Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH:24]=C)[CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[O:28]1CCCC1.O=[O+][O-].[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:28])[CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: C=Cc1cc(-c2n[nH]c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Reactant: C1CCOC1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2ncc3[nH]nc(-c4ccc(C#N)c(CO)c4)c3c2cc1OC
Temperature: 78 °C
Reaction time: 0.33 h

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-vinylbenzonitrile (247 mg, 693 μmol) is dissolved in N,N-dimethylformamide (1.5 ml), tetrahydrofuran (6.0 ml) and ethanol (9.0 ml) and cooled to (−) 78° C. The reaction solution is subsequently treated with ozone (oxygen flow of ozone generator 50 l/h) for 4 min, nitrogen is then passed through (2 min). After LC-MS check (aldehyde intermediate), NaBH4 (24 mg, 624 μmol) is added, and the reaction mixture is stirred at (−)78° C. for 20 min. The cold bath is subsequently removed, so that the reaction solution warms to room temperature. For purification, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness at 40° C. in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are lyophilised, giving 4-(7,8-dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (46 mg, 128 μmol) as a solid. MS: 361.4 (M+H+), TLC (HPTLC): Rf=0.38 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:36])([CH3:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]([CH3:36])([CH3:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:23])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), tert-butyl 2-amino-2-methylpropylcarbamate (64 mg, 0.338 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (58 mg, 0.45 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was used in the next step without further purification. MS: (M+H)+=482.1.
Reaction SMILES: O.[CH3:2][N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4]1.C(=O)([O-])O.[Na+].[C:23]([C:25](=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:26](ON1C(=O)CCC1=O)=[O:27])#[N:24]>O1CCOCC1>[C:23]([C:25](=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:26]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]([CH3:2])[CH:4]=1)=[O:27])#[N:24]
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Reactant: N#CC(=Cc1ccccc1F)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C[C@H](NC(=O)C(C#N)=Cc2ccccc2F)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To water (60 mL)-dioxane (60 mL) suspension of 1-methyl-L-tryptophan (2.1 g) was added sodium hydrogencarbonate (0.8 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Dioxane (80 mL) solution of the compound obtained in Example 120 (2.6 g, 9.2 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, water was added thereto, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with a 10% aqueous citric acid solution, and thereafter extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel chromatography (BW-127ZH, chloroform:methanol=50:1), to give the captioned compound (0.6 g, 17%) as an amorphous solid product.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH:10]1[C:11]2[N:12]([C:20]3[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH3:14])=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
To carbazole (5.02 g) in DMSO (50 mL) is added 4-fluoroacetophenone (3.45 g) and K2CO3 (10.4 g), and the mixture is stirred at 135° C. overnight. The mixture is poured into water to afford a precipitate, which is isolated by filtration and washed with water. The crude product thus obtained is further purified by recrystallization from TBME (tert-butyl methyl ether), giving the product as a light brown solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 2.71 (s, 3H), 7.32 (ddd, 2H), 7.41-7.50 (m, 4H), 7.72 (d, 2H), 8.15 (d, 2H), 8.21 (d, 2H).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]([S:10]([C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:27])=[CH:18][N:19]=[C:20]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:9])(C)(C)C.[C:29]([C:33]([OH:35])=[O:34])([F:32])([F:31])[F:30]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:33]([OH:35])=[O:34].[F:30][C:29]([F:32])([F:31])[C:33]([OH:35])=[O:34].[Cl:27][C:17]1[C:16]2[C:21](=[CH:22][C:13]([S:10]([N:8]([CH3:9])[CH2:7][C:6]([OH:28])=[O:5])(=[O:11])=[O:12])=[CH:14][CH:15]=2)[C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[N:19][CH:18]=1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine t-butyl ester (255 mg, 5.96 mmol) was dissolved in CF3CO2H (4.0 mL) and CH2Cl2 (2.0 mL), and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine bis(trifluoroacetate) (349 mg, 0.56 mmol) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH:4]([N:8](C)C)[N:5](C)[CH3:6])C.C1(=O)[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(=O)(O)O.NC(N)=N.Cl>C1(C)C=CC=CC=1.CO>[O:17]=[C:14]1[CH2:15][CH2:16][C:6]2[N:5]=[C:4]([NH2:8])[N:2]=[CH:1][C:12]=2[CH2:13]1
Reactant: O=C1CCC(=O)CC1
Reactant: CN(C)C(N(C)C)N(C)C
Agent: Cl
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ncc2c(n1)CCC(=O)C2

