Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[H][H]>[Pt].CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: [H][H]
Reactant: CSc1nc(C)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pt]
Solvent: CO
Product: CSc1nc(C)n(-c2ccc(N)cc2)n1
Yield: 68 %

Procedure:
A mixture of 2.5 parts of 5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and petroleumether. The product is filtered off and dried, yielding 1.5 parts (68%) 4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp. 130°-136° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26]Br>CC#N>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26][NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 2-amino-3-(4-nitrophenyl)propanoate 2 (6 g) in CH3CN (30 ml) is added, pulverized K2CO3 (11.095 g), 2,6-dichlorobenzyl bromide (6.42 g). The mixture is stirred at RT for 6 h then filtrated on decalite and evaporated. The residue is placed in CH2Cl2 (100 ml) and washed three time with water (100 ml) dried over MgSO4 and evaporated. The residue is purified by silica gel chromatography using AcOEt/hexane 10/90 as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][N:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(Cl)ncc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1cc2ccc(Cl)nc2cn1

Procedure:
A mixture of 1.08 g (6 mmoles) of 6-chloro-1,7-naphthyridin-2-one and 10 ml of POCl3 were warmed at reflux for one hour to give a clear solution. Upon cooling, a precipitate formed and the mixture was poured cautiously over ice. CH2Cl2 was added and the mixture was neutralized with solid K2CO3. The CH2Cl2 layer was separated and the aqueous layer washed twice with CHCl3. The combined organic layers were washed with water, dried over K2CO3 and evaporated to give a white solid. The solid was recrystallized from hexane/acetone to give 1.14 g (95% of theoretical) of the desired product as short, white needles having a melting point of 213°-216° C. Analysis calculated for C8H4Cl2N2 : C, 48.27; H, 2.03; N, 14.08. Found: C, 48.80; H, 2.09; N, 14.55.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-methoxyphenylboronic acid (152 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (79 mg, yield 99%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:14]([F:16])[F:15])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][C:19]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH:14]([F:15])[F:16])([CH3:13])[CH2:11][O:12][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[C:19]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:20]=2)=[CH:8][CH:9]=1
Reactant: CC(CO)(c1ccc(Cl)cc1)C(F)F
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(COCc1ccc(F)c(Oc2ccccc2)c1)(c1ccc(Cl)cc1)C(F)F

Procedure:
0.44 g (10 mmol) Sodium hydride dispersion (55%) was freed from oil by washing three times with dry toluene. It was suspended in 10 ml dry dimethoxyethane and then, with stirring, 1.77 g (8.0 mmol) 2-(4-chlorophenyl)-2-difluoromethylpropanol and 2.24 g (8.0 mmol) 4-fluoro-3-phenoxybenzyl bromide added. After stirring for five hours at room temperature a thin layer chromatogram (Merck DC silica gel 60F254 plate, using hexane/ethyl acetate 1:1 as eluant, Rf : 0.57) showed that no starting material was present.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
A mixture of 3,4-dichloroaniline (1.127 g, 6.95 mmol) and methyl 5-chloropyrazine-2-carboxylate (0.6 g, 3.48 mmol) in dioxane (32 mL) was heated at 100° C. for 7 days, then cooled to room temperature and concentrated. The residue was triturated with methanol and filtered. The brown filter cake was washed with methanol and dried to yield methyl 5-(3,4-dichlorophenylamino)pyrazine-2-carboxylate (0.53 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.44 (1H, s), 8.81 (1H, d, J=1.26 Hz), 8.30 (1H, d, J=1.51 Hz), 8.21 (1H, d, J=2.26 Hz), 7.46-7.73 (2H, m), 3.58 (2H, s). LCMS: R.T.=4.07; [M+H]+=298.12.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:12][S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:28](Br)[C:29]#[CH:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:30][C:29]#[CH:28])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCN(C(Cc1ccccc1)C(=O)OC)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
A DMF (8 mL) solution of 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (prepared according to example 2, step I) (200 mg) was cooled to 0° C. and then propargyl bromide (80%, 0.07 mL, 0.61 mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (185 mg, 85%) as a solid. 1H NMR (CDCl3, 400 MHz): δ7.20-7.17 (m, 3H), 7.10-7.08 (m, 2H), 6.56 (s, 1H), 4.42-4.29 (m, 3H), 3.86 (s, 3H), 3.56 (s, 3H), 3.32 (dd, 1H), 3.26 (dd, 1H), 2.66, 2.35 (2s, 6H), 2.21 (t, 1H), 2.08(s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][S:15]([O-:17])=[O:16].[Na+]>CS(C)=O.O>[CH3:14][S:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])(=[O:17])=[O:16]
Reactant: CS(=O)[O-]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C#N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (400 mg, 2.12 mmol) was suspended together with sodium methanesulfinate (216 mg, 2.12 mmol) in DMSO (2 ml) and stirred at 80° C. for 22 hours. The reaction was then cooled, diluted with 25 ml H2O and filtered. Filtered solids were evaporated from toluene to give 536 mg of the title substance (quant).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[S:8][C:9]([C:12]2[CH2:19][S:18][CH:17]3[N:14]([C:15](=[O:28])[CH:16]3[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:10][N:11]=1.C(N(CC)CC)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH:32]([O:31][C:29]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[C:9]1[S:8][C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])=[N:11][CH:10]=1)[CH:16]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:15]2=[O:28])=[O:30])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)CCl)s3)CSC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Chloroacetyl chloride (12.37 g) is added to a solution of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (60 g) in tetrahydrofuran (350 cc) cooled to 0° C., and triethylamine (16.3 cc) is then added in 6 minutes. After 1 hour at 0° C., the reaction mixture is diluted with a half-saturated sodium bicarbonate solution (800 cc) and extracted with ethyl acetate (3×200 cc). The combined organic phases are washed with a saturated sodium chloride solution (250 cc) and dried, after which they are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give an orange froth (78 g) which is recrystallised from acetonitrile (300 cc) to give cream crystals (37.4 g) of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-chloroacetamido-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>CS(C)=O>[C:8]1([C:6]2[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: CC(=O)NCCNc1cc(Cl)nc(-c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(N2CCNCC2)nc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 49.3 %

