Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC1[N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[N:16]=1.Cl>>[C:33]1([C:26]2([N:23]3[CH2:24][CH2:25][CH:20]([N:19]4[C:18]5[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=5[N:16]=[C:6]4[N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[CH2:21][CH2:22]3)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCC=CCC2)CC1
Agent: Cl
Product: C1=CC(c2ccccc2)(N2CCC(n3c(N4CCNCC4)nc4ccccc43)CC2)CCCC1
Yield: 40.3 %

Procedure:
This was prepared according to the procedure described in Example 67 using 1-N-t-butoxycarbonylpiperazine instead of 4-t-butoxycarbonylaminopiperidine, and 2-chloro-1-[1-(1-phenyl-4-cyclohepten-1-yl)-4-piperidinyl]benzimidazole as starting material which was prepared in Preparation 9. Overall yield was 40.3%. HCl salt was amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C:21]#[N:22])[C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:4][CH:3]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH2:20][C:21]2[NH:30][N:29]=[N:28][N:22]=2)=[CH:4][CH:3]=1
Reactant: N#CCN(c1ccc(Cl)cc1)c1nc(=O)c2cccnc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(N(Cc2nnn[nH]2)c2ccc(Cl)cc2)sc2ncccc12
Yield: 35.1 %

Procedure:
A mixture of 74 mg (0.23 mmol) of 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl]amino]acetonitrile and 1 ml of DMF was put in a 20 ml flask. To the mixture were then added 146 mg of sodium azide and 120 mg of ammonium chloride with stirring. The mixture was then stirred at a temperature of 120° C. for 4 hours. The resulting reaction mixture was allowed to cool, poured into water, and then extracted with ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then washed with cold ethanol to obtain 30 mg of 2-[N-(4-chlorophenyl)-N-(1H-tetrazol-5-ylmethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH2:1]([N:5]([CH3:42])[C:6](=[O:41])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C:35]3=[O:39])[C@H:31]3[C@H:22]2[C:23]2[CH:24]=[CH:25][C:26]([OH:40])=[CH:27][C:28]=2[CH2:29][CH2:30]3)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([N:5]([CH3:42])[C:6](=[O:41])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[OH:39])[C@H:31]3[C@H:22]2[C:23]2[CH:24]=[CH:25][C:26]([OH:40])=[CH:27][C:28]=2[CH2:29][CH2:30]3)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)CSCCCCCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Solvent: CO
Product: CCCCN(C)C(=O)CSCCCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1

Procedure:
One reduces the N-butyl-(5-(4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-11beta-yl)-phenoxy)-pentylthio)-N-methyl acetamide obtained in Example 76 using sodium borohydride in methanol. In this way one obtains the expected product.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:14]([O-])([OH:16])=[O:15].[N+](C1C=CC=CC=1)([O-])=O>C(Cl)(Cl)Cl>[N+:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:13])([O-:16])=[O:15]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 100g portion of soluble anhydrite was added to a solution of 32.9g toluene in 100 ml chloroform. Then a 22.6g portion of anhydrous nitric acid was added to the dispersion over a 30-minute period. Stirring at 25°C was continued for an additional 2 1/2 hour period. Nitrobenzene was added before the last half hour period and was used as the internal standard. Gas chromatographic analysis showed a 93.2% yield of nitrotoluene with the proportion being 49.1% ortho, 2.1% meta, and 48.8% para.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8](O)[CH2:7]1)=[O:5])[CH3:2].S(Cl)([Cl:25])=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([Cl:25])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(O)C1
Product: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(Cl)C1

Procedure:
1 gm (3.3 millimols) of 5-hydroxy-1,2,4,5-tetrahydro-11methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was stirred for 2 hours with 20 ml of thionyl chloride at room temperature. The excess thionyl chloride was then distilled off in vacuo, the residue was dissolved in chloroform, the solution was dried with sodium sulfate, and the solvent was distilled off. After purification of the residue on a silicagel column with benzene/ethyl acetate (8:2) as the eluant, the yield was 0.55 gm (52% of theory), m.p. 131° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][N:16]1[C:20]([CH:21]([NH2:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][CH:18]=[N:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:20]([CH:21]([NH:27][S:34]([C:32]2[S:33][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:36])=[O:35])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][CH:18]=[N:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(CC)C(N)c1ccnn1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1OCc1ccccc1
Yield: 62.5 %