Procedure:
A solution of tris(dimethylamino)methane, 25.0 g (172 mmol), in 100 ml toluene is added dropwise, under nitrogen, to a solution of the monoethylene ketal of 1,4-cyclohexanedione, 25.0 g (160 mmol), in 300 ml of toluene. The resulting solution is evaporated in-vacuo and the residue is dissolved in 600 ml of methanol along with 38.72 g (320 mmol) of guanidine carbonate. The pH of the solution is adjusted to 9 with 15% hydrochloric acid and the mixture is refluxed for 16 hours. The solvent is evaporated and the yellow residue is washed with cold water and recrystallized from absolute ethanol to yield 11.0 g of 5,6,7,8-tetrahydro-6-ketoquinazolin-2-amine, ethylene ketal as yellow prisms; mp 214°-217° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:19][NH2:20]>CN(C=O)C.O>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:19][NH:20][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)N=C=O
Reactant: COCCOCOc1ccc(CN)cc1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
tert-Butylisocyanate (2.9 mL, 25.5 mmol) followed by triethylamine (9.8 mL, 68 mmol) was added to a magnetically stirred solution of 3-bromo-4-(2-methoxyethoxymethoxy)benzyl-amine (5 g, 17 mmol) in DMF (50 mL) and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with water (10 mL) and the dilution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatographic (silica gel) employing 100% ethyl acetate as eluent to give 1-[3-bromo4-(2-methoxyethoxymethoxy)benzyl]-3-tert-butylurea (5.3 g).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:62])[C@@H:24]([NH:25][C:26](=[O:61])/[C:27](/[C:48]4[N:49]=[C:50]([NH:53]C(OC(C)(C)C)=O)[S:51][CH:52]=4)=[N:28]\[O:29][C:30]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])=[CH2:31])[C@H:21]3[S:20][CH2:19][C:18]=2[S:63][CH:64](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:53][C:50]1[S:51][CH:52]=[C:48](/[C:27](=[N:28]/[O:29][C:30]([C:32]([OH:34])=[O:33])=[CH2:31])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:62])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:63][CH2:64][S:65][C:66]4[N:67]=[N:68][NH:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:61])[N:49]=1
Reactant: C=C(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: C=C(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 0.83 h
Yield: 77.1 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-diphenylmethoxycarbonylvinyloxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (910 mg: 0.723 mMol.) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40° C. is added a solution of aluminum chloride (0.77 g: 5.79 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 50 minutes. The reaction mixture is mixed with 1N-hydrochloric acid (5.8 ml), diluted with water, washed with ethyl acetate, and concentrated under reduced pressure to remove the remaining organic solvents. The resulting aqueous solution is subjected to chromatography over styrene divinylbenzene copolymer (methanol: water=4:1), and resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyvinyloxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (326 mg) as pale yellow white powder. Yield: 77%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH3:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Cc1cc(Br)cn2ccnc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Temperature: 23 °C
Yield: 90.9 %

Procedure:
A mixture of 6-bromo-8-methyl-imidazo[1,2-a]pyridine (example C.20 step 1) (7.0 g, 33 mmol), commercially available 4-(trifluoromethyl)phenylboronic acid (6.929 g, 36 mmol), Pd(PPh3)4 (383 mg, 1 mol %) and 1M Na2CO3-solution (77 mL, 77 mmol) in DME (150 mL) was stirred at reflux for 1 h. Cooled to 23° C., diluted with water, extracted with EtOAc, washed the organic layer with brine, dried over MgSO4. Removal of the solvent in vacuum left a brown solid, which was purified by silica gel column chromatography with EtOAc/MeOH to give the title compound as a white solid (8.29 g, 91%). MS (ISP) 277.1 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]2)[N:13]=3)[CH:7]=[C:6]([CH3:28])[C:3]=1[CH:4]=O.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:21]2)[N:13]=3)[CH:7]=[C:6]([CH3:28])[C:3]=1[CH2:4][N:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C=O
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1CN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (22.4 mg, 0.058 mmol), azetidine-3-carboxylic acid (29.5 mg, 0.29 mmol), and acetic acid (26.9 μl, 0.466 mmol) in 1:1 CH2Cl2/MeOH (2.0 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (6.59 mg, 0.105 mmol) was then added, and the resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo, dissolved in DMSO (2 mL)+trifluoroacetic acid (20 μL), filtered, and purified by rpHPLC (10-100% acetonitrile/water+0.1% TFA) to provide 1-((2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 469.2; Observed: 470.1 (M++1). (2,6-
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:14])=[C:10]([NH2:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2].CO.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[O-2].[O-2].[Mn+4].C(O)(=O)C>[C:1]([N:4]1[C:12]2=[CH:11][C:10]3[NH:13][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:14][C:9]=3[CH:8]=[C:7]2[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Reactant: O=Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CC(C)(C)c2cc3nc(-c4ccccc4)[nH]c3cc21

