Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH:17]1([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][NH2:30])[CH:23]=2)[CH2:19][CH2:18]1.C(O[CH:35]=[C:36]([C:39]#[N:40])[C:37]#[N:38])C>CCO>[NH2:40][C:39]1[N:29]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=2[CH3:28])[C:21]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:31])[N:30]=[CH:35][C:36]=1[C:37]#[N:38]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C#N)c1N
Temperature: 65 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
DIPEA (3.4 g, 26.5 mmol) was added to the solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (8.45 g, 26.5 mmol) and 2-ethoxymethylene malononitrile (3.2 g, 26.5 mmol) in EtOH (100 mL) and stirred at 65° C. for 3 h. The solvent was removed the residue was suspended in EtOAc (−100 mL), and water was added to this suspension. The solid product was filtered. The filtrate was washed by water, brine, dried over Na2SO4, concentrated, and purified by column chromatography on silica gel eluted with EtOAc. The product, combined from filtration and chromatography, was obtained as a beige solid (7.1 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1SC.[O-][Mn](=O)(=O)=O.[K+].[O-:22][S:23]([O-:26])(=S)=O.[Na+].[Na+].[C:29](O)(=O)C>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[S:23]([CH3:29])(=[O:26])=[O:22]
Reactant: CC(=O)O
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)CCc1ccc(F)cc1SC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCc1ccc(F)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 3-(4-fluoro-2-methylsulfanyl-phenyl)-propionic acid methyl ester (1 g, 4.3 mmol) in acetic acid (10 ml) was added dropwise the solution of KMnO4 (1.3 g, 8.2 mmol) in 10 ml H2O. The mixture was stirred at room temperature for 3 hours, and then poured into saturated Na2S2O3 solution and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over Na2SO4. The product was purified by column chromatography to give the titled compound (1.2 g, yield 98%)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([CH3:28])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OC(=O)C)C>[CH3:28][C:19]1[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:26]([CH3:27])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(C)c(O)cc1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)cc1C
Temperature: 0 °C
Yield: 90.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.27 g) was added to an ice-cooled mixture of methyl 4-hydroxy-2,5-dimethylbenzoate (0.144 g) and pyridine (0.095 g) in methylene chloride (10 mL) with stirring. The mixture was stirred at room temperature for 30 min, and poured into a mixture of ethylacetate and 2 mol/L hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10/1) to afford the title compound (0.226 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1.CC(C)=[O:18].O.S([O-])(O[O-])(=O)=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([S:8]([CH2:9][CH2:10][C:11]([CH3:12])([OH:13])[CH3:14])=[O:18])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1
Reactant: CC(C)(O)CCSc1cc(Br)cnc1N
Reactant: CC(C)=O
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(O)CCS(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 4-[(2-amino-5-bromopyridin-3-yl)thio]-2-methylbutan-2-ol (83 mg, 0.28 mmol) in a mixture of methanol (750 μL), acetone (750 μL) and water (450 μL) was added potassium peroxymonosulfate (131 mg, 0.21 mmol) and the reaction mixture was stirred for 90 minutes at 0° C. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (35% to 80% ethyl acetate in hexane) gave 4-[(2-amino-5-bromopyridin-3-yl)sulfinyl]-2-methylbutan-2-ol (52 mg, 60%); MS (EI) for C10H15BrN2O2S: 308 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([Cl:22])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:6])=[O:4].[CH2:28]([N:30]([CH2:33]C)[CH2:31]C)[CH3:29].BrCC(Cl)=[O:38].CNC>ClCCl>[Cl:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:23]([Cl:26])=[CH:24][CH:25]=[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:29](=[O:38])[CH2:28][N:30]([CH3:33])[CH3:31])[CH3:6])[C:8]=3[Cl:27])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: CCN(CC)CC
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Cl
Reactant: O=C(Cl)CBr
Agent: CNC
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN(C)C)c3Cl)cccn2c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-chloro-2-methylimidazo[1,2-a]pyridine (200 mg), triethylamine (0.1 ml) and dichloromethane (2 ml) was added bromoacetyl chloride (0.042 ml) in a dry ice-acetone bath. After 20 minutes, to the mixture was added 50% aqueous solution of dimethylamine (0.42 ml). The mixture was stirred for 1 hour at ambient temperature. The reaction mixture was washed with aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography (dichloromethane:methanol=20:1, V/V) to yield colorless crystals (191 mg) of 3-chloro-8-[2,6-dichloro-3-[N-[N-(N,N-dimethylglycyl)glycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=1.N[C:27]1[CH:28]=C2C(=C[CH:35]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:1](=[O:3])[CH2:2][CH:27]([CH3:28])[CH3:35])=[CH:24][CH:25]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNCc1ccc(F)cc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Product: CC(C)CC(=O)N(CCCCNC(=O)OC(C)(C)C)Cc1ccc(F)cc1