Procedure:
In a flask containing a mixture of triethylamine (0.045 mL, 0.325 mmol) and {1-[1-(benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}amine (0.081 g, 0.296 mmol) in CH2Cl2 (1 mL) at ambient temperature was added 5-chlorothiophene-2-sulfonyl chloride (0.064 g, 0.296 mmol). After 16 h the mixture was diluted with CH2Cl2 (10 mL) and poured into saturated aqueous NaHCO3 (10 mL). The organic phase was separated and washed sequentially with 1N HCl solution, distilled water, brine and then dried over MgSO4, filtered, and concentrated to an oil. Purification by flash chromatography (hexane/EtOAc, 4:1) afforded the product as a solid (0.084 g, 62%). Mass Spectrum (+ESI): 454 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][C@@H:2]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:34])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](Cc1ccc(C(F)(F)F)cc1)[C@H](O)c1ccncc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (70 mg, 0.24 mmol) in acetonitrile (5 ml) were added 4-fluoronaphthalenecarboxylic acid (45 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxy-1H-benzotriazole (36 mg, 0.24 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (55 mg, 50%).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[CH2:1]([N:5]([C:29]([C:24]1[NH:25][C:26]([CH2:27][CH3:28])=[C:22]([Cl:21])[N:23]=1)=[O:30])[CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCNC1CN(c2nc(C)c(C(=O)OCC)s2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C)c(C(=O)OCC)s2)C1
Yield: 79.4 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 2-[3-(n-butylamino)azetidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (230c) (98 mg, 0.33 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (58 mg, 0.33 mmol), WSC hydrochloride (190 mg, 0.99 mmol), 1-hydroxybenzotriazole (46 mg, 0.33 mmol) and N-methylmorpholine (0.07 mL, 0.66 mmol), to obtain 119 mg of the title compound as a white solid (79%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:24][CH3:25])=[N:12][N:13]2COCC[Si](C)(C)C)=[CH:9][CH:8]=1)=O.Cl.[CH2:28]([O:35][C:36]1[CH:37]=[C:38]([NH:42]N)[CH:39]=[CH:40][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([O:35][C:36]1[CH:37]=[C:38]([N:42]2[C:5]([C:7]3[CH:15]=[C:14]4[C:10]([C:11]([CH2:24][CH3:25])=[N:12][NH:13]4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:39]=[CH:40][CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCc1nn(COCC[Si](C)(C)C)c2cc(C(=O)/C=C/N(C)C)ccc12
Reactant: NNc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: CCc1n[nH]c2cc(-c3ccnn3-c3cccc(OCc4ccccc4)c3)ccc12
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
(2E)-3-(dimethylamino)-1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)prop-2-en-1-one (256 mg, 0.685 mmol) and 3-benzyloxyphenylhydrazine hydrochloride (270 mg, 1.1 mmol) were dissolved in ethanol (4 mL) in a 10 mL sealed tube. The mixture was subjected to microwave radiation (300 watts, 160° C.) for 5 minutes. The solvent was removed and the residue was extracted with ethyl acetate, then washed with water and brine. Removal of volatiles provided a tan solid, which was purified by column chromatography on silica gel, eluting with a 10-50% hexane/ethyl acetate gradient over 10 minutes (flow rate 20 mL/min), to give 160 mg (59%) of 6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole. 1 H NMR (CDCl3) δ 1.4 (t, 3H), 3.0 (q, 2H), 5.0 (s, 2H), 6.6 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.1 (m, 2H), 7.2 (t, 1H), 7.3, (m, 5H), 7.6 (d, 1H), 7.8 (m, 1H), 9.7 (br s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([OH:13])[C@H:10]([OH:12])[CH3:11].N1C=CN=C1>ClCCl>[O:13]([CH2:9][C@H:10]([OH:12])[CH3:11])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: C[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
A solution of tert-butyldimethylchlorosilane (9.9 g, 65.7 mmol) in dichloromethane was added dropwise to a solution of (R)-(−)-1,2-propanediol (5 g, 65.7 mmol) and imidazole (4.47 g, 65.7 mmol) in anhydrous dichloromethane at 0° C. The reaction mixture was stirred at 0° C. for 30 min before dilution with dichloromethane. The solution was washed with water three times followed by the addition of brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure to afford 12.0 g (96%) of (2R)-1-(tert-Butyldimethylsiloxy)propan-2-ol.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 114 %

