Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[F:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:26][CH2:25][O:24][C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[F:21])=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccccc1F
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccccc2F)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-fiuorophenoxy)ethanol (1.17 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The dichloromethane extract was evaporated and the residue was purified by HPLC (dichloromethane-hexane; 4:1) and the resulting solids were crystallized from dichloromethane-diethyl ether to give 0.8 g of 4-[[2-(2-fiuorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 112°-113° C.
Reaction SMILES: CNC1N=C(C(O)=O)[CH:6]=[C:5]([CH2:12]CC)[N:4]=1.[CH2:15]([C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=1)[CH:16]([CH3:18])[CH3:17].C(N)(C)C>>[CH2:15]([C:19]1[N:24]=[C:23]([NH:4][CH:5]([CH3:12])[CH3:6])[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Reactant: CCCc1cc(C(=O)O)nc(NC)n1
Solvent: CC(C)N
Product: CC(C)Cc1cc(C(=O)O)nc(NC(C)C)n1

Procedure:
The title compound is obtained as a beige solid (103 mg) in analogy to 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid and isopropylamine; LC-MS: tR=0.77 min, [M+H]+=238.04.
Reaction SMILES: [CH:1]1([C:4]2[C:13](F)=[C:12]3[C:7]([C:8](=[O:24])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][N:11]3[CH:15]([CH3:18])[CH2:16][OH:17])=[C:6]([F:25])[C:5]=2[F:26])[CH2:3][CH2:2]1.[H-].[Na+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH:1]1([C:4]2[C:5]([F:26])=[C:6]([F:25])[C:7]3[C:8](=[O:24])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][N:11]4[CH:15]([CH3:18])[CH2:16][O:17][C:13]=2[C:12]=34)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C(C)CO)c2c(F)c(C3CC3)c(F)c(F)c2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(C4CC4)c(F)c(F)c3c1=O)OCC2C
Reaction time: 15 h
Yield: 39.2 %

Procedure:
In 1.7 ml of N,N-dimethylformamide was dissolved 170 mg of ethyl 7-cyclopropyl-5,6,8-trifluoro-1-(2-hydroxy-1-methylethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate. To the resulting solution was added 20 mg of 60% sodium hydride. The resulting mixture was stirred at 80°-90° C. for 15 hours. The reaction mixture was added to a mixture of 5 ml of ethyl acetate and 5 ml of water. The resulting mixture was adjusted to pH 1.5 with 2N hydrochloric acid. The resulting crystals were collected by filtration to obtain 63 mg (yield: 39.1%) of ethyl 10-cyclopropyl-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[I:14][C:15]1[CH:24]=[CH:23][C:18]2C(=O)[CH2:20][O:21][C:17]=2[CH:16]=1.Cl>C1COCC1.O.CC(OC)(C)C>[I:14][C:15]1[CH:24]=[CH:23][C:18]2[C:11]([C:12]#[N:13])=[CH:20][O:21][C:17]=2[CH:16]=1
Reactant: O=C1COc2cc(I)ccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: N#Cc1coc2cc(I)ccc12
Reaction time: 0.5 h

