Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([Cl:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])[CH:9]=[CH2:10].[OH:29][N:30]=[C:31](Cl)[CH3:32]>ClCCl>[Cl:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:8][CH:9]3[O:29][N:30]=[C:31]([CH3:32])[CH2:10]3)[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(Cl)=NO
Reactant: C=CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(C)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Triethylamine (1.04 mL, 7.46 mmol) was added to a 0° C. solution of 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The reaction solution was allowed to warm slowly to room temperature and stir overnight under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.34 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br-].[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C1C=CC=CC=1>[Br-:19].[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][P+:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Br-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 2 h
Yield: 44 %

Procedure:
Bromination of 2-chloro-3-nitrotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 2 h and the displacement reaction was performed at 70° C. for 1 d, gave the phosphonium salt (554) (44%) as a light brown solid, mp (CH2Cl2/benzene) 224–228° C. 1H NMR (CDCl3) δ 8.09 (br d, J=8.3 Hz, 1H), 7.86–7.63 (m, 16H), 7.34 (t, J=8.1 Hz, 1H), 5.95 (d, J=14.6 Hz, 2H). Found: C, 58.68; H, 4.12; N, 2.79. C25H20BrclNO2P requires C, 58.56; H, 3.93; N, 2.73.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)=O.O.[OH-].[Li+].O1CCCC1.O>CO>[C:3](=[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:27][CH2:28]1)=[O:2]
Reactant: COC(=O)c1ccc(Cn2ccc3c(CC4SC(=O)NC4=O)cccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C=C1C=CC(Cn2ccc3c(CC4SC(=O)NC4=O)cccc32)=CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a mixture of 2.00 g of 5-[1-(4-methoxycarbonylbenzyl)indol-4-yl]methyl-2,4-thiazolidinedione prepared in Example 9 and 0.43 g of lithium hydroxide monohydrate, there were, in order, added 40 ml of tetrahydrofuran, 40 ml of water and 20 ml of methanol and the resulting mixture was stirred at 60° C. for 2 hours. After concentrating the reaction solution to about 40 ml, the concentrate was neutralized with a 10% citric acid aqueous solution, followed by extraction with dichloromethane (100 ml×3). The extract was washed with a saturated common salt solution, dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to give 1.54 g of 5-[1-(4-carbonylbenzyl)indol-4-yl]methyl-2,4-thiazolidinedione as pale yellow crystals. The yield thereof was found to be 80%.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]3[CH:22]=[N:21][N:20]([CH3:23])[C:18]3=2)[N:13]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:12]=1)[CH3:10]>C1COCC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:8][C:22]1[C:17]2[C:18](=[C:19]3[C:11]([CH2:9][CH3:10])=[CH:12][N:13]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:26])=[O:25])[C:14]3=[N:15][CH:16]=2)[N:20]([CH3:23])[N:21]=1
Reactant: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc3cnn(C)c3c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc3c(Br)nn(C)c3c12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
NBS (0.708 g, 3.98 mmol) was added to a solution of 8-ethyl-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.41 g, 3.98 mmol, Preparation #2, Step F) in THF (60 mL). The mixture was allowed to stir at rt. After 16 h additional NBS (0.106 g, 0.597 mmol) was added and reaction was stirred for about 3 h, then another portion of NBS (0.142 g, 0.796 mmol) was added. After another 1 h three equal portions of NBS (0.213 g, 1.19 mmol) were added over about 6 h. The mixture was then diluted with saturated aqueous Na2S2O3 (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was suspended in Et2O (10 mL) and sonicated for about 3 min. The precipitate was collected by filtration, washed with Et2O (10 mL) and dried in a vacuum oven at about 60° C. for about 3 h to give 3-bromo-8-ethyl-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.3 g, 75%): LC/MS (Table 2, Method c) Rt=1.58 min.; MS m/z: 433 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7](N(OC)C)=O.[CH2:14]([Mg]Cl)[CH3:15].[OH2:18]>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([CH2:7][C:14](=[O:18])[CH3:15])[CH:5]=[N:4][CH:3]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: O
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
