Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:24][NH2:25])[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:24][NH:25][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: CN(C)CCC(CN)c1ccc(Cl)cc1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(CCN(C)C)c1ccc(Cl)cc1

Procedure:
From 2-methylbenzoic acid and 3-(4-chloro-phenyl)-N1,N1-dimethyl-butane-1,4-diamine. LCMS (MH+): m/z=345.1, tR (minutes, Method A)=0.8
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:15]=[C:14]([NH2:26])[N:13]=2)(=O)=O)=CC=1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41].O>C(COC)OC>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:16]1[N:15]=[C:14]([NH2:26])[N:13]=[C:12]([NH:41][CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1
Reactant: NCc1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Nc1nc(NCc2ccccn2)c([N+](=O)[O-])c(-c2ccco2)n1
Reaction time: 16 h
Yield: 69.3 %

Procedure:
A solution of (2-amino-6-(2-furyl)-5-nitropyrimidin-4-yl) 4-methylbenzenesulphonate (478 mg, 1.27 mmol) in dimethoxyethane (15 mL) was treated with triethylamine (0.531 mL, 3.81 mmol) and 2-pyridinemethylamine (0.393 mL, 3.81 mmol), stirred for 16 h, poured into water (100 mL) and the resulting solid was filtered to give the title compound (275 mg, 69%) as a yellow solid; NMR δH (400 MHz, CDCl3) 8.70–8.58 (2H, m), 7.70–7.66 (1H, m), 7.55–7.54 (1H, m), 7.28 (1H, d, J 8.0 Hz), 7.24–7.20 (1H, m), 7.07–7.06 (1H, m), 6.54–6.52 (1H, m), 5.26 (2H, br s) and 4.83 (2H, d, J 5.0 Hz); Retention time 1.44 min.
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([C:9]1[CH:10]=[N:11][C:12]([N:16]2[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]2[CH2:22][OH:23])=[CH:13][C:14]=1[I:15])[CH3:8])(C)(C)C.Cl.C(N(C(C)C)C(C)C)C.[F:35][C:36]([F:54])([F:53])[C:37]1[CH:38]=[C:39]([C:47](C)([CH3:51])[C:48](Cl)=O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>ClCCl.C(OCC)C>[F:35][C:36]([F:53])([F:54])[C:37]1[CH:38]=[C:39]([C:47]([CH3:51])([CH3:48])[C:6]([N:7]([C:9]2[CH:10]=[N:11][C:12]([N:16]3[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]3[CH2:22][OH:23])=[CH:13][C:14]=2[I:15])[CH3:8])=[O:24])[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.6 %

Procedure:
To a solution of 8.94 g (19.9 mmol) (2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester in 85 ml dichloromethane were added 50 ml of a 2 M solution of hydrogen chloride in diethylether at 0° C. The reaction mixture was stirred at room temperature for 22 h and concentrated in vacuo. The residue was re-dissolved in 85 ml dichloromethane and treated with 17 ml (99.4 mmol) N-ethyldiisopropylamine. At 0° C. 19.0 g (59.7 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo. After addition of 250 ml methanol and 70 ml 3 N potassium hydroxide solution the mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove methanol and extracted with four 750 ml-portions of dichloromethane. The combined organic layers were washed with 500 ml 1 N sodium hydroxide solution and 500 ml brine, dried over sodium sulfate and evaporated. Flash-chromatography gave 11 g (87%) of the title compound as a light yellow foam.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH2:9][CH3:10])=[CH:5][N:6]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cnc(Br)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)c1cnc(Br)s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
2-Bromo-thiazole-5-carbaldehyde (1.00 g, 5.21 mmol) was dissolved in THF (10 ml). A solution of ethylmagnesium bromide (3 M in diethylether, 5.00 mL, 15.0 mmol) was added. The mixture was stirred for 18 h. The reaction was poured into sat. ammonium chloride solution/ice (100 mL) and diluted with ethyl acetate (100 ml). The organic phase was separated, washed with sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes provided 1-(2-bromo-thiazol-5-yl)-propan-1-ol (480 mg, 42%). Unreacted 2-Bromo-thiazole-5-carbaldehyde (465 mg, 46%) was also obtained.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.Cl.[Pd]>[F:21][C:17]1([F:20])[CH2:18][CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: FC1(F)CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: FC1(F)CCN(C2CCNCC2)CC1

