Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([C:14]([OH:16])=O)[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2].[C:22]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)(N1C=CN=C1)=O.N1CCNCC1>ClC(Cl)C>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([C:14]([N:29]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:22]3)=[O:16])([CH3:17])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Agent: C1CNCCN1
Solvent: CC(Cl)Cl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)N1CCNCC1)O2
Reaction time: 1 h

Procedure:
2.7 g (0.009 mol) of 3,4-dihydro-6-acetoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid are dissolved in 200 cm3 of anhydrous dichloroethane. 1 eq of carbonyldiimidazole (0.009 mol), i.e. 1.5 g, is added. The mixture is left to stir for 1 h and then 7.5 g of piperazine (0.009 mol) dissolved in 200 cm3 of dichloroethane are added. The oil obtained after evaporation is purified on a silica column by eluting with a CH2Cl2 /ethanol/NH4OH (88/10/2) mixture and crystallized from isopropyl ether.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[CH3:20][NH:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][N:23]=1.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:28][C:25]2[CH:24]=[N:23][C:22]([NH:21][CH3:20])=[N:27][CH:26]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: CNc1ncc(C=O)cn1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1ncc(CNc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 9.72 mg, 0.04 mmol) and 2-methylamino-pyrimidine-5-carbaldehyde (138, 11.0 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in 400 μL of dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=378.3.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a Tetrahydrofuran (THF) (220 mL) solution of 2-carboxymethyl-4-nitro-benzoic acid (10.0 g, 44.4 mmol) was added sodium borohydride (5.06 g, 133 mmol) in portions. The contents were cooled to 0° C., and boron trifluoride diethyl etherate (21.3 mL, 133 mmol) was added dropwise over 1 hr. The contents were allowed to warm to 25° C. and stirred for 16 hrs. The reaction was cooled to 0° C. and cautiously quenched with aqueous sodium hydroxide (1 N, 178 mL). The contents were stirred for 3 hrs, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0° C. and the product was filtered off. After drying, the product was obtained as a white solid 7.78 g (89%, mp 79-81° C.). IR 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1.1H NMR (CD3)2SO δ8.05 (d,J=9 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J=9 Hz, 1H), 5.42 (t,J=5 Hz, 1H), 4.74 (t, J=5 Hz, 1H), 4.64 (d, J=5 Hz, 2H), 3.63 (m, 2H), 2.80 (t, J=6 Hz, 2H). 13C NMR (CD3)2SO δ149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9. Anal. Calcd for C9H11NO4 :C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[F:32])[OH:6])[CH3:2].I[CH2:35][CH3:36]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][Si:15]([C:28]([CH3:29])([CH3:31])[CH3:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]=1[F:32])[O:6][CH2:35][CH3:36])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Reactant: CCI
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Temperature: 25 °C