44 g (180 mmol) of 5-bromo-N-methoxy-N-methylnicotinamide are dissolved in 200 mL of THF and 60 mL (180 mmol) of ethylmagnesium chloride solution (3M in ethyl ether) are added dropwise. The reaction medium is stirred at room temperature for one hour, poured into water and extracted with ethyl acetate. The organic phase is separated out after settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). 4 g (11%) of 1-(5-bromo-3-pyridyl)propanone are collected.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[C:20]([C:28](O)=[O:29])=[CH:21][N:22]2[CH:27]=[CH:26][CH:25]=[N:24][C:23]=12>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:20]3[N:19]=[C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:22]4[CH:21]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2cccnc2n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2cccnc2n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and imidazo[1,2-a]pyrimidine-2-carboxylic acid (163 mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 168 mg (54%). 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 4.32-4.45 (m, 2H), 4.49-4.56 (m, 1H), 6.92 (d, 1H), 7.13-7.16 (m, 1H), 7.84 (d, 1H), 7.95 (d, 1H), 8.03-8.06 (m, 2H), 8.25 (s, 1H), 8.67-8.69 (m, 1H), 8.75 (d, 1H), 8.97-8.99 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][O-:18].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH3:17])[N:3]=1
Reactant: C[O-]
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and sodium methylate in methanol. EI-MS m/e (%): 216 (M+, 100), 215 ([M—H]+, 36).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.C(O)(=O)C.O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[N:1][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:12])=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C=O)c1
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(C=Nc2cccc3nc(C)ccc23)c1
Yield: 102.7 %

Procedure:
To 1.17 g (7.4 mmol) 5-amino-2-methylquinolin and 1 g (7.4 mmol) 3-methoxybenzaldehyde in 39 ml toluene are added 1 ml acetic acid. The mixture is heated over 3 hours under reflux while water is trapped in a Dean Stark apparatus. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene. 2.1 g of [(3-methoxyphenyl)methylene]-2-methylquinolin-5-amine are obtained as product. 0.31 ml (3.6 mmol) 1,1,1-trifluoroepoxypropane in 17 ml THF and are cooled to −104° C. and 1.59 ml of a 2.5 M n-butyl lithium solution in hexane are added over 3 hours while the temperature does not exceed −99° C. 10 Minutes after complete addition 1.5 g (5.4 mmol) [(3-methoxyphenyl)methylene]-2-methylquinolin-5-amine in 5 ml THF are added over 0.5 hours while the temperature temperature does not exceed −99° C. After 0.5 hours at −100° C. 4 ml diethyl ether are added and the reaction mixture is warmed to 20° C. over one hour. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 30 to 40%) yields 800 mg of the desired epoxide.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH3:11][CH:12]1OC(C)OC(C)O1>C(O)C(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CC1OC(C)OC(C)O1
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)CO
Solvent: O
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 12 °C
Yield: 183.1 %

Procedure:
A mixture of 1002.6 g of metformin hydrochloride, 359.1 g of paraldehyde and 51.6 g of toluene-4-sulfonic acid monohydrate in 2405.9 g of isobutanol was heated under reflux for 6 hours. Some of the solvent was removed by distillation. The mixture was cooled to 12° C., and the white precipitate was separated off, giving 953.8 g (81.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:26]1[C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=[C:27]1[C:40](Cl)=[O:41]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:40]([C:27]1[S:26][C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloroaniline (0.145 g, 0.508 mmol) and triethylamine (0.113 mL, 0.812 mmol) in tetrahydrofuran (1 mL, 10 mmol) was added a solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.107 g, 0.406 mmol) in tetrahydrofuran (4 mL). The reaction was stirred overnight and concentrated in vacuo. Aqueous work up gave a yellow solid which was purified on silica by MPLC to give 150 mg of N-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4C[CH2:22][CH2:21][C:20](=O)[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.C[Mg]Br.C([O:42][CH2:43][CH3:44])(=O)C>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:43]4([CH3:44])[OH:42])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)ncc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added methylmagnesium bromide (3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and aqueous saturated NH4Cl solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The products were purified by silica chromatography with DCM and methanol, two products were eluded with 95% DCM and 5% methanol no separation. The two diastereomers were taken on as a mixture without further purification.