Procedure:
Sodium hydride (37.3 g; 0.886 mol; 1.2 eq; 60 wt % dispersion in oil) was suspended in hexanes (120 mL) under N2. The sodium hydride was allowed to settle and the hexanes were syringed out of the flask and dry THF (100 mL) added. The NaH was washed again and the THF decanted. A fresh portion of dry THF (300 mL) was added and diethylcyanomethylphosphonate (0.886; 1.2 eq) was added drop wise over 35 min while keeping the temperature at 20-22° C. A solution of 6-iodo-1-benzofuran-3(2H)-one (192.0 g; 0.74 mol) in THF (1.75 L) then added over 35 min at 15-25° C. After 30 min stirring, 6N HCl (750 mL), MTBE (750 mL), and H2O (500 mL) were added. The layers were separated, sodium sulfate was added to the organic layer. The organics were filtered and concentrated. The resulting red solids were suspended in MTBE (500 mL), washed four times with 1N HCl (400 mL). The solvent was evaporated to afford 214 g of the title product. 1H-NMR (400 MHz, CDCl3): δ 3.75 (bs, 1H), 7.34 (d, 1H), 7.60 (s, 1H), 7.62 (dd, 1H), 7.91 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 32.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(4-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethylphenylisocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (111 mg, 32%). EI-MS m/z 340(M−H)−.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([C:9]2[N:10]([CH2:26][CH3:27])[C:11]3[C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][N:14]=[CH:13][C:12]=3[N:25]=2)=[N:6][O:7][N:8]=1.O=[CH:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]>ClCCCl>[C:34]([O:33][C:32](=[O:38])[NH:31][CH2:30][CH2:29][N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:16]2[C:11]3[N:10]([CH2:26][CH3:27])[C:9]([C:5]4[C:4]([NH2:3])=[N:8][O:7][N:6]=4)=[N:25][C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:18])[CH2:20][CH2:21]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: Cl
Solvent: ClCCCl
Product: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCN(CCNC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of the free base from Example 250, Step 3 (prepared by eluting a sample of the dihydrochloride salt through an SCX cartridge using ammonia (10%) in ethanol) and tert-butyl N-(2-oxoethyl)carbamate (0.065 g, 0.41 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 20 mins. This was then treated according to the method of Example 200 to afford the title compound; MS (ES+) m/e 486 [M+H]+.
Reaction SMILES: S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:5][C@H:6]1[O:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]12([CH2:34][NH:35][C:36](=[O:45])[C:37]3[C:42]([Br:43])=[CH:41][N:40]=[C:39]([OH:44])[CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O.O>[C:24]12([CH2:34][NH:35][C:36](=[O:45])[C:37]3[C:42]([Br:43])=[CH:41][N:40]=[C:39]([O:44][CH2:5][C@@H:6]4[CH2:7][O:8]4)[CH:38]=3)[CH2:31][CH:30]3[CH2:32][CH:26]([CH2:27][CH:28]([CH2:29]3)[CH2:33]1)[CH2:25]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ncc1Br
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OC[C@@H]2CO2)ncc1Br
Temperature: 60 °C
Yield: 25.5 %

Procedure:
A suspension of (S)-glycidyl nosylate (0.29 g), caesium carbonate (1.82 g) and N-(1-adamantylmethyl)-5-bromo-2hydroxyisonicotinamide (0.41 g) (Example 35(ii)) in anhydrous N,N-dimethylformamide (6 ml) was heated at 60° C. under nitrogen for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with water (50 ml) and extracted into ethyl acetate (3×20 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 to 0:1) to afford the sub-titled compound (0.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O.[OH:25][C:26]1[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:39](Cl)=[O:40])[CH:32]=2)[CH:27]=1>C1(C)C=CC=CC=1>[OH:25][C:26]1[C:35]([C:36]([NH:1][C:2]2[CH:3]=[C:4]([S:10]([N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[O:37])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:39]([NH:19][C:23]3[CH:22]=[C:21]([S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:11])=[O:12])[CH:20]=[CH:2][C:7]=3[O:8][CH3:9])=[O:40])[CH:32]=2)[CH:27]=1
Reactant: CN1CCCC1=O
Reactant: CCN(CC)S(=O)(=O)c1ccc(OC)c(N)c1
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Cl)cc2c1
Solvent: Cc1ccccc1
Product: CCN(CC)S(=O)(=O)c1ccc(OC)c(NC(=O)c2ccc3cc(O)c(C(=O)Nc4cc(S(=O)(=O)N(CC)CC)ccc4OC)cc3c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
3-Amino-4-methoxydiethylaminosulfonylbenzene (15.6 g), N-methyl-2-pyrrolidone (86.1 g) and toluene (34.3 g) were dissolved at room temperature and the acid chloride (5.4 g) obtained in Example 6 was gradually added, and then the mixture was amidated at 90° C. for 24 hours. After the reaction solution was cooled to 25° C. and filtered, toluene was distilled off under reduced pressure. Then, the solution was crystallized by using methanol (350.1 g). The resultant product was filtered and then dried to obtain 8.9 g of 2-hydroxy-3,6-bis(2-methoxy-5-diethylaminosulfonylphenyl-aminocarbonyl)naphthalene as a cream powdered crystal (DSC analysis value: 245.0° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:40]=1[C:41](Cl)=[O:42]>ClCCl>[CH2:1]([N:3]([CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)([OH:10])[C:6]([F:8])([F:9])[F:7])[C:41](=[O:42])[C:40]1[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:39]=1[CH3:38])[CH3:2]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol (25 mg, 0.063 mmol) was dissolved in anhydrous dichloromethane (0.15 ml). N,N-diisopropylethylamine (0.011 ml, 0.13 mmol) was then added followed by 2,6-dimethylbenzoyl chloride in DCM (10.6 mg, 0.065 mmol as a 100 μl aliquot of 80.8 mg in 0.76 ml DCM) and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed successively with aqueous sodium bicarbonate and water and then dried through a hydrophobic frit and evaporated and the crude product purified by mass directed autopreparation (System B). Product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts were washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (13.1 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cnn(-c2ccc(C(=O)O)cc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a suspension of 4-(4-methylpyrazol-1-yl)benzoic acid (0.75 g) in dichloromethane (15 ml) was added oxalyl chloride (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo yielded 4-(4-methylpyrazol-1-yl)benzoyl chloride (0.77 g), which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:42]([O:45][CH2:46][CH2:47]Br)(=[O:44])[CH3:43]>>[C:42]([O:45][CH2:46][CH2:47][N:8]([C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])[C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:44])[CH3:43]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I