Procedure:
A solution of 2.8 g (9.5 mmol) 1′-benzyl-4,4-difluoro-[1,4′]bipiperidinyl in 300 mL MeOH was hydrogenated in the presence of 1.2 g Pd/C (10%) at 50° C. and 50 psi hydrogen pressure with the addition of a few drops of 1 M HCl until the calculated volume of hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down under reduced pressure. The residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:14]O>>[CH3:14][O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:12]=[C:11]([OH:13])[CH:10]=1
Reactant: CO
Reactant: O=C(O)C=Cc1cc(O)cc(O)c1
Product: COC(=O)C=Cc1cc(O)cc(O)c1

Procedure:
FIG. 8 illustrates examples of synthetic schemes for producing alkylated derivatives of 3,5-dihydroxycinnamic acid. In the illustrated synthetic schemes, 3,5-dihydroxycinnamic acid 51 is first esterified in MeOH to produce 3,5-dihydroxycinnamic acid methyl ester 52, which is then reacted with 1 or 2 eq. of an alkylating agent RX in the presence of TBAI and K2CO3 to produce the mono-alkylated intermediate 53 or the dialkylated intermediate 55. The esters 53 and 55 are then hydrolyzed under basic conditions to produce the corresponding acids 54 and 56, respectively.
Reaction SMILES: [OH:1][C:2]1(C(C)(C)C)[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15](C3C=NOC=3C)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]1[C:23]([CH3:26])([CH3:25])[CH3:24].[OH-:31].[Na+].Cl>O1CCCC1>[OH:1][C:2]1[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]([CH2:6][C:5]([C:8]#[N:9])=[C:4]([OH:31])[CH3:3])=[O:16])[O:10][N:9]=2)=[CH:4][C:3]=1[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: [OH-]
Reactant: Cc1oncc1C(=O)NCc1cc(C2=CC(C(C)(C)C)C(O)(C(C)(C)C)C=C2)no1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)=C(C#N)CC(=O)NCc1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1

Procedure:
4.0 g (0.01 mol) of the product from Example 52 were dissolved in 50 ml of absolute tetrahydrofuran, and 20 ml of 1N NaOH were added while cooling with ice; once the reaction was complete (monitoring by TLC), the mixture was acidified with 22 ml of 1N HCl and extracted with dichloromethane; this was followed by washing, drying and concentration. The remaining residue was crystallized from tert-butyl methyl ether/petroleum ether. Yield: 3.3 g.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[N:3]=1.[CH3:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([NH:1][S:29]([C:27]1[S:28][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:31])=[O:30])=[N:3][N:4]2[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=1
Reactant: COc1cccc2c1c(N)nn2Cc1ccc(C(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(C)s1)nn2Cc1ccc(C(N)=O)cc1
Reaction time: 3 h
Yield: 14 %

Procedure:
A solution of 4-{[3-amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (32.4 mg, 0.2 mmol) in pyridine 3.6 mL) was added to 5-methyl-thiophenesulfonyl chloride (for a preparation see Intermediate 32) (0.30 mmol). The reaction mixture was shaken briefly and allowed to stand for 3 h at 21° C. prior to concentration by blowdown. The residue was dissolved in 1:1 MeOH-DMSO (0.6 mL) and purified by Mass Directed AutoPrep on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier (Method C). The solvent was evaporated in vacuo using the Genevac to give the title compound (12.5 mg, 14%). LCMS (System A) RT=0.86 min, ES+ve m/z 457 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)=O)=[CH:4][CH:3]=1.[NH2:28][NH2:29].O>CCO.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:29][N:28]=[C:11]([C:13]3[N:14]=[N:15][N:16]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:17]=3)[CH:10]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COc1ccc(Cn2cc(C(=O)CC(=O)Cc3ccc(F)cc3)nn2)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)[nH]n3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 4-(4-fluorophenyl)-1-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]butane-1,3-dione (0.6 g, 1.6 mmol) and anhydrous EtOH/AcOH (20 mL/5 mL) was added dropwise NH2NH2.H2O (1.0 mL, 9.6 mmol) at 0° C. and the mixture was stirred at RT overnight. The mixture was evaporated, the residue washed with anhydrous Et2O (4×5 mL) and the resulting precipitate was dried in oven to yield the title compound (0.5 g, 84.0%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([NH:16][CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[N:24]=[CH:23]1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH:17]1([N:16]([CH:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:13]=2)[CH3:15])[C:27]([C:25]2[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=2)=[O:28])[CH2:20][CH2:19][CH2:18]1
Reactant: CC(NC1CCC1)c1ccnc(-c2ccc(F)cc2)c1
Reactant: Cn1cnc(C(=O)Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(c1ccnc(-c2ccc(F)cc2)c1)N(C(=O)c1cn(C)cn1)C1CCC1
Yield: 85.7 %

