Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.[CH3:15]OS(OC)(=O)=O.[OH-].[Na+]>CN(C)C=O>[CH3:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)O)c2ccccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A cooled (0° C.) suspension of 60% sodium hydride-oil dispersion (0.96 g, 24 mmol) in anhydrous N,N-dimethylformamide (15 mL) under nitrogen was treated in portions with indole-3-carboxylic acid (1.62 g, 10 mmol), and the mixture was stirred at 45°±5° C. for 30 minutes. Dimethylsulfate (3.03 g, 24 mmol) was added, and the mixture was heated to 100° C. for 30 minutes, cooled, and added to ice water (100 mL). The suspension was filtered and the wet solid was washed with water and taken up in 50% aqueous methanol (40 mL). The mixture was treated with 50% aqueous sodium hydroxide (3.0 g, 37.5 mmol) and refluxed for 30 minutes, then the methanol was removed in vacuo and replaced with water. The aqueous solution was extracted with ether (50 mL), then acidified with 3N HCl to pH 3 (15 mL). The suspension was filtered and the solid was washed with water and dried exhaustively m vacuo in the presence of Drierite. Recrystallization from acetonitrile afforded 1.32 g (75%) of colorless crystals; mp 201°-202° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[CH2:15][C:16]([NH:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:17].[H-].[Na+].FC(F)(F)S(O[CH2:36][CH:37]([F:39])[F:38])(=O)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[CH2:15][C:16]([N:18]([CH2:36][CH:37]([F:39])[F:38])[C:19]1[N:20]=[CH:21][S:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:17]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(-c2ccc(Cl)s2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1scnc1N(CC(F)F)C(=O)Cc1c(Cl)ccc(-c2ccc(Cl)s2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, 300 mg (0.65 mmol) of methyl 4-({[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]acetyl}amino)-1,3-thiazole-5-carboxylate were dissolved in 15 ml of tetrahydrofuran, and 23 mg (0.97 mmol) of sodium hydride were added at room temperature. The reaction mixture was stirred at RT for 5 min, and a solution of 167 mg (0.78 mmol) of 2,2-difluoroethyl trifluoromethanesulfonate in 6 ml of THF was then added over a period of 10 min. The mixture is then stirred at RT for 12 h. The THF is removed under reduced pressure and the residue is taken up in water. The aqueous phase is extracted with dichloromethane and the organic phase is dried and concentrated by evaporation. The residue is chromatographed (acetonitrile/water (0.05% trifluoroacetic acid 20/80 to 100/0)). This gave 120 mg of methyl 4-[{[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]acetyl}(2,2-difluoroethyl)amino]-1,3-thiazole-5-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH2:18]([NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[C:26]([F:39])[CH:25]=1)=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)=[C:26]([F:39])[CH:25]=1)=[O:22])[CH3:19]
Reactant: CN1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C)C3)c(F)c1
Yield: 26 %

Procedure:
Method as example 147 using 4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 21) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) as starting materials. The crude reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford a light yellow solid (61 mg, 0.15 mmol, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:8][C:7]3[C:13]4[C:18]([CH2:19][C:6]=3[C:5]=2[CH:4]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4.O1CCN(B)CC1.Cl.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:8][C@@H:7]3[C:13]4[C:18]([CH2:19][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4
Reactant: COc1cc(C)c2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: BN1CCOCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.4 %