Procedure:
The title compound was prepared as described in Example 278, substituting 3-methylbutanoyl chloride for acetyl chloride and tert-butyl 4-(4-fluorobenzylamino)butylcarbamate for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Li+].CC([N-]C(C)C)C.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1([CH2:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH3:29])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid methyl ester (10.1 g 41.8 mmol) in 140 ml of dry THF at −78° C. was added LDA (59 ml of a 1.0 M solution in THF, 59 mmol) over 15 min. The resulting orange solution was stirred at −78° C. for 1 hr and then treated dropwise with 2-methylbenzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc. The combined organic extracts were washed with brine, and concentrated in vacuo to an orange gum. Chromatography (SiO2, eluting with 20 to 30% EtOAc in hexanes) and evaporation of solvent in vacuo, afforded the product as a white solid.
Reaction SMILES: [CH3:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3].C1CCCCC1.[Br:17][C:18]1[CH:19]=[C:20]([C:27]([CH3:36])([CH3:35])[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1.C1COCC1>>[Br:17][C:18]1[CH:19]=[C:20]([C:27]([CH3:36])([CH3:35])[CH2:28][C@:29]([CH2:1][S@:2]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[O:3])([OH:34])[C:30]([F:31])([F:32])[F:33])[C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1.[Br:17][C:18]1[CH:19]=[C:20]([C:27]([CH3:36])([CH3:35])[CH2:28][C@@:29]([CH2:1][S@:2]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[O:3])([OH:34])[C:30]([F:31])([F:32])[F:33])[C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Br)cc2c1OCC2
Reactant: Cc1ccc([S@@](C)=O)cc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc([S@](=O)C[C@@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Product: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 44 %
Yield: 21 %

Procedure:
To a suspension of (R)-(+)-methyl p-tolylsulfoxide (8.80 g, 57.0 mmol) in 100 mL of anhydrous THF at −78° C. was added LDA mono(tetrahydrofuran) 1.5 M solution in cyclohexane (38.0 mL, 57.0 mmol) over 20 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (18.2 g, 51.9 mmol) dissolved in 40 mL of THF was then added by cannula over 15 minutes. After 1 hour at −78° C., the reaction mixture was quenched with 300 mL of water and extracted with three 300 mL portions of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, then brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 10%-25% EtOAc-hexanes) afforded sequentially (S)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (11.5 g, 44%) and (R)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (5.47 g, 21%). The diastereomeric excess was determined to be >99% for both isomers (HPLC peak area).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].C([O-])(=O)C.[Na+].[NH2:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[N:21]=[CH:20][CH:19]=1.C([N:34](CC)CC)C.Cl>O.C(O)(C)C>[NH2:17][C:18]1[N:22]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[N:21]=[CH:20][C:19]=1[N:34]=[N:9][C:6]1[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=1
Reactant: Nc1ccnn1-c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1c(N=Nc2ccc(S(=O)(=O)O)cc2)cnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
7.79 g (45 mmol) of sulfanilic acid was diazotized, 7.38 g (90 mmol) of sodium acetate was added, and the reaction mixture was allowed to agitate at 0 to 5° C. for a about 15 more minutes. Then, 9.2 g (45 mmol) of 5-amino-1-(4-nitrophenyl)-1H-pyrazole from Step 11.1 (dissolved in 20 mL of dimethyl-formamide) was added dropwise over a period of 30 minutes. During the addition, the reaction mixture assumed a yellow-brown color, and an increasingly thick suspension formed. The suspension was diluted with about 50 mL of cold water, and the reaction mixture was allowed to stand overnight at room temperature. The precipitate was then removed by suction filtration and washed with a small amount of cold water. The moist, crude product thus obtained (about 14 g) was then suspended in 100 mL of isopropanol, 10 mL (72 mmol) of triethylamine was added, and the mixture was heated at reflux. After about 30 minutes, the reaction mixture was cooled slightly, and to it was added dropwise 14.5 mL (112 mmol) of a 25% hydrochloric acid solution which produced a thick, ocher-yellow suspension. The suspension was cooled to 0 to 5° C. and the precipitate was removed by suction filtration and washed with a small amount of ethyl acetate. The residue was dried at 60° C. under vacuum. This gave 12.18 g (31.4 mmol), 69.7% of the theoretical) of 5-amino-1-(4-nitrophenyl)-4-(4-sulfophenylazo)pyrazole; melting point: 135-136° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[C:16]([N:20]1[C:25](=[O:26])[C:24]([Cl:27])=[C:23]([SH:28])[CH:22]=[N:21]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([N:20]1[C:25](=[O:26])[C:24]([Cl:27])=[C:23]([S:28][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:3]=[C:2]([Cl:1])[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:6]=2)[CH:22]=[N:21]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: FC(F)(F)C(Cl)=Cc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(C=C(Cl)C(F)(F)F)cc2)c(Cl)c1=O