Procedure:
A solution of N-{1-[2-(4-fluorophenyl)pyridin-4-yl]ethyl}cyclobutaneamine (100 mg), 1-methyl-1H-imidazole-4-carbonyl chloride (110 mg) and triethylamine (100 mg) in chloroform (5 mL) was stirred at room temperature overnight. Water was added thereto, followed by extraction with chloroform, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) to afford the title compound (120 mg).
Reaction SMILES: [C:1]1(=[N:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:23]>N1C=CC=CC=1>[C:13]1([S:19]([OH:21])(=[O:12])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:13][O:23][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][C:1]2=[N:11][OH:12]
Reactant: ON=C1CCCc2ccccc21
Reactant: O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cccc2c1CCCC2=NO
Product: O=S(=O)(O)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.8 %

Procedure:
10 g (0.042 mole) of tetralone-1-oxime are dissolved in 80 ml of anhydrous pyridine. 10.8 g of benzenesulfonic acid chloride are added dropwise in the course of 15 minutes at room temperature and the solution is left to stand for 12 hours. 5 ml of water are then added, after which the solution is poured into 300 ml of ice-cold 4 N HCl. The resulting precipitate is filtered off, dried and recrystallized from ethanol. 13.6 g (92.8% yield) of 5-methoxy-tetralone-1-oxime benzenesulfonate, of melting point 142°-144° C., are isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]2[CH2:23][N:22]([CH3:24])[CH2:21]2)=[C:15]([N+:25]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:48](OC2C=CC=CC=2)=[N:49][C:50]#[N:51])=CC=1>O1CCCC1.[Pt].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH:20]3[CH2:23][N:22]([CH3:24])[CH2:21]3)/[C:48](=[N:49]/[C:50]#[N:51])/[NH:25][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1CC(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])C1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CC(n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 151.1 %

Procedure:
Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(1-methyl-azetidin-3-yl)-amine (4.23 mmol, 1.90 g), triethylamine (9.31 mmol, 1.30 mL) in tetrahydrofuran (20 mL), add 5% platinum on carbon (200 mg) and hydrogenate (50 psi) at 35° C. for one hour. Filter off the catalyst, rinse with pyridine (20 mL), add diphenyl N-cyanocarbonimidate (4.65 mmol, 1.11 g) and stir at room temperature overnight under nitrogen. Dilute with ethyl acetate, wash with 5% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain approximately 3 g of an orange oil. Purify on an 80 g silica gel column eluting with 5% methanol in dichloromethane to obtain ˜930 mg of a yellow semi-solid. Dissolve in a minimum amount of methanol and let sit. White solids form. After 30 min filter off the solids and rinse with methanol to obtain the title compound as a white solid (815 mg, 41%). LC-MS m/z 470.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33].CN([CH:37]=[O:38])C>>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]([NH:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[O:38])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: NCc1ccccn1
Reactant: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 100 °C
Reaction time: 26 h
Yield: 34 %

Procedure:
A mixture of 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (1.02 g, 2.24 mmol), 2-picolylamine (369 mg, 3.41 mmol), Pd(dppf)C12 (92 mg, 0.13 mmol) triethylamine (5.2 mL, 3.8 g. 37 mmol) and DMF (50 mL) was flushed with carbon monoxide and stirred under an atmosphere of CO at 100° C. for 26 h. The solvent was removed in vacuum and the residue was taken up in EtOAc, filtered and evaporated. The residue was chromatographed on SiO2 to give the title compound (391 mg, 34%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:16]([Al](CC(C)C)CC(C)C)C(C)C.C(I)I.[OH-].[Na+]>C(Cl)Cl>[CH:13]1([CH2:12][C:11]2[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][C:10]=2[OH:15])[C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:14]1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ICI
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(CC2CC2)c1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The compound of Example 5 (1.0 g, 4.8 mMol) was dissolved in methylene chloride (20 cm3) and transferred to a 100 ml three-neck round bottom flask under an argon atmosphere at 0° C. Triisobutylaluminum (2.95 g, 3.76 ml, 14.9 mmol) was added dropwise via a dropping funnel. The reaction mixture was stirred for about 20 minutes while maintaining the temperature at 0° C., then methylene iodide (1.67 g, 0.5 ml, 6.2 mmol) was added via syringe, and the reaction mixture was stirred at room temperature for about four hours then slowly poured into an ice cold solution of 10% sodium hydroxide. The aqueous layer was extracted twice with about 25 ml of methylene chloride, and all of the organic fractions were combined, dried over magnesium sulfate and concentrated in vacuo to give the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=CC(CCl)=C[N:3]=1.[CH3:11][S-:12].[Na+].[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1>CCOCC>[Cl:1][C:2]1[C:7]([Cl:8])=[C:14]([CH3:18])[C:15]([S:12][CH3:11])=[CH:16][N:3]=1
Reactant: C1CCOC1
Reactant: ClCc1cnc(Cl)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Product: CSc1cnc(Cl)c(Cl)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2,3-dichloro-5-chloromethylpyridine (3.75 g, 19.1 mmol) in THF (30 mL) was added solid sodium thiomethoxide (2.01 g, 29 mmol) in one portion and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ether (100 mL), washed with 0.1 N aqueous HCl (50 mL) solution and brine (50 mL), dried over anhydrous MgSO4, filtered, concentrated, and dried to give 3.55 g of 2,3-dichloro-5-methylthio-methylpyridine as a dark yellow liquid in 89% crude yield. The crude product was analytically pure without further purification. GC-MS: calcd for C7H7Cl2NS [M]+ 208. Found 208.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2.O.[NH2:20][NH2:21].CCOC(C)=O.O>O1CCOCC1>[NH:20]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2)[NH2:21]
Reactant: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1