Procedure:
To a solution of 5.0 g (0.020 mol) of 5,10-dihydro-8-methoxy-6-methylindeno[1,2-b]indole in 50 ml of tetrahydrofurane was added 8.1 g (0.080 mol) of morpholino borane and dropwise 6.3 ml of conc. hydrochloric acid. The initially exothermic reaction mixture was stirred at room temperature for 72 hour. An additional 6.3 ml of conc. hydrochloric acid was then added and the mixture stirred over night. 25 ml of water was then added and the mixture evaporated. The residue was suspended in 200 ml of water and 5 ml of conc. hydrochloric acid and the mixture was heated on a water bath until most of the solid material had dissolved. The solution was then filtered hot and the filtrate cooled and alkalinized by addition of 10M sodium hydroxide solution. Filtration and washing with water gave 1.93 g (38.4%) of the title compound 1H NMR (CDCl3) δ: 2.08 (3H,s), 3.15-3.25 (1H,dd), 3,42-3.55 (1H,dd), 3.7 (3H,s), 4.1-4.22 (1H,t), 5.22-5.28 (1H,d), 6.42-6.46 (1H,d), 6.6-6.65 (1H,d), 7.14-7,25 (3H,m), 7.3-7.4 (1H,m).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: O=C(Cc1cccc(Cl)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(3-chlorophenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.62-7.66 (m, 4H), 7.47 (t, J=1.8 Hz, 1H), 7.31-7.42 (m, 3H), 3.74 (s, 2H); MS (ESI−) M/Z 422 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:18]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:18][C:13]1[NH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: COC(=O)c1c[nH]cc1-c1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c(Cl)c1-c1cccc(C#N)c1
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 16.5 g (72.9 mmol) of methyl 4-(3-cyano-phenyl)-1H-pyrrole-3-carboxylate in 150 ml of tetrahydrofuran are added portionwise 9.93 g (74.4 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 6 hours at reflux. After cooling, 250 ml of water are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 17.1 g of methyl 5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured powder after recrystallizing from acetonitrile, filtering off and drying.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[C:12]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc(C(O)(c2ccccc2)C(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CO
Product: CN(C)CCOc1ccc(C(=C(CCOCc2ccccc2)c2ccc(Cl)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-1-phenylbutan-1-ol (10.7 g) is dissolved in methanol (70 ml) and concentrated hydrochloric acid is added to make the solution acidic. The mixture is stirred for 4.5 h at room temperature and then at 50° C. for 1 h. The solvent is evaporated and the product is purified by flash chromatography (eluent toluene:triethylamine 24:1). The yield is 5.6 g as a mixture of E- and Z-isomers (1:2).
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:61](Cl)(=[O:63])[CH3:62]>ClC(Cl)C>[C:61]([N:11]([CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][S:2](=[O:51])(=[O:1])[CH2:7][CH2:6]1)[C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)(=[O:63])[CH3:62]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(N(CCN3CCS(=O)(=O)CC3)C(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.05 g, 0.071 mmol) in dichloroethane (1 mL) and Hunig's base (0.062 mL, 0.355 mmol) was added acetyl chloride (0.020 mL, 0.284 mmol). The mixture was heated to 50° C. After heating the mixture for 71.25 h, the mixture was cooled to rt and was directly loaded onto a 12 g Thomson silica gel column and was purified by Biotage flash chromatography using a 0-5% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and were concentrated under reduced pressure to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.054 mmol, 75%) as a clear, colorless film. LCMS: m/e 747.5 (M+H)+, 2.26 min (method 2).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[O:9])[CH2:2]1>CO>[O:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[O:9])[CH2:2]1
Reactant: O=C(NCC1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Solvent: CO
Product: O=C(NC[C@@H]1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1

