Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:31])(=[O:30])[NH2:32])=[O:15])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A benzene (30 ml) solution containing 3.00 g (13.5 mmol) of 4-phenylethynylbenzoic acid and 2 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.32 g (13.50 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain 4.00 g (yield: 78.7%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:16][CH2:17]1
Reactant: OCCN1CCN(CC2CN(Cc3ccccc3)CCO2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OCCN1CCN(CC2CNCCO2)CC1
Yield: 79.1 %

Procedure:
4-Benzyl-2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (16 g) is dissolved in ethanol (160 ml), and thereto is added palladium hydroxide (1.6 g). The mixture is subjected to de-benzylation at 50° C. under hydrogen atmosphere. Five hours later, the mixture is filtered through a cerite pad, and the filtrate is concentrated under reduced pressure. The resulting crystals are washed with diethyl ether-n-hexane to give 2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (9.09 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19](=[N:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[N:44][O:45][CH3:46])[C:40](OC)=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.ClCCl>CO>[CH3:18][C:19](=[N:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[N:44][O:45][CH3:46])[CH:40]=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: CON=C(C(=O)OC)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CON=C(C=O)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 47.3 %

Procedure:
1M diisobutylaluminum hydride/toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-α-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at -65° C. or lower over 4 minutes, and the mixture was stirred at -78° C. to room temperature for 3 hours. Methanol (7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-α-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless oil.
Reaction SMILES: [F:1]C1C=C2C(N=C(O)C3N2C(C(F)(F)F)=NN=3)=CC=1.P(Cl)(Cl)(Cl)=O.C(N(CCC)CCC)CC.[Cl:35][C:36]1[C:37]2[N:38]([C:47]([C:50]([F:53])([F:52])[F:51])=[N:48][N:49]=2)[C:39]2[C:44]([N:45]=1)=[CH:43][CH:42]=[C:41](F)[CH:40]=2>>[Cl:35][C:36]1[C:37]2[N:38]([C:47]([C:50]([F:53])([F:52])[F:51])=[N:48][N:49]=2)[C:39]2[C:44]([N:45]=1)=[CH:43][C:42]([F:1])=[CH:41][CH:40]=2
Reactant: Fc1ccc2nc(Cl)c3nnc(C(F)(F)F)n3c2c1
Reactant: Oc1nc2ccc(F)cc2n2c(C(F)(F)F)nnc12
Agent: CCCN(CCC)CCC
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc2c(c1)nc(Cl)c1nnc(C(F)(F)F)n12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame-dried 250 ml. three-necked reaction flask under a dry nitrogen atmosphere, there were placed 12.5 g. (0.046 mole) of 8-fluoro-4-hydroxy-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline and 85 ml. of phosphorus oxychloride together with 17.5 ml. of tri-n-propylamine. The reaction mixture was then refluxed overnight for approximately 16 hours and finally cooled to room temperature (~20° C.) prior to being slowly poured over 1000 ml. of ice/water with the aid of mechanical stirring. The resulting aqueous mixture was next stirred for an additional period of 30 minutes at room temperature, followed by extraction with three-300 ml. portions of chloroform. The combined chloroform layers were then successively washed with saturated aqueous sodium bicarbonate solution, water and saturated brine and finally dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained a yellow solid product which consisted of 10.47 g. (79%) of pure 4-chloro-8-fluoro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 135°-138° C. Mass Spectrum: m/e, 292/290 (P+).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:23][N:22]=1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:25]=2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(-c2cc(CCl)no2)cc1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccc(F)cc2)on1

Procedure:
Synthesized in a manner similar to Example 23 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(4-fluorophenyl)isoxazole: MS (ES) m/z 428 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:19][C:20](=[O:35])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([CH3:34])[CH:22]=3)[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[NH:7][C:6]=2[CH:36]=1.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+].ClCl>CN(C)C=O.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:19][C:20](=[O:35])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([CH3:34])[CH:22]=3)[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:7]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:6]=2[CH:36]=1
Reactant: Cc1cc(C(=O)NC(Cc2ccc(O)cc2)c2nc3ccc(Cl)cc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: COC(=O)CBr
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)Cn1c(C(Cc2ccc(O)cc2)NC(=O)c2ccc(C(=O)N3CCCC3)c(C)c2)nc2ccc(Cl)cc21
Yield: 30 %

Procedure:
Prepared analogously to Example 6b from N-[1-(6-chloro-1H-benzimidazol-2-yl)-2-(4-hydroxyphenyl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, methyl bromoacetate, and potassium carbonate in dimethylformamide. Yield: 30%; Rf value: 0.33 (silica gel; dichloromethane/ethanol=19:1); C31H31ClN4O5 (575.06); mass spectrum: (M+H)+=575/577 (chlorine isotope) and (M−H)−=573/575 (chlorine isotope).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>CO.[Pt].[C]>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([NH:17][CH2:16][CH2:15][NH:18][CH:7]2[CH2:6][C:5]([CH3:11])([CH2:12][CH3:13])[NH:4][C:3]([CH3:14])([CH2:1][CH3:2])[CH:8]2[CH3:9])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Reactant: NCCN
Agent: [Pt]
Solvent: CO
Product: CCC1(C)CC(NCCNC2CC(C)(CC)NC(C)(CC)C2C)C(C)C(C)(CC)N1
Reaction time: 106 h

