Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][C:33]=1[F:41]>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)=[C:33]([F:41])[CH:34]=1)(=[O:37])[NH2:38]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: NC(=O)c1ccc(Br)c(F)c1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)cc4F)ccc3o2)CC1
Yield: 39.2 %

Procedure:
Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromo-3-fluorobenzamide (105 mg, 0.48 mmol) as an off-white solid. M.P.: 194-197° C. MS (m/z): 426.0 [M+H]+.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:21])[CH2:17][NH:18][CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3].O1CCCC1.[O-:37][C:38]#[N:39].[K+]>O>[CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:20]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)=[O:21])[CH2:17][N:18]([C:38]([NH2:39])=[O:37])[CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: N#C[O-]
Reactant: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CNC)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CN(C)C(N)=O)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Temperature: 50 °C
Yield: 87 %

Procedure:
To a solution of N-(propylsulfonyl)-D-isoleucyl-3-(methylamino)-N1-(4-cyanobenzyl)-L-alaninamide (500 mg, 1.0 mmol) in water (1.3 ml)/tetrahydrofuran (3 ml), potassium cyanate (243 mg, 3 mmol) was added under stirring at 50° C. and then further stirred under the same conditions. After stirring for 3 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give N-(propylsulfonyl)-D-isoleucyl-3-[(aminocarbonyl)(methyl)amino]-N1-(4-cyanobenzyl)-L-alaninamide (430 mg, 0.87 mmol; yield 87%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].Cl.[N:11]([O-])=[O:12].[Na+].[Cl-].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: COCCNCCOC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCCN(CCOC)N=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To the mixture of 133 g of bis(2-methoxyethyl)amine, 145 ml of concentrated HCl (36%) and 400 g of ice, 70 g of sodium nitrite dissolved in 250 ml of water was added dropwise slowly while keeping the reaction temperature at 10° C. or below, and then stirred for 2 hours at 10° C. or less and for further 2 hours at room temperature. 250 g of sodium chloride was added thereto, and the mixture was thrice extracted with 500 ml of ethyl acetate and dried with magnesium sulfate. After removing the solvent, the mixture was purified by a silica gel column by using the mixed solvent (hexane/ethyl acetate: 3/1) to obtain 85 g of bis(2-methoxyethyl)nitrosoamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([O:24]C)=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:26][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].O.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:26][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:9])=[O:10]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Temperature: 100 °C
Yield: 100.4 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-Fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 68, 0.6 g) and lithium hydroxide monohydrate (1.5 g) in dioxane (45 mL) and water (13.8 mL) was stirred and heated at 100° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was diluted with water and acidified to pH3 with 1M hydrochloric acid. The precipitated solid was collected by filtration to give (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.58 g) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[ClH:11].[NH2:12]O>C(#N)C>[ClH:11].[NH2:12][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: NO
Reactant: COC(=O)C1CSCC1=O
Agent: Cl
Solvent: CC#N
Product: COC(=O)c1cscc1N
Yield: 62.3 %

