Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:11][N:9]1[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CC(CCN(C)c2ccccc2)Oc2ncccc2C1=S
Reaction time: 48 h

Procedure:
To a suspension of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione in 100 ml of toluene was added 11.49 g (0.11 mole) N-methylaniline and the mixture heated to reflux with stirring for 2 days (after approx. 6 hr, 23.0 g (0.22 mole) additional N-methylaniline was added). Toluene was removed by rotary evaporation (90° C., water aspirator). The N-methylaniline was removed also by rotary evaporation (90° C., vacuum pump). The residue was taken up in 100 ml of chloroform and washed with 3×30 ml dilute aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (80° C., water aspirator). More N-methylaniline was removed with the vacuum pump at 90° C. for several hours. To the residue was added 150 ml of ethyl acetate at which point some product crystallized out. However, since much remained in solution, preparative HPLC on a silica gel column eluting with 60% hexane/40% ethyl acetate was effected. After concentrating the flasks containing the product, crystallization was effected induced by seeding. The chromatographed product was recrystallized from ethyl acetate/isopropyl alcohol and amounted to 1.1 g m.p. 164°-5° C. Approximately 2 g additional was collected by recrystallization of crude product, m.p. 163°-4° C. The combined yield was 3.1 g (26%).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:7])=[CH:33][CH:34]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(C)c2)cc1
Yield: 100.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methylphenyl)benzamide (285.0 mg, 0.62 mmol) and acetic anhydride (0.071 ml, 0.74 mmol), the procedure of Inventive Example 94 was repeated to obtain 311.8 mg (99.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:22][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:10]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=2)(=[O:14])=[O:13])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
This title compound was prepared following procedure described in example 42 step 2 wherein 3-(3,4-dichloro-benzenesulfonylamino)-pyrazine-2-carboxylic acid methyl ester was treated with 2M NaOH and methanol. Usual work up afforded the above title product as a white powder. MS: (M+Na)/z=382.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].I[CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: CS(=O)(=O)NCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCCNS(C)(=O)=O)c1
Temperature: 80 °C
Yield: 23.6 %

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (231 mg) and N-(2-iodoethyl)methanesulfonamide (274 mg) were dissolved in DMF (10 ml), sodium hydride (64 mg, 60% dispersion in mineral oil) was added and the reaction heated at 80° C. for 20 hours. The solvent was evaporated in vacuo and the residue purified by SPE (5 g, Si), eluting with a chloroform/methanol gradient (0-5% methanol). The solvents were evaporated under vacuum from the product fractions to give methyl 4-bromo-3({2-[(methylsulfonyl)amino]ethyl}oxy)benzoate as a colourless gel (83 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:13](=[O:32])[CH2:14][C:15]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=2[S:17](=[O:31])(=[O:30])[N:16]=1)[CH3:12])=O)C.[O-]CC.[Na+]>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:7]([CH2:8][CH2:9][CH2:10]2)[N:11]([CH3:12])[C:13](=[O:32])[C:14]=1[C:15]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=2[S:17](=[O:31])(=[O:30])[N:16]=1
Reactant: CCOC(=O)C1CCCC1N(C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 60 °C
Reaction time: 16 h
Yield: 3.4 %

Procedure:
A solution of the crude 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-methyl-amino}-cyclopentanecarboxylic acid ethyl ester in ethanol (20 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.648 g) and stirred for 16 h at 60° C. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and dried in vacuo. The residue was purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 50%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(4-hydroxy-1-methyl-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (7.5 mg, 0.017 mmol, 3.4% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.49-1.69 (4H, m), 1.85-2.22 (3H, m), 2.88-3.20 (3H, m) 3.05 (3H, s), 3.90 (1H, bs), 7.50-7.64 (3H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C17H20N4O6S2 440.08, found 441.2 [M+H+].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:28]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:15]3[CH:7]=[C:8]([CH3:28])[S:9][C:10]=3[N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2ncnc(NCCc3ccc4c(c3)OCO4)c2c1Cl
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 5-chloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1]Br.[C:3]([CH:5]([C:9](=[O:11])[CH3:10])[C:6]([NH2:8])=[S:7])#[N:4].C(=O)(O)[O-].[Na+].C(OC)(C)(C)C>C(O)(=O)C>[NH2:8][C:6]1[S:7][N:4]=[C:3]([Br:1])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C(C#N)C(N)=S
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(=O)c1c(Br)nsc1N