Reaction SMILES: [Cl:1][C:2]([CH:5](Cl)[CH3:6])=[CH:3][CH3:4].[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][C:14](=[S:16])[S-:15])=[C:11]([CH3:19])[CH:10]=1.C([NH+](CC)CC)C>>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][C:14](=[S:15])[S:16][CH:5]([CH3:6])[C:2]([Cl:1])=[CH:3][CH3:4])=[C:11]([CH3:19])[CH:10]=1
Reactant: Cc1cc(Cl)ccc1NC(=S)[S-]
Reactant: CC=C(Cl)C(C)Cl
Agent: CC[NH+](CC)CC
Product: CC=C(Cl)C(C)SC(=S)Nc1ccc(Cl)cc1C

Procedure:
The reactant, 2-chloro-1-methyl-2-butenyl 4-chloro2-methyldithio-carbanilate is prepared by following the procedure of Example 2 wherein 3,4-dichloro-2-pentene and triethylammonium 4-chloro-2-methyldithiocarbanilate are reacted.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:25])([CH2:15][C:16]#[C:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:13][OH:14].O>C(Cl)Cl>[CH3:11][C:12]([CH3:25])([CH2:15][C:16]#[C:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH:13]=[O:14]
Reactant: CC(C)(CO)CC#CCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)CC#CCN1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a solution of oxalyl chloride (152 μl; 1.74 mmol) in DCM (4 mL) at −78° C. was added a solution of DMSO (237 μl; 3.34 mmol) in DCM (2 mL). The mixture was stirred for 5 min before the addition of a solution of 2,2-dimethyl-6-morpholin-4-ylhex-4-yn-1-ol (307 mg; 1.45 mmol) in DCM (2 mL). The mixture was stirred again at −78° C. for 15 min and TEA (1.05 mL) was added. It was then brought back to rt and stirred for 2 h. Water was added. Organic phase was washed with a saturated solution of NaHCO3 and brine. It was dried over magnesium sulfate, filtrated and concentrated to give the title compound as a colorless oil (303 mg, quantitative). 1H NMR (CDCl3) δ: 9.51 (s, 1H), 3.73 (m, 4H), 3.27 (m, 2H), 2.56 (m, 4H), 2.36 (m, 2H), 1.14 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].[Cl-].C([NH2+]CCCC)CCC.[N+:21]([CH2:24][CH2:25]O)([O-:23])=[O:22].C([BH3-])#N>C(OC(=O)C)CC(C)C.CO.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][CH2:25][CH:24]([N+:21]([O-:23])=[O:22])[CH2:5]2
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=[N+]([O-])CCO
Agent: CCCC[NH2+]CCCC
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CC(=O)OCCC(C)C
Product: O=[N+]([O-])C1COc2c(Br)cccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Commercially available 3-bromosalicylaldehyde (0.5 g; 2.5 mmol), di-n-butylammonium chloride (0.2 g; 1.2 mmol) and 2-nitroethanol (0.36 g; 4.0 mmol) were refluxed for 8 hours in i-pentylacetate with a Dean-Stark apparatus under nitrogen atmosphere. The solvent was evaporated and the product was dissolved in dichloromethane (15 ml) and cyanoborohydride (0.5 g; 8.1 mmol) in methanol (15 ml) was added. The mixture was stirred for 30 minutes at room temperature. Water was added and the mixture extracted with dichloromethane. The phase were separated and the organic layer was dried (MgSO4). The solvent was evaporated yielding 400 mg (63%) of 8-bromo-3-nitrochroman as an oil.