Procedure:
1.2 g of 4-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzyl bromide and 0.8 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.7 g of potassium carbonate in 10 cc of dimethylformamide.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([N:29]([C:37](=[O:39])[CH3:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:21][C@@H:20]2[CH3:40])=[O:18])=[CH:13][CH:12]=1)C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:37]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5][C:4]([OH:41])=[O:3])=[CH:12][CH:13]=2)=[O:18])[C@@H:20]([CH3:40])[CH2:21]1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)CNCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic ethyl ester was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to form a white precipitate. The solid was filtered to give {[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic acid (0.003 g, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].[H-].[Na+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:23][C:22]1[C:17]([C:15]([O:14][CH3:13])=[O:16])=[N:18][CH:19]=[CH:20][N:21]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COC(=O)c1nccnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nccnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.5 %

Procedure:
To a stirred solution of 2,3-dichlorobenzenesulphonyl chloride (0.246 g) and methyl-3-aminopyrazine-2-carboxylate (0.153 g) in 1,2-dimethoxymethane (3 mL) was added portionwise sodium hydride (0.1 g of a 60% dispersion in oil) over 1 hour. The mixture was stirred at room temperature for 20 h, was poured into water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with dichloromethane to afford the titled compound (0.085 g) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([NH2:17])=[CH:14]3)=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(=O)[C:20](C)=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:38]1[CH2:42][O:41][CH2:40]C1>CCOCC>[CH3:20][O:21][CH:42]([O:41][CH3:40])[CH2:38][NH:17][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][N:8]([CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:9]=2)[CH:14]=1
Reactant: Nc1ccc2nn(CCN3CCCC3)cc2c1
Reactant: C1CCOC1
Reactant: CC(=O)C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Product: COC(CNc1ccc2nn(CCN3CCCC3)cc2c1)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(2-pyrrolidin-1-ylethyl)-2H-indazol-5-amine (1.14 g, 0.497 mmol) in 62 mL of dry THF was added 2.04 mL of dimethyl glyoxal in ether (45% glyoxal by weight). A slurry of NaBH(OAc)3 (1.66 g, 7.83 mmol) in THF (10 mL) was slowly added via addition funnel over 60 minutes, and the mixture stirred at room temperature for 12 hours, after which an additional equivalent of NaBH(OAc)3 was added. After an additional 12 hours, the mixture was quenched with saturated NaHCO3, filtered, and the solvents removed under reduced pressure. The residue was purified via column chromatography eluting with 5–15% Et3N in EtOAc to provide 650 mg (2.04 mmol) of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.55–1.73 (m, 4 H) 2.39–2.49 (m, 4 H) 2.85–2.96 (m, 2 H) 3.05–3.20 (m, 2 H) 3.28–3.33 (m, 6 H) 4.31–4.45 (m, 2 H) 4.48–4.61 (m, 1 H) 5.14–5.32 (m, 1 H) 6.37–6.50 (m, 1 H) 6.74–6.91 (m, 1 H) 7.21–7.42 (m, 1 H) 7.83–8.02 (m, 1 H); MS (ESI) m/z 319 [M+H]+.
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=[C:12]([Cl:23])[N:11]=1)(=O)=O.ClC1N=C(N2CCOC[C@H]2C)C=C(CCl)N=1.[I-].[Na+]>CC#N.CCOC(C)=O>[Cl:23][C:12]1[N:13]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[CH:15]=[C:10]([CH2:9][S:2][CH3:1])[N:11]=1
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: C[S-]
Agent: C[C@@H]1COCCN1c1cc(CCl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Reaction time: 16 h
Yield: 91 %