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1.0 g, 5.85 mmol) in 15 mL of DMSO was added 1-methylhexahydro-1H-1,4-diazepine (0.8 mL, 6.42 mmol) and potassium carbonate (2.4 g, 17.4 mmol). The reaction mixture was heated at 80° C. for 16 h at which time the reaction was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to give 1-methyl-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (1.77 g, 6.67 mmol) as a yellow solid containing residual DMSO. ESIMS (M+H)+=266
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([C:10](Cl)=[O:11])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:13]([C:16]1[C:21]([NH:22]C(C2SC=C(C3CC3)N=2)=O)=[C:20]([Cl:33])[C:19]([O:34][CH3:35])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:13]([C:16]1[C:21]([NH:22][C:10]([C:7]2[S:8][CH:9]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[N:6]=2)=[O:11])=[C:20]([Cl:33])[C:19]([O:34][CH3:35])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]
Reactant: O=C(Cl)c1nc(C2CCC2)cs1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CC3)cs2)c1Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CCC3)cs2)c1Cl
Yield: 70 %

Procedure:
N-(6-Acetyl-2-chloro-3-methoxyphenyl)-4-cyclobutylthiazole-2-carboxamide 268b was synthesized from compound 267b (5.48 g, 1.2 eq.) as a white solid in 70% yield, following the procedure as described for compound 268a. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.96-2.12 (m, 2H), 2.34-2.44 (m, 4H), 2.59 (s, 3H), 3.70-3.78 (m, 1H), 3.99 (s, 3H), 6.88 (d, J=8.82 Hz, 1H), 7.20 (s, 1H), 7.68 (d, J=8.76 Hz, 1H), 10.33 (br s, 1H); MS (ESI, EI−): m/z=365 (MH+).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7]Cl)[CH3:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][N:17]1[C:18]2[C:14](=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)[C:15](=[O:22])[C:16]1=[O:21])[CH3:3]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCN(CC)CCCCl
Agent: Cl
Product: CCN(CC)CCCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
This compound was prepared by the same method as that described in reference example 8, using 3-diethylaminopropyl chloride hydrochloride in place of 2-diethylaminoethyl chloride hydrochloride, and using 5-chloroisatin in place of the compound of reference example 1.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][O:18][C:16]([C:15]1[CH:14]=[C:13]([CH:22]=[CH:21][CH:20]=1)[CH2:12][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:17]
Reactant: O=C(O)c1cccc(S)c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2cccc(C(=O)O)c2)c1
Reaction time: 16 h
Yield: 99.2 %