Procedure:
To a well stirred solution under N2 of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester (14.9 g) in Tol (100 ml) was added Ag2O (14.7 g). The mixture was heated in an oil bath at 115–120° C. and iodoethane (12.8 ml) in Tol (50 ml) was slowly added from a dropping funnel. After a total of 2 h and 4 h more iodoethane (7.7 ml each) was added. After a total of 5.5 h heating was stopped and the mixture was left to stir over night at RT. The solids were filtered away over 1 cm of dicalite and were washed with AcOEt. The solvent was evaporated to obtain 16.3 g of crude product as a yellow oil. CC (Hept/CH2Cl2 9:1 to pure CH2Cl2) afforded 10.5 (66%) of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester next to 2.6 g (17%) of recovered starting material. Colorless oil. MS 453.2 (4, [M−OEt]+), 441.1 (24, [M−tBu]+)425.2 (100, [M−COOEt]+).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])([O-])=O.[H][H].C(#N)C>C(O)C.[Pt]>[NH2:1][C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
In 10 ml of ethanol, 1 g (2.88 mmol) of 2-nitro-4,5,3',4'-tetramethoxybenzophenone (prepared according to Example 2) was hydrogenated on 100 mg of platinum/activated carbon (5 percent Pt, moist, H2O content 50 percent) at 40° C. and a hydrogen pressure of 2 bar. After 5 h, the reaction mixture was cooled to room temperature, and 10 ml of acetonitrile was added. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 0.88 g of 2-amino-4,5,3',4'-tetramethoxybenzophenone as a beige solid. The yield of the product was 96 percent of theory.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 29.5 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (104 mg, 0.75 mmol) and followed by 3-bromo-2,2-dimethyl-propan-1-ol (125 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 30%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][N:4]=1.[CH2:31]([Li])CCC.CON(C)C(=O)C1C=CN=C(OC)C=1>O1CCCC1>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:9]([C:7]4[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=4)[CH3:31])[N:16]3[N:17]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(C(=O)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Reactant: [Li]CCCC
Agent: COc1cc(C(=O)N(C)OC)ccn1
Solvent: C1CCOC1
Product: CC(c1cc[nH]c(=O)c1)c1cccc2nc(Nc3ccc(C(F)(F)F)cc3)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
(2-Methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanone. A stirred mixture of 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyridin-2-amine (1.53 g, 4.28 mmol) in tetrahydrofuran (35 mL) was heated briefly with a heat gun under nitrogen until all solids dissolved. The resulting clear red solution was cooled with a dry ice acetone bath under nitrogen. n-Butyllithium (5.76 mL, 9.21 mmol, 1.6 M in hexane) was added dropwise slowly via syringe. During the addition the reaction became black-colored. After 40 min N,2-dimethoxy-N-methylisonicotinamide (4.61 mL, 9.21 mmol, 2 M in tetrahydrofuran) was added. The cold bath was removed and the resulting mixture was warmed to 0° C. over 15 min. After 30 min at 0° C., water (20 mL) was added and the resulting mixture was stirred vigorously at room temperature for 15 min. The resulting mixture was diluted with ethyl acetate and shaken in a separatory funnel. The layers were separated and the organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was dissolved in hot ethyl acetate and purified using flash chromatography (Biotage) (10-100% ethyl acetate in hexane). Fractions containing the desired product were combined and concentrated on a rotary evaporator down to ˜10 mL of ethyl acetate. Hexane (10 mL) was added. Solids were collected by vacuum filtration, washed with hexane, and dried under high vacuum to give the desired product (0.864 g, 2.090 mmol, 49% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.23 (s, 1H), 8.43 (d, J=5.47 Hz, 1H), 7.93 (dd, J=0.98, 8.79 Hz, 1H), 7.77 (dd, J=7.42, 8.98 Hz, 1H), 7.53-7.60 (m, 2H), 7.45-7.53 (m, 3H), 7.31 (dd, J=1.37, 5.27 Hz, 1H), 7.16 (s, 1H), 3.91 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ (ppm)-60.23 (s, 3F); MS (ESI) m/z 414.2 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][C:26]2[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1>C(Cl)CCl>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][C:26]2[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nc2c(s1)CCCC2
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2nc3c(s2)CCCC3)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 38 %

Procedure:
4-Hydroxy-2-methyl-N-(4,5,6,7-tetrahydro-2-benzothiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 2-amino4,5,6,7-tetrahydro-benzothiazole.Yield: 38% of theory; m.p. 255°-257° C, (decomp.; from ethylene chloride).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([Si:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[O:45][CH:46]1[CH2:51][CH2:50][CH:49](O)[CH2:48][CH2:47]1)([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:49]3[CH2:48][CH2:47][CH:46]([O:45][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:51][CH2:50]3)=[CH:17][CH:18]=1)[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](OC1CCC(O)CC1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (4 g, 14.74 mmol) in dry THF (100 mL) and DMF (75 mL) was added triphenyl phosphine (5.8 g, 22.11 mmol) and 4-(t-butyl-diphenyl-silanyloxy)-cyclohexanol (6.27 g, 17.69 mmol). The reaction mixture was cooled to 0° C. and DEAD (3.48 mL, 22.11 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography using DCM as solvent to give 4.73 g (53%) of N-adamantan-2-yl-4-[4-(t-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-benzamide as an oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-3-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.27 g) in methylene chloride (8.1 ml) was added dropwise a solution of m-chloroperbenzoic acid (86 mg) in methylene chloride (5.4 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and recrystallized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 251) (148 mg).
Reaction SMILES: [C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:22](=[O:24])[CH3:23])(=O)C>>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:22](=[O:24])[CH3:23])[O:7][C@H:1]1[C:10]1[Se:11][CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=1)(=[O:3])[CH3:1]
Reactant: NC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2nc(C(N)=O)c[se]2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-β-D-ribofuranosylselenazole-4-carboxamide (1.0 g, 3.25 mmol), N,N-dimethylaminopyridine (catalyst, 80 mg) and acetic anhydride (15 ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and coevaporated with water (10 ml×2) to provide COMPOUND 3 as a white crystalline product which was triturated with water and collected by filtration. The product was recrystallized from water containing a few drops of ethanol to provide white needles: yield 1.2 g (85 percent), mp 117-119 degrees C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:15][C:16]1[CH:21]=C(C(C)(C)C)C(O)=[C:18](C(C)(C)C)[CH:17]=1.CC(=C)CCO>O.C1CCCCC1>[CH3:2][C:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH:16]([CH3:21])[CH:17]=[CH:18][O:3]1
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C(C)CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCCCC1
Product: CC1C=COC(C)(c2ccccc2)C1
Temperature: 94 °C