Procedure:
6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-2) (26.2 g, 102 mmol) and hydrazine hydrate (26.2 g, 102 mmol) in 1,4-dioxane (400 mL) was stirred at 100° C. for 3 days. To the mixture was added EtOAc and water. The resulting solid was collected by filtration to give 6-hydrazino-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-3) as yellow powder.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(Cl)Cl>C(Cl)CCl>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2,2,2-trifluoroethanol (5.0 g, 50.0 mmol) and triethylamine (10.5 ml, 7.6 g, 75.0 mmol) in 25 ml of ethylene chloride at -10° is added methanesulfonyl chloride (4.25 ml, 6.3 g, 55.0 mmol) over 20 min. maintaining the temperature at 0° to -10°. After addition is complete, the mixture is stirred at 0°-5° for 30 min. It is then poured into ice water and additional methylene chloride is added. The layers are separated, and the methylene chloride layer is washed with cold 10% HCl, with cold saturated sodium bicarbonate, with cold water until neutral, and with cold brine. The organic layer is dried over calcium sulfate with swirling and is filtered and the solvent is removed to give 2,2,2-trifluoroethyl methansulfonate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][Zn]C.C1(C)C=CC=CC=1.CO>O1CCOCC1>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: C1COCCO1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (21.54 g, 40 mmol) in 1,4-dioxane (300 mL) was bubble with argon for 10 min. The reaction mixture was treated with 2N dimethylzinc in toluene (40 mL, 80 mmol) under argon. The reaction mixture was treated with PdCl2(dppf)CH2Cl2 adduct (0.326 g, 0.400 mmol) and heated to 80° C. After 2 h, the reaction was check by HPLC. The reaction was cooled to room temperature and slowly added MeOH until reaction was quenched. After quenched, the reaction mixture was diluted with NaHCO3 (sat'd) (200 mL) and extracted with EtOAc (3×, 200 mL). The EtOAc layers were stirred with activated carbon (darco G-60, 100 mesh, powder) for 1 h. The reaction mixture was filtered through pad of SiO2 (3″×3″) and washed with EtOAc. The reaction mixture was concentrated. IPA (350 mL) was to the reaction mixture and heated to reflux. After 2 h, the reaction mixture was cooled to room temperature and filtered and washed with IPA and water (200 mL). The product was dried under vacuum at 60° C. for 2 days. Title compound was obtained as an off-white solid (17.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 519 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4].[CH3:19][NH2:20]>CO>[CH3:19][NH:20][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4]
Reactant: COC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid methyl ester (50 mg, 0.20 mmol) was suspended in 1 mL of a 33% solution of methylamine in methanol. The suspension was stirred at room temperature for 21 h. Another 2 mL 33% methylamine in methanol was added and the resulting solution stirred another 8 h at room temperature then 15 h at 30° C. The reaction mixture was concentrated in vacuo leaving a yellow solid which was crystallized from DMF/MeOH/CHCl3 to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid methylamide, 36 mg (72%) as a yellow solid: m.p. 321-322° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.81 (s, 3H), 3.15 (m, 2H), 3.40 (m, 2H), 7.32 (app t, J=7.8 Hz, 1H), 7.61 (d, J=8.1Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.95 (br q, 1H), 8.09 (br t, 1H), 11.46 (br s, 1H). MS (electrospray, [M+Na]+) 266. Anal. (C13H13N3O2.0.4 H2O) C, H, N.