Procedure:
A mixture of 3-mercaptobenzoic acid (154 mg, 1.00 mmol), methyl 3-(bromomethyl)benzoate (229 mg, 1.00 mmol) and K2CO3 (414 mg, 3.00 mmol) in DMF (1 mL) was stirred for 16 h, then solvent removed. The resulting residue was purified by silica gel chromatography to give 300 mg (90%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:15]([O:17]CC)=[O:16])[OH:14].O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:15]([OH:17])=[O:16])[OH:14]
Reactant: CCOC(=O)C1(O)CCSc2c(OC)cc(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)cc2c1SCCC2(O)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice/water-cooled solution of 6-chloro-4-hydroxy-8-methoxythiochromane-4-yl-carboxylic acid, ethyl ester (2.26 g, 7.46 mmol; see step (iv) above) in THF (20 mL) was added a solution of lithium hydroxide monohydrate (0.68 g, 16 mmol) in water (10 mL). The temperature was allowed to slowly rise to ambient overnight. THF was removed in vacuo, the residue was washed with diethyl ether, acidified with 2 M aq. HCl and then extracted with ethyl acetate. Drying (MgSO4) and removal of the solvent in vacuo afforded the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](/[N:9]=[CH:10]/[N:11](C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.N[OH:16]>CO>[Br:1][C:2]1[C:3](/[N:9]=[CH:10]/[NH:11][OH:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)/C=N/c1ncc(Cl)cc1Br
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON/C=N/c1ncc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A mixture of 108a (2 g, 10 mmol) and hydroxylamine hydrochloride (1.4 g, 20 mmol) in MeOH (10 mL) was stirred at 100° C. for 0.5 h. The mixture was extracted with Ethyl acetate (20 mL×4) and the combined organic phase was washed with water. It was then concentrated under reduced pressure to afford 108b (2 g, 80%), which was used for next step without further purification. LCMS: [M+H]+ 250.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[N:6]([C:14]([CH3:19])([CH3:18])[C:15]([O-:17])=O)=[N:7][C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=O.C[O-].[Na+].O>CO>[N:7]([C:8]([CH3:12])([CH3:13])[C:9]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])=[N:6][C:14]([CH3:19])([CH3:18])[C:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17]
Reactant: CCCCN
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCCC
Temperature: 10 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
34.9 Grams of n-butylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol is dropwise added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 58.0 g (yield 85.5%) of 2,2'-azobis [N-butyl-2-methyl propionamide] as pale yellow crystal. The solubility is shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]1=[O:25].Cl>C(O)C.O.[Fe]>[NH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)c1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(N)cc(Cl)c2Cl)c1=O
Temperature: 65 °C
Yield: 23.2 %

Procedure:
In flask were placed 7.47 grams (0.019 mole) of 3-(2,3-dichloro-5-nitrophenylmethyl)- 1 -methyl-6-trifluoromethyluracil and 5.68 grams (0.94 mole) of powdered iron in 115 mL of ethanol and 9 mL of water. Dropwise, 9.0 mL of concentrated hydrochloric acid was added to the reaction mixture. Upon completion of addition, the reaction mixture was heated to 65° C. and maintained at this temperature for three hours. After being cooled to ambient conditions, the reaction mixture was filtered through Celite filter aid, and the collected precipitate was washed several times with ethanol. The solid removed by filtration was then dissolved in ethyl acetate, and this solution was washed twice with a saturated aqueous solution of sodium chloride. The dark brown solution was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 1.62 grams of 3-(5-amino-2,3-dichlorophenylmethyl)-1-methyl-6-trifluoromethyluracil as a solid. This reaction was repeated.
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: NC(=O)C1C2C=CC(C2)C1Nc1nc(Cl)ncc1Cl
Product: NC(=O)C1C2C=CC(C2)C1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
The title compound was prepared from 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179. Product was isolated as a tan solid. LCMS (m/e) 510 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.71 (d, 1H, J=6.8 Hz), 7.53 (d, 1H, 8.86 Hz), 7.41 (s, 1H), 7.26 (s, 1H), 7.00 (d, 1H, J=8.3 Hz), 6.31 (m, 1H), 6.28 (m, 1H), 4.13 (t, 1H, J=8 Hz), 3.54 (s, 4H), 2.88 (s, 1H), 2.46-2.78 (m, 11H), 2.11 (d, 1H, J=9 Hz), 1.95 (m, 2H), 1.41 (d, 1H, J=9 Hz), 1.31 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]1[NH:14][C:13](=O)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][CH2:6][C@H:7]1[NH:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][O:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC[C@@H]1COCc2ccccc2C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC[C@@H]1COCc2ccccc2CN1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of compound 14e (171 mg, 0.65 mmol) in THF (6 mL) at 0° C. was added LiAlH4 (247 mg, 6.5 mmol). The reaction mixture was heated under reflux for 16 h, cooled to rt, quenched with H2O and filtered. The mixture was extracted with CHCl3 (10 mL), washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was washed with hexanes to give compound 14f (129 mg), which was used in the next step without further purification.