Procedure:
Into a 1-liter three neck flask equipped with stirrer, condenser, Barrett Trap, thermometer, addition funnel and heating mantle is placed 288 gms (2.4 moles) of acetophenone, 150 ml cyclohexane, 1 g of concentrated sulfuric acid and 1 g of Ionol® . The resulting mixture is heated to reflux temperature (94° C). Then 208 gms (2.4 moles) of 3-methyl-3-buten-1-ol is added, dropwise from the addition funnel, to the reaction mass with stirring while maintaining the reaction mass at reflux. Water of reaction formed is azeotroped over into the Barrett Trap. The reaction mass is heated for a period of 10 hours, during which time 24 ml water collected. At the end of the 10 hour period, the reaction is cooled to room temperature and 2 gms of a 50% sodium hydroxide solution are added. The reaction mass is then rushed over using a 2 inches splash column after adding thereto 10 gms Primol® and 0.1 gms Ionol®. Fractions collected and fractionation data for this rush over is as follows:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:28](=[O:43])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)[CH:32]=1)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH:41]=[N:40][N:39]=[N:38]5)[CH:32]=4)[CH2:29][C:28](=[O:43])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige powder (5.5 mg).
Reaction SMILES: CO[C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1S[N:10]=[CH:9][N:8]=1.S1C(N)=NC=N1.N1C=[CH:28][C:27](N)=NC=1>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][NH:6][C:7]2[CH:28]=[CH:27][N:10]=[CH:9][N:8]=2)=[CH:3][CH:15]=1
Reactant: Nc1ccncn1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: Nc1ncns1
Product: COc1ccc(CNc2ccncn2)cc1

Procedure:
N-(4-methoxybenzyl)pyrimidin-4-amine (INTERMEDIATE AC) was prepared in a manner analogous to INTERMEDIATE A wherein 1,2,4-thiadiazol-5-amine was replaced with pyrimidin-4-amine
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.[F-].[Cs+].C(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)cc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.112 g, 0.209 mmol), pyridine-3-boronic acid (0.077 g, 0.626 mmol), and cesium fluoride (0.111 g, 0.731 mmol) in dry ACN (7 mL) is purged with N2 and then treated with 1,1′-bis(diphenylphophino)-ferrocene palladium (II) chloride complex with DCM (0.031 g, 0.042 mmol). The mixture is heated to 100° C. and stirred for 5 hours under N2. The reaction is cooled, and the crude mixture is absorbed on silica gel and purified by flash chromatography using 2/1 hexanes/ethyl acetate to afford 0.089 g (79%) of the title compound. Rf=0.33 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H28O4NF3 535, found 536 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].Cl[C:14]1C=C(C=CC=1CC(C1C=CC(O)=CC=1O)=O)C(OC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:14])=[O:7]
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(Cl)c1
Reactant: COc1cc(C(=O)O)ccc1C
Product: COC(=O)c1ccc(C)c(OC)c1

Procedure:
starting with 3-methoxy-4-methylbenzoic acid (see step 1 of Intermediate F). MS (ESI): m/z 181.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:14]=[C:15]([CH3:21])[C:16]([Cl:20])=[C:17]([CH3:19])[CH:18]=1>>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:14][C:15]=1[CH3:21]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cc(Br)cc(C)c1Cl
Product: COc1ccc(-c2cc(C)c(Cl)c(C)c2)cn1

Procedure:
The title compound is prepared from 2-methoxy-pyridine-5-boronic acid and 5-bromo-2-chloro-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.21 min; Mass spectrum (ESI+): m/z=248/250 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.19 (s, 4H), 3.77 (s, 3H), 4.13 (s, 4H), 6.88-7.02 (m, 4H), 7.23-7.27 (m, 1H), 7.45-7.71 (m, 3H).