Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64]O>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:64][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][N:58]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: OCc1ccccn1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (7 g), 1,1′-(azodicarbonyl)dipiperidine (9.9 g), tributylphosphine (12.2 mL), pyridin-2-ylmethanol (2.8 mL) and tetrahydrofuran (350 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.6 g, 31%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: C1COCCN1
Solvent: CCO
Product: Brc1cn2ccnc2c(N2CCOCC2)n1
Yield: 27.8 %

Procedure:
A solution of 1 g (3,6 mol) of 6,8-dibromoimidazo[1,2-a]pyrazine and 1 g (11.2 mmol) of morpholine in 15 ml of anhydrous ethanol is brought to reflux for 12 hours. After evaporation of the solvant and chromatography on an alumina column (eluant=CH2Cl2), 0.88 g (Yld=85%) of 6-bromo 8-morpholinoimidazo[1,2-a]pyrazine (m.p. 191° C.) is obtained.
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([C:20]3([CH3:24])[CH2:23][CH2:22][CH2:21]3)[N:15]=2)[CH:11]=1>C(OCC)(=O)C.[Cu](I)I>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([C:20]3([CH3:24])[CH2:23][CH2:22][CH2:21]3)[N:15]=2)[CH:11]=[C:10]([NH2:2])[CH:18]=1
Reactant: Cc1cc(Br)cc2cn(C3(C)CCC3)nc12
Reactant: CN1CCCC1=O
Agent: I[Cu]I
Agent: N
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc2cn(C3(C)CCC3)nc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Copper oxide (I) (50 mg), NMP (2.5 mL), and concentrated aqueous ammonia (2.5 mL) were added to 5-bromo-7-methyl-2-(1-methylcyclobutyl)-2H-indazole obtained in the above-described Step 1 (536 mg), and the reaction solution was stirred in a microwave reactor at 100° C. for 5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then washed successively with water three times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 7-methyl-2-(1-methylcyclobutyl)-2H-indazol-5-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(Cl)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(F)c(Cl)c1
Yield: 55.6 %

Procedure:
To a solution of (3-chloro-4-fluoro-phenyl)-acetonitrile (1 g, 5.9 mmol) in THF (30 mL) was slowly added BH3-THF (8.26 ml). After the addition, the reaction mixture was heated to reflux for 3 hours. MeOH was added to quench the reaction and volatiles were removed under reduced pressure. The crude product was first dissolved in aq. HCl solution (30 mL) and impurities were removed by exaction with EtOAc (2×30 mL). The pH of the aqueous solution was adjusted to 8 using K2CO3 and the mixture was then extracted with DCM (3×30 mL). The combined organic layers were then washed with brine, dried with anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (570 mg, 55.8%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.[CH2:33]([O:35][CH2:36][CH2:37]Br)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][CH2:34][CH2:33][O:35][CH2:36][CH3:37])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CCOCCBr
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Product: CCOCCOCCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 51, 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-bromoethyl ethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=O>>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1/[CH:20]=[C:6]1/[C:7](=[O:12])[C:8]2[C:4]([CH2:5]/1)=[CH:3][C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=2
Reactant: Cc1cc2c(cc1C)C(=O)CC2
Reactant: O=Cc1ccncc1Br
Product: Cc1cc2c(cc1C)C(=O)/C(=C/c1ccncc1Br)C2

Procedure:
The title compound 92 is prepared according to the procedure reported in Example 35.3 with 5,6-dimethyl-1-indanone (0.40 g, 2.5 mmol) and 3-bromo-4-pyridinecarboxaldehyde (0.45 g, 2.5 mmol) as reactants. Yellow solid. (Yield 0.48 g, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[C:6](=[O:9])[CH2:7]Br)[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[C:6](=[O:9])[CH2:7][O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
316 g (2 mol) of 4-bromo-2,2-dimethyl-3-keto-butanoic acid ethyl ester were added dropwise, at 30° C., to 246 g (2 mol) of 4-chlorophenol and 210 g of potassium carbonate in 1,000 ml of dimethylformamide. The mixture was stirred for 20 hours at room temperature and 2 hours at 40° C. The reaction mixture was then introduced into 2,000 ml of water. The aqueous phase was extracted by shaking twice with 500 ml of methylene chloride at a time and the organic phase was extracted by shaking twice with 250 ml of water each time. The combined organic phases were dried, concentrated and distilled. 324 g (56% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester of melting point 125-135° C./0.1 mm Hg were obtained.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[CH:21]=[CH2:22])=[CH:7][CH:6]=1)([CH3:4])=[O:3].[Cl:23][C:24]1[C:29](I)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[C:29](/[CH:22]=[CH:21]/[N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][CH:19]=[N:20][C:12]=3[NH:11][C:8]2[CH:9]=[CH:10][C:5]([P:2]([CH3:1])([CH3:4])=[O:3])=[CH:6][CH:7]=2)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccnc(Cl)c1I
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccnc(Cl)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 120 °C