Procedure:
5-(Acetoxyacetamido)-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide was alkylated with 2-bromoethyl acetate according to the procedure in Example 25a. Yield of crude product =97%.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][CH2:10][CH2:11][S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[OH2:18].[CH3:19][OH:20]>>[CH3:16][N:15]([CH3:17])[S:12]([CH2:11][CH2:10][NH:9][C:8]1[C:3]([C:1]([O:20][CH3:19])=[O:18])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:14])=[O:13]
Reactant: O
Reactant: CO
Reactant: CN(C)S(=O)(=O)CCNc1cccnc1C#N
Product: COC(=O)c1ncccc1NCCS(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 4 h

Procedure:
2-[(2-cyanopyridin-3-yl)amino]-N,N-dimethylethanesulfonamide (1.4 g, 5.5 mmol) was dissolved in 50 mL MeOH and placed in a 100 mL pressure flask. The solution was cooled to −78° C. and HCl gas was bubbled through the solution until the volume of the solution had noticeably increased. The flask was sealed and the reaction warmed to room temperature and stirred for 4 hours. At this time, LCMS (sampled after re-cooling the reaction to −78° C.) showed only a small amount of starting cyano compound remaining. Water (1 mL, 55 mmol) was added and the reaction transferred to a flask equipped with a reflux condenser. The reaction was refluxed for 1.5 hours, stirred at room temperature overnight, then refluxed for 2 more hours, then stirred at room temperature for 48 hours. The solution was evaporated to dryness to give a green/yellow foam that was then partitioned between CHCl3 and saturated NaHCO3. The layers were separated and the aqueous was extracted circa 10 times or until very little UV-active material was removed. The organic layers were dried over Na2SO4, filtered and evaporated to give the product as a clear oil that solidified upon standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][NH:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCCC1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC1CCNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39.
Reaction SMILES: Br[C:2]1C(Br)=C(NC([C@@H]2C[C@H]2C)=O)SN=1.[Br:15][C:16]1[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:18][CH:17]=1.O>O1CCCC1.C(OCC)(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]([OH:24])([CH3:2])[CH3:23])[CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Reactant: CC(=O)c1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cccc(Br)n1
Yield: 98 %

Procedure:
Add a solution of methyl magnesium bromide (3.0; M, 9.7; mL, 29.09; mmol) in tetrahydrofuran dropwise over 20; min to a cooled solution of 1-(6-bromo-pyridin-2-yl)-ethanone (5; g, 24.25; mmol) in anhydrous tetrahydrofuran (48.5; mL) at 0° C. Upon completion of the reaction, add water (exothermic), dilute with ethyl acetate (50; mL) and separate the layers. Extract the aqueous layer once with ethyl acetate (50; mL). Dry the combined organic layers over sodium sulfate, filter and concentrate to give the title compound as a pale yellow liquid (5.69; g, 98%) that is used without further purification. 1H NMR (CDCl3) δ 1.55; (s, 6H), 4.07; (s, 1H), 6.59; (t, 1H), 7.37; (t, 2H), 7.55; (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[N:16][OH:17])=[CH:4][CH:3]=1.N1C=CC=CC=1.O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N+:16]([O-:17])=[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: ON=C1CCCCC1=NNc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: [O-][n+]1c2c(nn1-c1ccc(Cl)cc1)CCCC2
Yield: 12.6 %