Procedure:
N-{2-[(6-Chloro-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (27) (1.5 g) and piperazine (4.44 g) were dissolved in DMSO. To this was added sodium hydrogencarbonate (2.16 g) and the mixture heated to 110° C. for 3 hrs. The reaction mixture was cooled to ambient temperature then partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was washed with ethyl acetate (2×200 ml) and the combined organics washed with brine (100 ml), dried over magnesium sulfate then filtered. Removal of the solvent in vacuo furnished the title compound (0.865 g).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:13](Cl)(=O)C>CO>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C=Cc1ccc(C)cc1

Procedure:
A solution of 6.0 g (37.0 mmol) of 4-methylcinnamic acid in 120 ml of anhydrous MeOH was treated with 6 ml of acetyl chloride and stirred at reflux for 18 hours. Evaporation of the MeOH gave the title ester as a white solid, mp 53.5°-57.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.C(N(CC)CC)C>ClCCl.[Cu]>[N+:8]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([O:12][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:5][C:6]=1[CH3:11])([O-:10])=[O:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (1.67 g), 3-trifluoromethylbenzene boronic acid (3.8 g), copper (1 acetate (1.82 g) and triethylamine (2.02 g) in dichloromethane (50 ml) was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and purified by silica gel chromatography eluting with light petroleum (b.p. 60-80° C.)/ethyl acetate (19:1) to give the title product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][C:26]=1[O:27][CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[N:25][C:26]([O:27][CH3:28])=[C:21]([F:20])[CH:22]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1ncc(B(O)O)cc1F
Product: COc1ncc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)cc1F
Yield: 59.5 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (175 mg, 0.48 mmol) and 5-fluoro-6-methoxypyridine-3-boronic acid (162 mg, 0.96 mmol) were reacted. After purification the title compound (106 mg, 61% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bm, 1H), 8.15 (m, 1H), 7.92 (a dd, J=5.2, 9.0 Hz, 1H), 7.65 (a d, J=10.7 Hz, 1H), 7.56 (a t, J=9.0 Hz, 1H), 4.10(s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=372, HPLC 2.59 min.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:31]=1)([CH3:3])[CH3:2]>C(O)(=O)C.CO.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([S:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[C:14]([NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:31][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1ccc2c(Nc3cc(N)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A slurry of the compound prepared in Example 95A (0.7 g, 1.73 mmol) and 10% Pd/C (100 mg) in acetic acid (10 ml) and methanol (10 mL) was placed under a hydrogen balloon atmosphere with stirring for 20 hours at room temperature. The slurry was filtered and the solvent removed under vacuum to provide the title compound as an acetic acid salt (540 mg, 63%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=7.0 Hz, 6H), 1.91 (s, 6H), 3.27 (m, 1H), 6.55 (d, J=8.8 Hz, 2H), 6.62 (m, 1H), 6.69 (m, 1H), 6.95 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 8.75 (s, 1H), 8.99 (m, 1H), 9.52 (s, 1H), 11.57 (bs, 1H); MS (ESI+) m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][NH:30][C:31]([NH:33][OH:34])=[NH:32].[ClH:35]>C(O)C>[ClH:35].[OH:34][NH:33][C:31]([NH:30][N:29]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)=[NH:32]
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccsc1)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (243 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (393 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. To the residue was added ether (3 ml), and the mixture was stirred at 90° C. (bath temperature) for 2 hours and cooled to give crystals, which were filtered, washed with ethanol and dried to give 5-(1-hydroxyguanidin-3-yl)imino-4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 103) (233 mg) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(Br)c(N)n1
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-diaminopyrimidine (1.0 g, 9.1 mmol) in chloroform (30 mL) was added N-bromosuccinimide (1.62 g, 9.08 mmol). The solution was stirred in the dark for 12 hours, at which time it was added to CH2Cl2 (150 mL) and 1N NaOH (50 mL). The solid that formed was filtered, rinsed with water and concentrated in vacuo, yielding 1.4 g (74%) of 5-bromopyrimidine-2,4-diamine: LCMS (m/z): 189/191 (MH+); 1H NMR (DMSO-d6): δ 7.78 (s, 1H), 6.58 (bs, 2H), 6.08 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][C@H:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C@@H:18]([C:21]([O:23]CC)=[O:22])[CH2:19][O:20][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][C@H:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C@@H:18]([C:21]([OH:23])=[O:22])[CH2:19][O:20][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)ccc2O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1ccc2c(c1)OC[C@H](C(=O)O)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 67.9 %

