15 mL) and pyridine (15 mL) was added CDI (1.55 g, 9.57 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 4-Bromo-benzene-1,2-diamine (1.63 g, 8.7 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (10 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 5-Bromo-2-piperidin-4-yl-1H-benzoimidazole (1.47 g, 55%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]3[CH2:18][O:17]3)[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S-:27].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]([OH:17])[CH2:18][S:27][CH3:26])[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCOC(C2CO2)C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC(O)C1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
To a solution of a mixture (420 mg) of tert-butyl (6RS,7RS)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate and tert-butyl (6SR,7SR)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate in DMF (2 mL) was added sodium thiomethoxide (114 mg), and the mixture was stirred at room temperature for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous potassium carbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (130 mg) in a less polar fraction as colorless crystals.