Procedure:
A mixture of 2.2 g. (10 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline, 200 ml. methanol, 5.2 ml. acetic acid, 1.0 ml. benzaldehyde and 50 mg. manganese dioxide is stirred for 3 hours at ambient temperature while passing in air. The reaction mixture is then filtered, the filtrate evaporated and the residue chromatographed on silica gel. After evaporation of the appropriate fractions and trituration with diethyl ether, there is obtained 0.8 g. (26% of theory) of the title compound; m.p. 225°-227° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[CH3:18][O:17][N:16]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
4-(Trifluoromethyl)benzoyl chloride (5.0 g, 23.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.3 mmol, 1.1 eq.) were combined in CH2Cl2 (200 mL) at 0° C. and treated with pyridine (4.3 mL, 52.6 mmol). After stirring for 2 hours, the mixture was allowed to attain ambient temperature, diluted with diethyl ether and washed with water, aqueous HCl, and water the organic phase was separated and concentrated to provide the title compound which was used directly in the next step. 1H NMR (300 MHz, d6-DMSO) 7.90 (m, 4H), 3.52 (s, 3H), 3.28 (s, 3H); MS (DCI/NH3) m/e 234 (M+H)+.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([O:14][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:13])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)O)cc1
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 2(S)-(p-toluenesulfonyloxy)propionic acid (4.4 g) to a cold solution of 10ml of isobutylene and 0.4 ml of concentrated sulfuric acid in 30 ml of methylene chloride in a pressure vessel, seal, and agitate at room temperature for 48 hours. Pour into 50 ml of 15% sodium carbonate solution, dry over magnesium sulfate and concentrate to obtain t-butyl 2(S)-(p-toluenesulfonyloxy)propionate as an oil (NMR δ1.37). Distilled material (Kugelrohr, 120° ) has [α]D26 =-45.9° (EtOH, c=1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[C:10]#[N:11].[H][H].C([O-])(=O)C.[K+].CO>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[C:4]([NH2:9])[C:3]([C:10]#[N:11])=[CH:2][N:7]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cnc(N)cc1N
Reaction time: 2 h

Procedure:
A suspension of 21.3 g of 6-bromo-2,4-diamino-5-cyanopyridine (JACS, 80:2838-2840 (1958)) and 1 g of 20% palladium on charcoal in 250 mL of tetrahydrofuran was shaken in a Parr apparatus under an atmosphere hydrogen. After 2 hours, the reaction was stopped and 10 g of potassium acetate and 50 mL of methanol added. The reaction was recharged with hydrogen and shaken for 18 hours. The solvents were removed under reduced pressure and the residue crystallized from isopropyl alcohol to afford the title compound 2,4-diamino-5-cyanopyridine, mp 201-202° C.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.C[O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)=O.CO>C1(C)C=CC=CC=1.C1COCC1>[OH:23][CH2:24][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C@@H:32]([OH:36])[CH2:31][CH2:30][CH2:29]2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1ccc2c(c1)CCC[C@@H]2O
Temperature: -10 °C

Procedure:
To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1 M solution in toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the reaction mixture was cooled in an ice-salt bath (bath temp.=−10° C). BH3—SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the reaction mixture was stirred for an additional 1 h. The reaction mixture was allowed to stir for 72 h at RT. The reaction mixture was poured into an addition funnel, and the mixture was added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temperature was kept below 0° C. The mixture was concentrated in vacuo to get a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.35-1.50 (m, 2H), 1.55-1.75 (m, 2H), 2.30 (s, 1H), 2.35-2.60 (m, 2H), 4.22 (s, 2H), 4.33 (s, 1H), 6.78 (s, 1H), 6.87 (d, 8.0 Hz, 1H), and 7.12 (d, 8.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[O:35]1[CH:36]=[CH:37][C:33]([C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[C:29]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:28]=2)=[O:32])=[CH:34]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.93 min, MH+ 505. NMR: δH [2H6]-DMSO 9.99, (1H, s), 9.32, (1H, t), 9.15, (1H, d), 8.95, (1H, b), 8.38, (1H, s), 8.33, (1H, dd), 7.81, (2H, d), 7.75, (1H, d), 7.68, (1H, d), 7.33-7.30, (2H, m), 7.21, (1H, s), 7.11, (2H, m), 7.01, (1H, s), 4.51, (2H, d), 2.99, (3H, s), 2.32, (3H, s).
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=O)[S:8][C:9]=1[N+:10]([O-:12])=[O:11].N1C=CC=CC=1>CCO>[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=[N:2][OH:3])[S:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=[N+]([O-])c1sc(C=NO)cc1Br
Temperature: 25 °C
Yield: 88 %

Procedure:
Hydroxylamine hydrochloride (85 g, 1.2 mol) was added to a solution of 4-bromo-5-nitro-thiophene-2-carbaldehyde (234 mg, 0.529 mmol, Example 286: step a) in EtOH (7.5 mL, 200 proof—anhydrous):pyridine (100 mL, anhydrous) at rt over 5 min. The reaction mixture was heated to reflux overnight, then cooled to rt. The solvents were removed in vacuo resulting in a solid residue that was washed with water and filtered. The solid was dried overnight under high vacuum to afford the title compound as a yellow solid (225 g, 88%). The solid was used for the next step without further characterization.