Procedure:
N-(4-(Dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (Example 3, 1 mmol), 2-chloro-3-iodo-4-methylpyridine compound (1.3 mmol), diisopropylethyl amine (3 mmol), palladium acetate (0.05 mmol), tri-o-tolylphosphine (0.1 mmol) in DMF (5 mL) was thoroughly purged with argon for 10-15 min. and sealed and heated for 120° C. for 18 h. until the starting materials disappeared. The reaction mix. was passed through celite, and washed with dichloromethane containing 30% methanol. The filtrate was concentrated in vacuo. The residue was purified by Biotage-S column chromatography using 1/1 hexane ethyl acetate, ethyl acetate and 1-10% methanol containing ethyl acetate: MS [M+H]+ 439.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:9][C:10]1[CH:11]=[C:12]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][SiH:23](Cl)[CH2:22][CH2:21]2)[CH:13]=[C:14]([F:17])[C:15]=1[F:16]>>[F:17][C:14]1[CH:13]=[C:12]([O:18][CH2:19][C@H:20]2[CH2:21][CH2:22][Si@H:23]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:24][CH2:25]2)[CH:11]=[C:10]([F:9])[C:15]=1[F:16]
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)cc(F)c1F
Reactant: CCCCCCCBr
Product: CCCCCCC[Si@H]1CC[C@H](COc2cc(F)c(F)c(F)c2)CC1

Procedure:
The general procedure of Example 1 was repeated using n-heptyl bromide and 4-(3,4,5-trifluorophenyloxymethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:6]([OH:23])=[CH:7][C:8]([OH:22])=[C:9]([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:10]=1>C(O)C>[Cl:4][C:5]1[C:6]([OH:23])=[CH:7][C:8]([OH:22])=[C:9]([C:11](=[N:2][NH2:3])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: NN
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=NN)c2cc(Cl)c(O)cc2O)cc1

Procedure:
Hydrazine hydrate (0.166 ml, 3.42 mmol) is added to a solution of 1-(5-chloro-2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (1a) (0.5 g, 1.71 mmol) in 95% ethanol (5 ml). The mixture is heated under reflux for 7 hours. Solvent is concentrated in vacuo, the residue treated with water, filtered of and recrystallyzed from 2-propanol.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]=[C:8]1[N:12]([CH3:13])[C@H:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:23]([CH3:27])[C:24](=[O:26])[CH3:25])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]=[C:8]1[N:12]([CH3:13])[C@H:11]([CH:14]=[C:23]([CH3:27])[C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N=C1CC[C@@H](C=O)N1C
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N=C1CC[C@@H](C=C(C)C(C)=O)N1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-5-allyloxycarbonylimino-2-formyl-1-methylpyrrolidine (0.46 g) in toluene (20 ml) was added 3-triphenylphosphoranylidenebutan-2-one and the mixture was stirred at 80° C. for 2 hours. The solvent was evaporated and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:2 V/V) to give (2S)-5-allyloxycarbonylimino-1-methyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.54 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH3:32]>O1CCCC1>[F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: N
Reactant: CCOC(=O)c1cn2c3c(c(-c4ccc(S(=O)(=O)Cl)cc4)c(F)cc3c1=O)OCC2C
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(-c4ccc(S(N)(=O)=O)cc4)c(F)cc3c1=O)OCC2C
Temperature: -78 °C
Yield: 56 %

Procedure:
Ethyl 9-fluoro-10-(4-chlorosulfonylphenyl)-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (0.5 g) was dissolved in dry tetrahydrofuran (80 ml) and the resulting solution was cooled to -78° C. with stirring. Ammonia (5 ml) was condensed into the reaction mixture and the yellow suspension was warmed gradually to ambient temperature over 16 hours. Solvent was removed in vacuo and the residue was triturated with water and filtered. Drying in vacuo afforded a solid (0.3 g, 56% yield): m.p. >250° C. NMR (DMSO-d6, 250 MHz): 8.74 (s, 1H), 7.96 (d, 2H, J=10 Hz), 7.74 (d, 2 H, J= PG,91 10 Hz), 7.60 (d, 1H, J=10 Hz), 7.50 (s, 2H), 4.90-4.75 (m, 1H), 4.55-4.45 (m, 2H), 4.25 (q, 2H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.30 (t, 3H, J=7 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])=[C:10]([F:25])[CH:9]=[C:8]([Cl:26])[C:6]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([SH:35])[CH3:34].O>CN(C)C=O>[Cl:26][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][S:35][CH2:33][CH3:34])[O:4][C:5]=2[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:10]([F:25])[CH:9]=1
Reactant: CCS
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CBr)oc23)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
1.5 g (3.3 mmol) of 3-(2-bromomethyl-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 0.7 g (5.1 mmol) of potassium carbonate were suspended in 20 ml of N,N-dimethylformamide, and 0.21 g (3.4 mmol) of ethylmercaptan was added thereto at room temperature, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 83.4%) of the desired product as a yellowish brown glassy substance. Refractive index: 1.5629 (20° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(N)cc1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(N)cc3)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 4-ethynylaniline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:11]([F:12])([F:14])[F:13])[CH:4]=[N:3][C:2]=2[N:1]=1)[CH3:16]
Reactant: CCSc1ccccc1C=O
Reactant: NC(=O)c1cc(C(F)(F)F)cnc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A mixture of 1.0 g of 2-amino-5-trifluoromethylpyridine-3-carboxylic acid amide, 810 mg of 2-ethylsulfanylbenzaldehyde, 1.01 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 12 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 975 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:22][C:21]=1[F:30]>>[F:30][C:21]1[CH:22]=[C:23]([C:26]([OH:29])([CH3:27])[CH3:28])[CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: CC(C)(O)c1ccc(CN)c(F)c1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1