Procedure:
197.3 g of 2,6-diethyl-2,3,6-trimethylpiperidine-4-one and 30.0 g of ethylenediamine are dissolved in one liter of methanol. 10 g of a platin-carbon catalyst (5% b.w. Pt) are added, and the solution is hydrogenated at 30°-35° C. and normal pressure. Hydrogenation is completed after 106 hours. The catalyst is filtered off, the solvent is evaporated in vacuo, and the oily residue is purified by molecular distillation at 150° C. and 0.005 mm Hg. N,N'-Bis-(2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-ethylenediamine (compound no. 7) is obtained as a practically colourless oil. If, instead of 30.0 g of ethylenediamine an equivalent amount of 1,6-hexamethylenediamine is used and otherwise the procedure described above is followed, after molecular distillation at 180° C. and 0.002 mm Hg. N,N'-Bis-(2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-hexamethylene-1,6-diamine (compound no. 8) is obtained in the form of a thick colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]#[N:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].N.[H][H]>[Ni].CO>[NH2:15][CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(CC#N)cc1Cl
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)c1ccc(CCN)cc1Cl
Reaction time: 4.5 h
Yield: 77 %

Procedure:
A mixture composed of 1.9 g (8.5 mmol) of ethyl 2-chloro-4-(cyanomethyl)benzoate, 0.5 g of Raney nickel in 70 ml of methanol containing a few ml of liquid ammonia is subjected to a hydrogen pressure of about 60 kg/cm2, at 50° C. for 5 h, and then at 80° C. for 4.5 h. After filtration of the reaction medium, 1.5 g of oil are obtained (Yield=77%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[SH:10])([O-])=O.[C:11](OC(=O)C)(=O)[CH3:12]>C(O)(=O)C.[Zn]>[CH3:11][C:12]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnccc1S
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc2cnccc2s1
Yield: 44.5 %

Procedure:
A mixture of 1.3 g of 3-nitropyridine-4-thiol in 4 ml of acetic acid and 15 ml of acetic anhydride containing 1.5 g of zinc dust was heated at reflux for four hours. The reaction mixture was cooled and concentrated to an oil. The oil was dissolved in 5N sodium hydroxide and the alkaline soluton was extracted with diethyl ether. The extracts were combined, dried and concentrated to dryness to afford 557 mg of 2-methylthiazolo[4,5-c]pyridine. M+Theory 150; Found 150.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([NH:17]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].C(NCC)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([NH2:17])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)[C@H](N)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.1 %

Procedure:
The compound (1.9846 g) obtained in Example 96-1 was dissolved in DMF (19 ml) and added with diethylamine (14 ml) and the whole was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.2212 g) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:28]=[CH:27][C:15]([C:16]([NH:18][NH:19]C(OC(C)(C)C)=O)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2>Cl.CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:27][CH:28]=1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Agent: Cl
Solvent: CO
Product: NNC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of tert-butyl 2-(4-(6-hydroxyquinolin-2-yl)benzoyl)hydrazinecarboxylate (240 mg, 0.633 mmol) and HCl/MeOH (20 mL, 4M) was stirred at 25° C. overnight. The resulting mixture was concentrated under reduced pressure to dryness to give the product (120 mg, yield 68%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CCO>[CH2:18]([N:20]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCNCC
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCN(CC)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), N-ethylethanamine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.3), 95 (4), 87 (6), 86 (bp), 75 (4), 58 (7).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:8][CH2:9][CH3:10]>C1COCC1.C(OCC)C>[OH:4]/[CH:2]=[C:8](\[CH2:9][CH3:10])/[C:7]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCC(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/O)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of potassium tert-butoxide (3.86 g, 34.4 mmol) in THF (20 mL) under nitrogen at room temperature was added a solution of ethyl butanoate (2.275 mL, 17.22 mmol) in diethyl ether (20.0 mL). The reaction mixture was stirred at rt for 3 hrs. The mixture was quenched and concentrated to give the title compound. LCMS: rt=2.34 min, [M+H+]=143
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C.[Cl:51]C1C=CC(S)=CC=1>>[Cl:51][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Sc1ccc(Cl)cc1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(Cl)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 4-chloro-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([CH3:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:24][CH2:23][C@H:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:21][CH:20]=1)[CH3:32]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: C[C@H](CN)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 83.1 %