Procedure:
To a solution of ethyl 6-(2-(R)-((2-(R)-(3-chlorophenyl )-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylate (650 mg) in ethanol (2 ml) were added water (20 ml) and concentrated hydrochloric acid (0.32 ml). This solution was stirred under reflux-heating for 5 hours while removing ethanol with Dean-Stark apparatus. After the solution was concentrated under reduced pressure, acetonitrile/water (1/1) (11 ml) was added to the residue, which was then dissolved under heating. The solution was neutralized with a 5% aqueous solution of sodium hydrogencarbonate. Acetonitrile (20 ml) was added, and the crystals precipitated were dissolved under heating. The resulting solution was filtered under heating and then cooled, and the resulting crystals were filtered to give 6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino )-propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylic acid (412 mg). The HPLC-2 analysis of the optical isomer showed 96.5% purity (R/S=96.5/3.5, the purity of the material optical isomer used=90.5%).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])#[C-:8].Br[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>O1CCCC1>[N+:7]([C:9]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])#[C-:8]
Reactant: BrCc1cccs1
Reactant: [C-]#[N+]C(CC)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [C-]#[N+]C(CC)(Cc1cccs1)C(=O)OC
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A suspension of potassium tert.-butoxide (5.5 g) in tetrahydrofuran (50 ml) is cooled to -30° C., and a solution of methyl 2-isocyanobutyrate (5.5 g) in tetrahydrofuran (10 ml) is added dropwise to the suspension at -30° C. The mixture is stirred at the same temperature for 30 minutes and a solution of 2-bromomethylthiophene (6.9 g) in tetrahydrafuran (10 ml) is added dropwise to the mixture. The mixture is stirred at room temperature for 4 hours, adjusted to pH 7 with acetic acid and then concentrated under reduced pressure to remove solvent. The residue is dissolved in a mixture of ethyl acetate and water and the organic layer is collected therefrom. The organic layer is washed with an aqueous saturated sodium chloride solution, dried and concentrated to remove solvent. The residue is distilled under reduced pressure, whereby methyl 2-isocyano-2-(2-thienylmethyl)butyrate (7.7 g) is obtained as pale yellow oil.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
A mixture of 5.2 g of ethyl 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetate, 20 ml of ethanol, 0.96 g of sodium hydroxide and 5 ml of water is stirred at room temperature for 10 minutes. The ethanol is distilled off under reduced pressure, and the residue is dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off, washed with water, and recrystallized from ethanol to give 2.3 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetic acid as colorless crystals melting at 217°-221°C with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][CH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:20]>C(Cl)Cl.N1C=CC=CC=1>[F:17][CH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:20]
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cnc2C1

Procedure:
Following the same procedure as described in example 31.5, a portion of crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (95 mg, 0.43 mmol) in CH2Cl2/pyridine 9/1 (10 ml) was treated with 4-((S)-2-fluoro-1-methyl-ethyl)benzenesulfonyl chloride (132 mg, 0.55 mmol). Purification by flash column chromatography (CH2Cl2:MeOH, 97:3) gave the title compound (100 mg, 55% for step 31.4 and this step) as a gum.