Procedure:
A racemic mixture of N-(4-{[tetrahydrofuran-3-ylmethyl]carbamoyl}phenyl)-1,3-dihydro-2H-isoindole-2-carboxamide (250 mg) was dissolved in methanol and separated using SCF-LC with a ChiralPak AD-H 21×250 mm column to provide N-(4-{[(3S)-tetrahydrofuran-3-ylmethyl]carbamoyl}phenyl)-1,3-dihydro-2H-isoindole-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (s, 1H), 8.38 (t, J=5.7 Hz, 1H), 7.75-7.79 (m, 2H), 7.64-7.69 (m, 2H), 7.30-7.41 (m, 4H), 4.78-4.79 (bs, 4H), 3.57-3.78 (m, 3H), 3.48 (dd, J=8.5, 5.2 Hz, 1H), 3.17-3.28 (m, 2H), 2.41-2.50 (m, 1H), 1.87-2.04 (m, 1H), 1.54-1.66 (m, 1H); MS (ESI(+)) m/e 366 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10]C(C1C=CC=C2C=1CN(C1SC(CCCOC3C=CC(C4C(C#N)=CSC=4)=CC=3)=C(C(O)=O)N=1)CC2)=O.[N+:48]([C:51]1[CH:52]=[C:53]([S:57]([NH:60][CH2:61][CH2:62][C:63]2[S:67][C:66]([N:68]3[CH2:77][CH2:76][C:75]4[C:70](=[C:71]([C:78](=[O:97])/C=C5/SC6C=CC=CC=6N/5COCC[Si](C)(C)C)[CH:72]=[CH:73][CH:74]=4)[CH2:69]3)=[N:65][C:64]=2[C:98]([O:100]CC)=[O:99])(=[O:59])=[O:58])[CH:54]=[CH:55][CH:56]=1)([O-:50])=[O:49]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:78]([C:71]1[CH:72]=[CH:73][CH:74]=[C:75]2[C:70]=1[CH2:69][N:68]([C:66]1[S:67][C:63]([CH2:62][CH2:61][NH:60][S:57]([C:53]3[CH:54]=[CH:55][CH:56]=[C:51]([N+:48]([O-:50])=[O:49])[CH:52]=3)(=[O:59])=[O:58])=[C:64]([C:98]([OH:100])=[O:99])[N:65]=1)[CH2:77][CH2:76]2)=[O:97]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)/C=C4/Sc5ccccc5N4COCC[Si](C)(C)C)c3C2)sc1CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCNS(=O)(=O)c3cccc([N+](=O)[O-])c3)s1)CC2

Procedure:
The title compound 70 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 70A: 1H NMR (DMSO-d6): δ 8.39-8.44 (m, 2H), 8.11-8.15 (m, 2H), 8.04 (d, J=7.98 Hz, 1H), 7.78-7.84 (m, 2H), 7.68 (d, J=7.36 Hz, 1H), 7.34-7.50 (m, 4H), 6.90 (d, J=8.29 Hz, 1H), 4.79 (s, 2H), 3.69 (d, J=5.98 Hz, 2H), 3.06-3.10 (m, 4H), 3.03 (t, J=5.98 Hz, 2H). ESI (+)/MS: 665 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(N2CCOCC2)c1

Procedure:
Compound is formed by reacting 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with morpholine under conditions described in general procedure B. Mp: 90-92° C. 1H NMR (300MHz, DMSO-d6): δ 10.16 (s, 1H), 8.19 (m, 1H), 7.81 (m, 1H), 7.58 (s, 1H), 7.53 (m, 3H), 7.40 (m, 2H), 7.17 (d, 1H, J=8.4), 7.01 (d, 1H, J=8.7), 4.30 (t, 2H, J=4.8), 3.74 (m, 4H), 3.57(m, 4H), 3.18 (m, 4H), 2.85 (t, 2H, J=5.7), 2.54 (m, 4H). MS: 462.2 (M+1).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]C.N1CCOCC1.[CH3:12][O:13][C:14]([C:16]1[C:20](=O)O[C:18]2=[CH:22][CH:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[CH:25]=[CH:26][C:17]=12)=[O:15]>C(O)C>[CH3:12][O:13][C:14]([C:16]1[C:17]2[C:18]([CH:22]=[CH:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=2)=[C:1]([CH2:2][CH3:3])[CH:20]=1)=[O:15]
Reactant: COC(=O)c1c2ccc(C(C)C)ccc-2oc1=O
Reactant: CCCC=O
Solvent: CCO
Solvent: C1COCCN1
Product: CCc1cc(C(=O)OC)c2ccc(C(C)C)ccc1-2