Procedure:
A mixture of 4-oxo-3-methoxycarbonyltetrahydrothiophene (6.5 g, 40.62 mmol), hydroxylamine hydrochloride (2.84 g, 40.62 mmol) and acetonitrile (30 mL) was stirred under reflux for 1 h. The mixture was then cooled and the solid which separated was filtered off and washed with dry ether to afford the title compound (4.9 g, 62%), mp 192-196° C.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1.CI.[Cl-].[NH4+].N>C(OCC)C>[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][C:26]([CH3:2])=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: [Li]CCCC
Reactant: CCCOc1ccc(-c2ccc(-c3ccc[se]3)cc2)c(F)c1F
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCCOc1ccc(-c2ccc(-c3ccc(C)[se]3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2.0 ml (11.8 mmol) of TMP are initially introduced at −15° C. in 15 ml of diethyl ether, and 7.0 ml (11.1 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min, a solution of 3.5 g (9.3 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene in 35 ml of diethyl ether is metered in, and the mixture is stirred at RT for 45 min. The batch is cooled to −70° C., and 3.0 ml (48.2 mmol) of methyl iodide are added. The mixture is warmed to RT and stirred for 3 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is briefly stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=1:1). The further purification is carried out by digestion in ethanol and recrystallisation from n-heptane/toluene (2:1). 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 143° C.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:34]1(C)C=CC=C[CH:35]=1>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([O:19][CH2:34][CH3:35])=[O:18])[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-(biphenyl-4-yl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 in toluene and ethanol.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].S(=O)(=O)(O)O.[Cl:16][C:17]1C(O)=C[CH:20]=[CH:19][C:18]=1[OH:24]>O>[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][CH:20]=[C:9]2[C:8]=1[O:7][C:5](=[O:6])[CH:4]=[C:3]2[CH2:2][Cl:1]
Reactant: Oc1cccc(O)c1Cl
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(CCl)c2ccc(O)c(Cl)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-chloro-3-oxobutanoate (4.91 mL) was added sulfuric acid (12.91 mL) at 0° C., then was added 2-chlorobenzene-1,3-diol (5.0 g) in several portions at 0° C. The mixture was warmed to room temperature and stirred at the same temperature for 2 h. The reaction mixture was poured into water under stirring at 0° C. The precipitate was collected by m filtration and washed with hexane to give the title compound (2.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:28])=[O:27])[CH:12]=3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:28])(=[O:39])=[O:27])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)=O)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To 439 mg of ethyl 9-p-chlorobenzyl-6-methylsulfinyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Example 24, in 10 cc of methylene chloride was added 353 mg of m-chloro perbenzoic acid. The resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with ether and washed consecutively with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 30% hexane/ethyl acetate and yielded 200 mg (42%) of the pure title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]O)[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.O>[N:22]([CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:23]=[N-:24]
Reactant: OCCc1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A mixture of 3-bromobenzeneethanol 4-methylbenzenesulphonate [Example H(b)] (3.96 g, 11.2 mmol) and sodium azide (22.4 mmol, 1.46 g) in DMSO (50 ml) was stirred at room temperature for 16 h, diluted with water (200 ml), extracted with diethyl ether (2×40 ml), the combined extracts washed with saturated aqueous sodium chloride (40 ml), dried over sodium sulphate and evaporated, to give the product as a pale yellow oil (2.46 g). M+ 227; 360 MHz 1H n.m.r (CDCl3) 7.52 (1H, s), 7.45-7.42 (1H, m), 7.31-7.25 (2H, m), 3.58 (2H, t, 7.0 Hz), 2.85 (2H, t, J 7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[O:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[O:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(2-benzofuranyl)benzoxazole (105 mg, 0.29 mmol) and 1,2,4-benzenetricarboxylic anhydride (57 mg, 0.29 mmol) the title compound was obtained (98 mg, 63%). 1H NMR (DMSO) δ 13.74(s, 1H), 8.43(dd, 1H), 8.32(d, 2H), 8.21(d, 1H), 8.10(d, 1H), 8.02(dd, 1H), 7.92(d, 1H), 7.72(dd, 1H), 7.67(t, 2H), 7.54(s, 1H), 7.47(d, 1H), 7.31(m, 2H), 4.03(s, 3H). MS 531.2 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:14][O:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]2[NH:1][C:16](=[O:18])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: C1CCOC1
Product: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reaction time: 3 h

Procedure:
10.0 g (50.7 mmol) 2-Amino-4,5-dimethoxy-benzoic acid were dissolved in 150 ml tetrahydrofuran. 6.52 g (22.0 mmol) triphosgene were added and the solution was boiled for 3 h. After equilibration to room temperature the reaction mixture was poured on a water/ice mixture. The residue was filtrated and rinsed with methanol.
Reaction SMILES: Cl[C:2]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[N:3]=1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[CH:10]1([C:9]2[C:2]([O:29][C:27]3[CH:26]=[CH:25][C:24]4[B:20]([OH:30])[O:21][CH2:22][C:23]=4[CH:28]=3)=[N:3][C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[C:5]([CH:8]=2)[C:6]#[N:7])[CH2:12][CH2:11]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(C2CC2)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinonitrile (360 mg, 1.29 mmol), compound benzo[c][1,2]oxaborole-1,5(3H)-diol (232 mg, 1.55 mmol) and Cs2CO3 (505 mg, 1.55 mmol) in DMSO (20 mL) was stirred at 40° C. overnight. The mixture was diluted by water, extracted by EtOAc, the separated organic layer was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether:EtOAc=10:1˜3:1) to afford 5-cyclopropyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(4-oxopentyloxy)nicotinonitrile. (200 mg, 40%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.20 (s, 1H), 7.86 (s, 1H), 7.75 (d, J=8.0, 1H), 7.24 (d, J=2.0, 1H), 7.16 (dd, J=8.0, 2.0, 1H), 4.97 (s, 2H), 3.94 (t, J=7.8, 2H), 3.29 (t, J=7.8, 2H), 2.02 (m, 4H), 1.65 (t, J=7.8, 2H), 0.92 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13][OH:14])=[N+:11]([O-:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:16].[SH:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1>C(Cl)(Cl)Cl>[CH3:23][N:19]1[CH:20]=[CH:21][N:22]=[C:18]1[S:17][CH2:2][C:3]1[C:12]([CH2:13][OH:14])=[N+:11]([O-:15])[C:10]2[C:5]([N+:4]=1[O-:16])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Cn1ccnc1S
Reactant: [O-][n+]1c(CO)c(CBr)[n+]([O-])c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1ccnc1SCc1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromomethyl-3-hydroxymethylquinoxaline-1,4-dioxide (0.01 mole) was suspended in 75 ml of chloroform and 2-mercapto-1-methylimidazole (0.01 mole) was added in one portion. The suspension was stirred at room temperature for about 2 hours. The product was collected by filtration. Yield, 3.82 grams (96%); m.p. 174-7° ).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1=NCCc2ccc(Br)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2ccc(Br)cc21