Procedure:
Prepared from 2-(4-Fluoro-phenoxy)-nicotinic acid and 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: -20 °C

Procedure:
190.7 g of 90% 3-chloroanthranilic acid, corresponding to 171.6 g (1.0 mol) of 100% 3-chloroanthranilic acid, are initially introduced, in 1,820.0 g of toluene, into a four-necked flask having a stirrer, a thermometer and a reflux condenser cooled down to -20° C., and 300.0 g of phosgene are then metered in at room temperature over a period of about 3 h while stirring thoroughly. The reaction mixture is heated to 100° C. and a further 150.0 g of phosgene are passed in over a period of 2 h. After that, the mixture is stirred at 100° C. for a further 1 h, and subsequently blown free of phosgene at this temperature using nitrogen. After cooling to about 25° C., the crystals which have precipitated out are filtered off with suction, and the filter cake is washed with 2×50 ml of toluene and dried at 100° C. in vacuo. 188.3 g of 3-chloroisatoic anhydride, having a purity by GC of >99%, are obtained, corresponding to 95.2% of theory.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O-:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29].[I-].[K+].O>COCCOCCOC>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)[O-])cc2[nH]1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OCC(O)CO)cc2[nH]1
Yield: 26 %

Procedure:
A mixture of sodium 2-(n-undecyl)indole-6-carboxylate (5.0 g) and 3-chloro-1,2-propanediol (1.64 g) in diglyme (50 ml) was refluxed for 30 minutes. Potassium iodide (2.5 g) was added and the mixture refluxed for 48 hours. The mixture was cooled, water (50 ml) was added and the resulting emulsion was extracted with dichloromethane (2×100 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated to dryness. The solid residue was recrystallised from cyclohexane, filtered off and dried to give (RS)-2,3-dihydroxyprop-1-yl 2-(n-undecyl)indole-6-carboxylate (1.5 g) in the form of a white solid, m.p. 110°-112° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=2Cl)(=[O:10])=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].[OH2:24]>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=2[OH:24])(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1O
Yield: 33.3 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(4-pyridinyl)-2,6-dichloro-3-nitrobenzenesulfonamide (540 mg, 1.55 mmol), 80% NaH (217 mg,7.25 mmol) and water (0.045mL, 2.46 mmol) were reacted to form the desired product (170 mg, 33%). EI-MS m/z 328(M-H)−.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH:15][CH3:16]>C(O)C.O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([N:15]([CH3:16])[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CNC
Solvent: O
Solvent: CCO
Product: CN(C)c1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In ethanol-water (2:1) (45 ml)was dissolved 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone (4.4 g) followed by addition of 50% dimethylamine (7.2 g), and the mixture was stirred at room temperature for 15 hours. After removal of ethanol, the residue was extracted with diethyl ether and the organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. This residue was washed with n-hexane and dried. White powder, 4.4 g. 1H-NMR (CDCl3) δ: 1.63(9H,s), 3.10(6H,s), 7.57(1H,s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([N:11]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[C:22](=[N:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([CH3:24])[CH3:23]>C1COCC1>[NH2:11][C:10]1[CH:20]=[CH:21][C:7]([C:22]([NH:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([CH3:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Reactant: CC(C)=NS(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(NS(=O)C(C)(C)C)c1ccc(N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of n-butyllithium in hexanes (1.65 M, 5.2 mL) was added dropwise to a solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (2.55 mL) in THF (14 mL) at −78° C. The resulting mixture was stirred for 1.5 h at −78° C. before a solution of N-isopropylidene-2-methylpropane-2-sulfinamide in THF (2.8 mL) was added dropwise at −78° C. The reaction mixture was stirred for an additional 1 h at −78° C. then allowed to warm to room temperature. After being stirred for 18 h at room temperature, the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was diluted with diisopropylether and extracted with 1 M citric acid solution. The aqueous extracts were combined and basified with sodium bicarbonate solid to pH>7. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes) gave the product (173 mg, 12%). 400 M Hz 1H-NMR (CDCl3) δ: 7.26 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.7 Hz, 2H), 3.66 (brs, 1H), 3.31 (s, 1H), 1.67 (s, 3H), 1.64 (s, 3H), 1.20 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1cccnc1
Product: N#Cc1cc(-c2cccnc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (38 mg, 50%), MS (ISP) m/z=303.5 [(M+H)+], mp 252° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).