Procedure:
n-Butyraldehyde (61.5 g, 0.853 mole) and morpholine (61.9 g, 0.71 mole) are added to cooled ethanol (400 ml), and then the compound (5) (68 g, 0.276 mole) is added thereto. The obtained mixture is stirred and warmed to dissolve the solid substance homogeneously. It is heated under reflux for 8 hours, and then the solvent is distilled off under reduced pressure to precipitate an oily material. The obtained oily material is dissolved in benzene (450 ml), washed twice with the same volume of water, three times with 1N HC1 (400 ml), and further twice with water (400 ml). The obtained benzene solution is passed through alumina (500 g), and the eluted solution is concentrated to obtain the compound (1) at a yield of 57.4 g, 81.2%. It is recrystallized in n-hexane to give the purified product (55 g) in the purple crystalline form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:15][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=452.0, tR (minutes, Method F)=3.03
Reaction SMILES: [Cl:1][C:2]([F:11])([F:10])[C:3](=O)/[CH:4]=[CH:5]/OCC.C[N:13](C)[CH:14]=[CH:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: CCO/C=C/C(=O)C(F)(F)Cl
Reactant: CN(C)C=CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(F)(F)Cl)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
(3E)-1-Chloro-4-ethoxy-1,1-difluorobut-3-en-2-one (7.36 g, 40 mmol) was dissolved in dry toluene (40 mL) and treated with 3-dimethylaminoacrylonitrile (4.61 g, 48 mmol) at room temperature. The solution was heated at about 100° C. for 3.5 hr. The solvent was then removed under reduced pressure and the remaining mixture was re-dissolved in DMF (20 mL), treated with ammonium acetate (4.62 g, 60 mmol) and stirred at room temperature overnight. Water was added to the reaction mixture and and the resulting mixture was extracted with ether-CH2CH2 (1:2, v/v) twice. The combined organic layer was washed with brine, dried, filtered and concentrated. The residue was purified on silica gel to give 3.1 g of 6-[chloro(difluoro)methyl]nicotinonitrile (A) as light colored oil in 41% yield. GC-MS: mass calcd for C7H3ClF2N2 [M]+ 188. Found 188.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:39])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:33])(=[O:32])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22]C(=O)OC(C)(C)C)=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:20]1[C:19]([CH3:31])([CH3:30])[S:18](=[O:32])(=[O:33])[C@@H:17]2[CH2:34][CH2:35][O:36][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:5]4[C:4]([CH3:39])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[CH:38][C:15]=3[C@@:16]2([CH3:37])[N:21]=1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Yield: 97.9 %

Procedure:
A solution of trans-isomer tert-butyl ((4aR,11bR)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (110 mg, 0.191 mmol) in DCM (2 ml) was treated with TFA (0.7 ml, 9.53 mmol) for 10 min at RT. The mixture was concentrated to dryness, redissolved in 0.5 ml of MeOH and neutralized with saturated solution NaHCO3. The precipitated material was extracted with ethyl acetate, organic extract was washed with water, brine, filtered through pad of celite and concentrated to afford N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-methylpicolinamide (Example 6a) (89 mg, 0.187 mmol, 98% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][NH:10][C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16]C)=[O:14].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:31])C>>[CH3:22][C:2]1([CH3:1])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][N:10]1[C:11]2[N:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13](=[O:14])[O:15][C:16]1=[O:31]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Product: CC1(C)[C@H]2CC[C@@H](Cn3c(=O)oc(=O)c4cccnc43)[C@@H]1C2

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 31A for the product of Example 3A (0.570 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 0.79 (d, J=9.56 Hz, 1H), 1.14 (s, 3H), 1.22 (s, 3H), 1.62 (m, 1H), 1.87 (m, 5H), 2.26 (m, 1H), 2.53 (m, 1H), 4.04 (dd, J=13.05, 6.07 Hz, 1H), 4.28 (dd, J=13.24, 9.19 Hz, 1H), 7.37 (dd, J=7.72, 4.78 Hz, 1H), 8.38 (dd, J=7.72, 1.84 Hz, 1H), 8.76 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH2:30][CH2:31][OH:32])[CH:29]=1)[CH2:5][N:6]1[CH2:26][CH2:25][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[C:28]([CH2:30][CH:31]=[O:32])[CH:27]=[C:4]([CH2:5][N:6]2[CH2:26][CH2:25][C:9]3([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)=[O:16])[CH2:10]3)[CH2:8][CH2:7]2)[CH:3]=1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(3-chloro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 52, step c) (0.242 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.059 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.323 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 30 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow foam. Yield 0.297 g. ink 476 (M+H)+ (APCI)