Reaction SMILES: [C:1](OC(OCCCC)=O)(OCCCC)=[O:2].[CH:16]([NH:19][CH2:20][CH2:21][OH:22])([CH3:18])[CH3:17].C(O)(=O)[CH2:24][C:25]([CH2:30]C(O)=O)([C:27](O)=O)[OH:26]>O1CCCC1>[C:25]([O:26][C:1]([N:19]([CH2:20][CH2:21][OH:22])[CH:16]([CH3:18])[CH3:17])=[O:2])([CH3:24])([CH3:27])[CH3:30]
Reactant: CC(C)NCCO
Reactant: CCCCOC(=O)OC(=O)OCCCC
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of dibutyl dicarbonate (25.0 g, 116 mmol) in tetrahydrofuran (40 ml) was added to a solution of 2-(isopropylamino)ethanol (10.0 g, 96.9 mmol) in tetrahydrofuran (60 ml) under ice-cooling. The mixture was stirred at room temperature for 3.5 hours, then a 10% aqueous citric acid solution (500 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (500 ml). The organic layer was washed with saturated brine (500 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=1/1) to give 24.0 g (quantitatively) of the target compound.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH3:5])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(C(C)(C)CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
To a solution of 2-methyl-2-p-tolyl-propan-1-ol (405 mg, 2.46 mmol) in DMF (5 mL) was added imidazole (335 mg, 4.92 mmol) followed by tert-butyldimethylsilyl chloride (465 mg, 3.08 mmol). The reaction was stirred for 24 h and water was added. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with water (4×). The organic solution was dried (MgSO4), filtered and concentrated. Medium pressure chromatography (hexanes) provided tert-butyl-dimethyl-(2-methyl-2-p-tolyl-propoxy)-silane (619 mg). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2H), 7.10 (d, 2H), 3.49 (s, 2H), 2.31 (s, 3H), 1.27 (s, 6H), 0.85 (s, 9H), −0.06 (s, 6H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:15][C:14]=1[N:35]=S(C)C.CSC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:12][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:15][C:14]=1[N:35]=[O:9]
Reactant: CC(C)n1nc(-c2nc(Br)c(N=S(C)C)nc2-c2ccccc2)ccc1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Product: CC(C)n1nc(-c2nc(Br)c(N=O)nc2-c2ccccc2)ccc1=O
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of m-chloroperbenzoic acid (70-75% purity) (1.66 g) in CH2Cl2 (40 ml) was added a solution of 6-{6-bromo-5-[(dimethyl-lambda˜4˜-sulfanylidene)amino]-3-phenyl-2-pyrazinyl}-2-isopropyl-3 (2H)-pyridazinone (2.01 g) in CH2Cl2 (20 ml) at −10˜-5° C. and the mixture was stirred at the same temperature for one hour. After addition of dimethyl sulfide (0.25 ml), the solution was stirred at the same temperature for 30 minutes. Sat. aq. Na2CO3 (50 ml) was then added to the mixture. An organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 6-(6-bromo-5-nitroso-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (0.896 g).
Reaction SMILES: C(OC([NH:8][CH:9]([CH:17]([OH:44])[CH:18]([NH:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.CO.C(N)(C)C.C(Cl)(Cl)Cl>>[NH2:8][CH:9]([CH:17]([OH:44])[CH:18]([NH:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 100 %

Procedure:
Using the procedure of Example 56 with the resultant compound of Example 55 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 100% yield, m.p. 158°-160° C. Mass spectrum (M+H)+ =504.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)C1C=CC=CC=1>O1CCCC1.C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (0.40 g) was dissolved in a mixed solvent of tetrahydrofuran (5 mL)-ethanol (5 mL), 10% palladium-carbon (50% containing water, 0.80 g) was added, and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether, and the obtained solid was washed with a mixed solvent of diethyl ether-hexane to give the title compound (0.31 g, yield 96%) as a pale-yellow solid. The pale-yellow solid was recrystallized from ethanol-hexane to give pale-yellow crystals. melting point 197-198° C.