Procedure:
In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at RT (temperature dropped from 20° C. to 18° C. over the addition and then in the next 5 minutes rose to 30° C.). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.07 (3H, s), 3.11-3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92-4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m/z: (ES+) MH+, 274.36.
Reaction SMILES: [ClH:1].Cl.CC1C=CC(S(O[CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=O)=O)=CC=1.[C:27](O)(=O)[CH3:28]>>[CH3:27][C:28]1[NH:25][C:22]2[C:21]([N:26]=1)=[C:19]1[C:18](=[CH:24][CH:23]=2)[O:17][CH2:16][CH:15]([CH2:14][Cl:1])[O:20]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: CC(=O)O
Reactant: Cl
Product: Cc1nc2c3c(ccc2[nH]1)OCC(CCl)O3

Procedure:
A solution of 2.3 g (5.4 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of acetic acid was refluxed under nitrogen for 24 hours. The solvent was removed in vacuum and the residue dissolved in 400 mL of ethyl acetate, washed with 300 mL of water and with 300 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a crude foam in vacuum. The crude product was column chromatographed on silica gel with 2% methanol in chloroform and the product fractions combined and concentrated in vacuum to give 1.1 g of the (R)-enantiomer of the title compound as a yellow oil. MS (+APCl) m/z 239 (M+H)+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:19]=[CH:18][C:13]3[N:14]([CH3:17])[N:15]=[N:16][C:12]=3[CH:11]=2)[C:7]#[C:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[N:1]1([CH:6]([C:10]2[CH:19]=[CH:18][C:13]3[N:14]([CH3:17])[N:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[CH:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC#CC(c1ccc2c(c1)nnn2C)n1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CC=CC(c1ccc2c(c1)nnn2C)n1ccnc1
Yield: 19.7 %

Procedure:
A mixture of 7 parts of 5-[1-(1H-imidazol-1-yl)-2-butynyl]-1-methyl-1H-benzotriazole, 0.1 parts of quinoline, 54 parts of ethyl acetate and 32 parts of ethanol was hydrogenated at 931.00 Pa and at room temperature with 0.3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of dichloromethane and 1,1'-oxybisethane. The product was filtered off and dried, yielding 1.4 parts (19.7%) of 5-[1-(1H-imidazol-1-yl)-2-butenyl]-1-methyl-1H-benzotriazole; mp. 104° C. (compound 240).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:34])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:23]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.Cl.[OH-].[K+]>C(O)(=O)C.O>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=[CH:17][C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:34])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)cc3nc21
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A solution of (RS)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4 -dihydrobenzo[b][1,8]naphthyridine (1.07 g) in acetic acid (10 cc) and 17.5% strength aqueous hydrochloric acid solution (10 cc) is heated to a temperature in the region of 100° C. for 40 minutes. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at approximately 60° C. The dry extract is taken up with ethanol (10 cc), drained and washed with ethanol (2×10 cc) and ethyl ether (2×10 cc). The solid obtained is suspended in water (30 cc) and heated to a temperature in the region of 95° C. After the addition of 2 N aqueous potassium hydroxide (1.35 cc) and stirring for 30 minutes, the solid is drained at approximately 95° C. and washed with water (3×20 cc) at approximately 80° C., ethanol (3×15 cc) at approximately 60° C. and ethyl ether (3×20 cc). After 1 recrystallization in a mixture of dimethylformamide (12 cc) and ethanol (6 cc), (RS)-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.7 g) is obtained in the form of a yellow solid, m.p. 265° C.