Procedure:
To a solution of 2-(4-chlorophenylhydrazono)cyclohexanone oxime (1.6 g) in a mixture of 15% aqueous solution of pyridine (25 ml) and tetrahydrofuran (20 ml), a solution of cupric sulfate (CuSO4.5H2O) (2.5 g) in water (10 ml) was added at room temperature, and the resultant mixture was heated under reflux for 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated aqueous cupric sulfate solution and water in order, dried and concentrated. The residue was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate as an eluent to give 0.2 g of 2-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (Compound No. 1). M.P., 100°-101° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].CCO[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.C(=O)(O)[O-].[Na+].[CH2:25]([OH:27])[CH3:26]>O>[CH2:1]([N:3]([CH2:26][CH2:25][O:27][CH:17]([O:16][CH2:15][CH3:14])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCNc1cccc(C)c1
Reactant: CCOCCOCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(C)OCCN(CC)c1cccc(C)c1

Procedure:
A mixture of 67.5 g(0.5 mole) of N-ethyl-3-methyl-aniline, 98.5 g (0.5 mole) of [β-(β-ethoxy)-ethoxy]ethyl bromide, 44.1 g (0.55 mole) of sodium bicarbonate, 5.50 ml of ethanol and 145 ml of water was refluxed for 80 hours. Ethanol was removed by distillation and the oil layer was extracted with ether. The extract was dried with potassium carbonate and then ether was removed, followed by distillation of the residue oil under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:16]1[C:20]2=[N:21][CH:22]=[CH:23][N:24]=[C:19]2[C:18]([NH2:25])=[N:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:25][C:18]2[C:19]3=[N:24][CH:23]=[CH:22][N:21]=[C:20]3[NH:16][N:17]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1n[nH]c2nccnc12
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)Nc1n[nH]c2nccnc12
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate 3) (0.10 g, 0.351 mmol), 1H-pyrazolo[3,4-b]pyrazin-3-amine (0.047 g, 0.702 mmol), HATU (0.133 g, 0.351 mmol) and N-methylmorpholine (0.069 ml, 0.702 mmol) in DMF (5 ml) was stirred at 75° C. for 90 minutes. After cooling to RT, the mixture was diluted with water (30 ml) and the resulting orange precipitate was filtered under vacuum and washed with water. Purification of the resulting solid by chromatography on silica eluting with iso-hexane:EtOAc (gradient of 0 to 100% EtOAc) to afforded the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.[O-]O.[OH-:22].[Na+].S(=O)(=O)(O)[OH:25]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[C:7]([S:8]([CH3:9])(=[O:25])=[O:22])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: COC(=O)N1CCN(c2cccc(SC)c2F)CC1
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Agent: [O-]O
Product: COC(=O)N1CCN(c2cccc(S(C)(=O)=O)c2F)CC1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To an ice cooled solution of methyl 4-[2-fluoro-3-(methylthio)phenyl]piperazine-1-carboxylate (1.4 g, 4.9 mmol) in sulfuric acid (1 M, 10 ml) was added sodium tungstate (0.016 g, 0.05 mmol) in one portion followed by dropwise addition of hydroperoxide (30%, 1.25 ml, 12.2 mmol). The reaction mixture was warmed to 55° C. and was stirred for 20 h. The reaction mixture was brought to ambient temperature and aqueous sodium hydroxide (5 M, 50 ml) was added. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (MgSO4) and evaporated to dryness to give the title compound. Yield (1.1 g). MS m/z (rel. intensity, 70 eV) 316 (M+, 58), 296 (30), 228 (bp), 216 (38), 56 (71).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a suspension of 2-bromo-5-methyl-benzoic acid (3.0 g, 14 mmol) in dichloromethane (100 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 8 ml, 16 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (15 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 2-bromo-5-methyl-benzoate (3.2 g, 99% yield).