Procedure:
Add bromine (195; mL, 3.81; mol) over 10; min to a heated solution of 2-cyano-3-oxo-thiobutyramide (550; g, 3.86; mol) in glacial acetic acid (5.80; L) at 40° C. and stir at room temperature for 15; h. Filter the reaction mixture, wash the collected solid with water and dry overnight under vacuum to give a dark red solid (1151; g). Slurry the solid with stirring in a saturated aqueous solution of sodium bicarbonate (8; L) for 30; min and filter. Wash the collected solid with water and dry overnight under vacuum to give a dark red solid (1022; g). Slurry the solid with stirring with methyl t-butyl ether (5.90; L) over 1 hour, filter and retain the filtrate. Repeat the above methyl t-butyl ether extraction process twice on recovered solid retaining the filtrate after each extraction. Combine the filtrates and concentrate to give the title compound as a yellow solid which is carried on without further purification (598; g, 72%). MS (m/z): 221, 223; (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]([N:16]=[C:17]=[O:18])[CH:14]=[CH2:15]>>[CH2:13]([NH:16][C:17]([N:7]1[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)N1CC(C)(C)NC(C)(C)CC1=O

Procedure:
Using the same conditions as in Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 9 parts of allyl isocyanate afforded 26 parts of 4-allylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one which was purified by distillation at 131°-135°C and 0.3mm pressure. The colourless oil gave the following elemental analysis by weight:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[CH3:12][C:11]([NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1)=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@@H]1CC[C@H](C(=O)O)C1
Solvent: c1ccncc1
Product: CC(=O)NC[C@@H]1CC[C@H](C(=O)O)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of cis-3-aminomethylcyclopentancarboxylic acid (0.2 g, 1.4 mmol) in pyridine (about 5 mL) was added acetic anhydride (about 1 mL) and the mixture stirred at about 70° C. for about 2 h. The solvent was removed under reduced pressure, water was added several times and evaporated in vacuo. A light, viscous oil was obtained and dried in vacuo over acetone reflux to give 0.25 g (97%) of cis-3-[(methylcarbonylamino)methyl]cyclopentancarboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=O)[CH:14]=1)#[N:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH2:20][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccsc2C=O)cn(-c2ccccc2)c1=O
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)Cc1sccc1-c1cc(-c2ccccc2C#N)c(=O)n(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of 20 mg of 3-(2-cyanophenyl)-5-(2-formylthiophen-3-yl)-1-phenyl-1,2-dihydropyridin-2-one, 0.1 ml of a 2M solution of diethylamine in tetrahydrofuran and 0.1 ml acetic acid in 2 ml of tetrahydrofuran was stirred at room temperature for 15 minutes, 20 mg of sodium triacetoxyborohydride were added and the mixture was stirred for 3 hours more. A 2N aqueous solution of sodium hydroxide was added thereto, the mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by an NH silica gel column chromatography to give 15 mg of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:31][CH:32]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (3.65 g, 17.4 mmol) was added dropwise under ice cooling to a solution of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate (4.52 g, 15.9 mmol) and triethylamine (2.65 mL, 19.0 mmol) in THF (80 mL), and the resulting solution was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from water-containing ethanol to thereby yield 6.67 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2ccc(Cl)cc2c(=O)o1

Procedure:
To 15 g of 2-amino-5-chlorobenzoic acid are added 80 ml of acetic anhydride, and the mixture is refluxed for 2 hours. The reaction medium is concentrated and the residue is recrystallized from ethanol. After filtering off and rinsing the precipitate, 10.25 g of the expected product are obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[N:13][C:12]=2[CH:16]=1>>[CH3:6][O:7][C:8]1[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:12]2[N:13]=[N:14][S:15][C:11]2=[CH:10][CH:9]=1
Reactant: COc1ccc2snnc2c1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc2snnc2c1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 50 mL of chlorosulfonic acid at 0° C. was added 4.15 g of 5-methoxy-1,2,3-benzothiadiazole under an inert atmosphere. The resulting mixture was heated at reflux for 30 minutes. After cooling to room temperature, the reaction mixture was added to 600 mL ice-water mixture. The precipitate was collected, washed with water and ether, and air dried to give 5.6 g of the title compound as a white solid, m.p. 131°-134° C.
Reaction SMILES: [CH2:1]([O:5][Zr:6](OCCCC)(OCCCC)[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].C(CC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:8]([O:7][Zr:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCO[Zr](OCCCC)(OCCCC)OCCCC
Solvent: CC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CCCCO[Zr]OCCCC