Procedure:
Following General Procedure F, (S)-tert-butyl 2-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (100 mg, 0.20 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.2 mL, 1.2 mmol) to afford the desired product (35 mg, 46%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.62 (d, J=5.4 Hz, 1H), 7.56 (dd, J=7.9, 1.9 Hz, 1H), 7.48 (dd, J=7.8, 1.9 Hz, 1H), 7.36 (dd, J=7.9, 1.7 Hz, 1H), 7.34-7.29 (m, 2H), 6.12 (d, J=5.4 Hz, 1H), 3.29-3.15 (m, 3H), 1.49 (d, J=6.5 Hz, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC >99% (AUC), tR=8.74 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[N:3]=[N:2]1.S(Cl)([Cl:13])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([Cl:13])=[O:10])[N:3]=[N:2]1
Reactant: O=C(O)CCc1c[nH]nn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCc1c[nH]nn1
Reaction time: 2 h

Procedure:
To a solution of 3-(1H-1,2,3-triazol-4-yl)propanoic acid (Example 19, step 2) (100 mg, 0.709 mmol) in DCM (5 mL) at RT under nitrogen was added thionyl chloride (0.621 mL, 8.50 mmol) and the reaction mixture stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title product.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9](=[O:23])[C@@H:10]([NH2:22])[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])[CH3:12].[OH:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]#[C:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39](O)=[O:40])[S:36][C:35]=2[CH:42]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[C@H:10]([NH:22][C:39]([C:37]1[S:36][C:35]2[CH:42]=[C:31]([C:30]#[C:29][C@@H:27]3[CH2:28][C@H:26]3[CH2:25][OH:24])[CH:32]=[CH:33][C:34]=2[CH:38]=1)=[O:40])[C:9]([O:8][CH3:7])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1
Reactant: COC(=O)[C@@H](N)C(C)(C)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](NC(=O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To a stirring solution of (S)-methyl 2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate 6.3 (1.4 g, 4.3 mmol), 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxylic acid (7.2, 900 mg, 3.3 mmol) in ACN (10 mL) at 0° C. was added triethylamine (1.8 mL, 13 mmol), followed by the portionwise addition of a suspension of HATU (2.6 g, 6.9 mmol) in ACN (10 mL), and the reaction mixture was stirred at 0° C. for 105 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2×), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3), which was carried through to the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(Cl)c2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(Cl)c2)n1
Yield: 18.8 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-amine (1.42 g, 5.69 mmol) and phenyl chloroformate (2.2 mL, 17.1 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-ylcarbamate (394 mg, 1.07 mmol, 19%). 1H NMR (300 MHz, DMSO-d6) δ 10.17 (br s, 1H), 7.62-7.58 (m, 3H), 7.48-7.39 (m, 3H), 7.25 (t, 1H), 7.09 (br s, 2H), 6.40 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH:34][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:27][CH2:26]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ccc2nc(-c3ccccc3)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(-c2nc3ccc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)nn3n2)cc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
365 mg of 6-chloro-2-phenyl[1,2,4]triazolo[1,5-b]pyridazine and 0.513 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 8 ml of n-butanol; 0.54 ml of N-ethyldiisopropylamine was added, followed by heating and refluxing for 19 hours. Ice water and sodium hydrogen carbonate were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the resulting crystal was recrystallized from ethyl acetate to yield 308 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>O>[ClH:1].[O:15]([CH2:14][CH2:13][O:12][C:11]1[C:2]([N:3]2[CH2:4][CH2:9][NH:10][CH2:11][CH2:2]2)=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc2ccccc2nc1OCCOc1ccccc1
Solvent: O
Product: Cl
Product: c1ccc(OCCOc2nc3ccccc3nc2N2CCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)quinoxaline (0.65 g, 2.15 mmol): yield 0.44 g (58%) as the free base. A portion of the free base was converted to its hydrochloride salt: mp 123-126° C.; HRMS m/z calcd for C20H22N4O2 (M)+ 350.1743, found 350.1748. Anal. (C20H22N4O2 1.75 HCl. 0.5 H2O) C, H, N.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([O:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[S:32][C:28]=2[CH:27]=1)[CH3:24]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:36][S:33]([C:31]2[S:32][C:28]3[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[CH:38]=[CH:37][C:29]=3[N:30]=2)(=[O:34])=[O:35])=[O:21])=[CH:19][CH:18]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CCOc1ccc2nc(S(=O)(=O)NC(=O)C(O)=CC(=O)N(Cc3ccc(F)cc3)OC)sc2c1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 6-ethoxy-benzothiazole-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 1.47 (t, 3, J=7), 3.62 (s, 3), 4.10 (q, 2, J=7), 4.75 (s, 2), 6.45 (s, 1), 7.02 (m, 2), 7.33-7.18 (overlapping m, 4), 8.05 (m, 1). 13C NMR (125 MHz, CDCl3) δ: 14.69, 48.31, 63.18, 64.48, 92.87, 103.88, 115.69, 115.86, 118.94, 126.40, 130.24, 130.30, 131.00, 139.50, 146.56, 158.71, 159.16, 159.36, 159.59, 161.69, 163.65, 170.75.