Procedure:
In close analogy to the procedure described above, 7-bromo-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N(C)CCO)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 152 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.91 min, m/z=447.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=O)=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([NH:40][CH2:41][C:42]([NH2:44])=[O:43])[CH2:38][CH3:39]>>[NH2:44][C:42](=[O:43])[CH2:41][N:40]([CH2:37][CH2:38][CH3:39])[C:33]([C:11]1=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1)=[O:35]
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CCCNCC(N)=O
Agent: Cl
Product: CCCN(CC(N)=O)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Step H) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 2-(propylamino)acetamide hydrochloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15]#[N:16])(=O)=O)=CC=1.[CH3:25][NH:26][CH3:27].C(N(CC)CC)C>C(O)C>[C:15]([CH2:14][C@H:13]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:12][N:26]([CH3:27])[CH3:25])#[N:16]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC#N)NC(=O)OC(C)(C)C)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C[C@H](CC#N)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution in ethanol (20 mL) of the compound (1.32 g) obtained in step (1) above, dimethylamine (about 50%, aqueous solution, 3.92 mL) and triethylamine (519 μL) were added and the mixture was stirred at 80° C. for an hour. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1-95:5) to give tert-butyl [(2S)-1-cyano-3-(dimethylamino)propan-2-yl]carbamate as a pale yellow oil (340 mg).
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>ClCCl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:33]=[N:32][CH:31]=[N:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3cncnc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3cncnc3)cc21
Reaction time: 3 h
Yield: 75.7 %

Procedure:
The (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyrimidin-5-yl)indolin-1-yl)propan-2-ylcarbamate (64 mg, 144 μmol) was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL, 13 mmol) was added. The resulting solution was stirred for three hours then concentrated. The residue was taken up in ethyl acetate and filtered and washed with hexanes to give the desired product (S)-2-amino-3-phenyl-1-(6-pyrimidin-5-yl-2,3-dihydro-indol-1-yl)-propan-1-one trifluoroacetate (50 mg, 76% yield) as the mono-trifluoroacetic acid salt. MS ESI (pos.) m/e: 345.1 (M+H).
Reaction SMILES: [NH3:1].Cl[C:3]1[NH:4][SH:5](=[O:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.O>C(O)C>[NH2:1][C:3]1[NH:4][SH:5](=[O:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(Cl)N1
Reactant: N
Solvent: CCO
Solvent: O
Product: NC1=NC(c2ccccc2)=C[SH](=O)(c2ccccc2)N1
Temperature: 100 °C
Yield: 93 %

Procedure:
To 75 ml of saturated a solution of ammonia in ethanol was added 3 g (0.01 mole) of 3-chloro-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide and the mixture was heated in an autoclave at 100° C. for 3 hours. The mixture was cooled, poured into water and the product was filtered off, washed with water and dried to obtain 2.6 g (93%) of 3-amino-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 169°-170° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:38]2[CH:39]=[CH:40][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
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: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(C(C)(C)C)cc2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester (1.0 g, 2.0 mmol), 4-tert-butylphenyl boronic acid (0.71 mg, 4.0 mmol), cesium carbonate (1.43 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0)(347 mg, 0.3 mmol) were suspended in 10 mL of 1,4-dioxane. The reaction was heated at reflux temperature overnight, cooled to room temperature and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to an oil residue, which was then purified by column chromatography, eluting the title compound from silica gel with a gradient of (0-70%) ethyl acetate in hexanes to yield 1.11 g of a yellow oil. MS: (+) m/z 577.2 (M+Na+).