Procedure:
In 86 g of toluene was dissolved 38.3 g (0.1M) of tetra-n-butoxyzirconium, and 30.0 g (0.3M) of acetylacetone was gradually added to the resulting solution with stirring. An exothermic reaction of the mixture took place to give di-n-butoxyzirconium trisacetylacetonato.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH:13][C:12](=O)[CH2:11]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:11][CH2:12][NH:13][CH2:14]1
Reactant: O=C1CC(CCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl
Temperature: 60 °C
Yield: 90.7 %

Procedure:
3.9 g of the 4-(2-tetrahydropyranyloxyethyl)-4-(3,4-dichlorophenyl)-2-pyrrolidone prepared above are dissolved in 50 ml of tetrahydrofuran and the solution is added to a suspension of 0.9 g of lithium aluminum hydride in 5 ml of THF heated to 60° C. The reaction mixture is heated for one hour at 60° C. and then cooled. 1 ml of water, 1 ml of 4N sodium hydroxide and 3 ml of water are added. The inorganic material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in ethyl ether, dried over MgSO4 and concentrated under vacuum to give 3.4 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1.C([O:17]C(=O)N(C1C(C)=NC=C(Br)C=1)CC)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(Br)cnc1C
Reactant: Cc1ncc(Br)cc1OC(C)C
Product: Cc1c(OC(C)C)cc(Br)c[n+]1[O-]

Procedure:
The title compound was synthesized in a similar manner as described for Stage 155.1.4 using 5-bromo-3-isopropoxy-2-methyl-pyridine (Stage 84.1.2, 2.108 mmol) as replacement for (5-bromo-2-methyl-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester to give the title compound as a slowly crystallizing orange solid. (HPLC: tR 2.75 min (Method A); M+H=246, 248 MS-ES).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CCCCCCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), hexylamine (0.170 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.329 g, 62%): TOF MS ES+ 347.2 (M+H)+, HRMS calcd for C18H24N4O2F 347.1883 (M+H)+, found 347.1897, time 0.57 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=11.4 min, 94.8% purity.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: COCCN
Product: COCCNc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Yield: 34 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 2-methoxyethylamine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate=50:50 to 0:100, 78 mg, 34%) which was obtained as an off-white foam. MS: m/e=407.4 [M+H]+.
Reaction SMILES: O[C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1.[Cl:23]N1C(=O)CCC1=O>>[Cl:23][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)N1Cl
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](Cl)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following the general procedure of Example 28 and making non-critical variations 3α-hydroxy-17β-methoxy-5α-androstane (Example 27, 0.47 g.) is reacted with N-chlorosuccinimide for 2 hours. The mixture is extracted with SSB, concentrated, and chromatographed on silica gel eluting with ethyl acetate-hexane (5:95) to obtain the title compound, upon recrystallization from methanol, NMR (CDCl3) 0.74, 0.84, 3.16, 3.33 and 3.75 δ; MS (m/e) 324, 309, 292, 277 and 251.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:27]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:25][C:24]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:23][C:22]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:18]2[CH:19]=[CH:20][C:21]3[N:27]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:25][C:24]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:48])[CH:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[CH:38][CH:39]=4)=[O:32])=[CH:23][C:22]=3[CH:49]=2)=[CH:4][CH:5]=1)[CH3:14]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OCCOCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10. v/v, 18.0 ml) were dissolved 4-(2-ethoxyethoxy)phenyl borate (246 mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (400 mg). To the solution was added potassium carbonate (259 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate→ethyl acetate:ethanol=10:1) and recrystallized from ethyl acetate-IPE to give 7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 25) (216 mg, 46%) as yellow crystals.