Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[C:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
4-Bromobenzonitrile (30 g), 3-methyl-1-butyne-3-ol (13.4 g), triphenylphosphine (0.7 g) and bis(triphenylphosphine)palladium(II) chloride (0.3 g) were dissolved in triethylamine (140 ml) under nitrogen atmosphere, and then copper(I) iodide (0.1 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off therefrom, followed by extracting with chloroform. The resultant was washed twice with 10% hydrochloric acid, and further with water twice, and then chloroform was distilled off therefrom. The residue was distilled under reduced pressure (140° to 160° C./5 mmHg) to give 3-methyl-1-(4'-cyanophenyl)-1-butyne-3-ol (23.5 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11].[CH3:12][O:13]C(Cl)Cl.Cl>ClCCl>[Br:5][C:6]1[S:7][C:8]([CH:12]=[O:13])=[CH:9][C:10]=1[CH3:11]
Reactant: COC(Cl)Cl
Reactant: Cc1ccsc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Aluminum chloride (14.6 g) was added portionwise to 2-bromo-3-methylthiophene (8.85 g) and dichloromethyl methyl ether (6.27 g) in dichloromethane (100 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and poured into ice water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-4-methyl-2-thiophenecarbaldehyde (8.0 g). 5-Bromo-4-methyl-2-thiophenecarbaldehyde (6.18 g) was dissolved in acetonitrile (100 ml), and sodium dihydrogen phosphate (1.3 g) in water (20 ml) and 30% aqueous hydrogen peroxide (3.8 ml) were added. Further sodium chlorite (4.07 g) in water (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid (6.01 g) as crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=3)[CH:16]=[C:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][C:17](=[CH:16][C:15]2[CH:14]=[C:13]([CH:32]=[CH:31][CH:30]=2)[O:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCCC3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(pyrrolidin-1-yl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.335 g, 0.769 mmol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.88 mL, 11.49 mmol). The resulting mixture was stirred for 1 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.224 g, 86.8%). 1H NMR (500 MHz, DMSO-d6): δ 7.59 (s, 1H), 7.23 (m, 1H), 6.95 (m, 1H), 6.89 (d, J=7.5 Hz, 1H), 6.82 (m, 3H), 6.25 (s, 1H), 3.27 (m, 4H), 2.98 (m, 2H), 2.86 (m, 2H), 2.49 (m, 2H), 2.34 (m, 2H), 2.02 (m, 4H); m/z (336.2, MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[N:7][CH:6]=1)=[O:4]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:9][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[N:7][CH:6]=1
Reactant: CNC(=O)C1=CN=C(N2CCN(C)CC2)CC1c1ccccc1C
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 65 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A solution of 1.5 g (4.6 mmol) (RS)-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-4,5-dihydro-pyridine-3-carboxylic acid methylamide in 15 ml CHCl3 was treated with 2.3 g (23.0 mmol) MnO2. The black suspension was heated to 65° C., stirred for 3 h at 65° C. and treated again with 2.3 g (23.0 mmol) MnO2, stirred for 3 h and added an other 0.9 g (9.2 mmol) MnO2. The reaction mixture was stirred for 10.5 h at 65° C., treated with 0.9 g (9.2 mmol) MnO2, stirred for 1 h at 65° C. and cooled to r.t. After filtration of the MnO2 the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CHCl3: MeOH=4:1) to yield 1.24 g (83.2%) product as beige foam.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15][CH3:16])[N:12]=1.ClC1C=CC=C(C(OO)=[O:56])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:41]=1)[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15]([CH3:16])=[O:56])[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCSC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCS(C)=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methylsulfanyl-ethyl)-2H-tetrazol-5-yl]-amine (270 mg) is dissolved in chloroform (3 ml), and thereto is added m-chloroperbenzoic acid (168 mg), and the mixture is stirred at room temperature for 3 hours. To the reaction solution is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=40:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfinyl-ethyl)-2H-tetrazol-5-yl]-amine (157 mg). MS (m/z): 708 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)[CH2:16]1)(C)(C)C>ClCCl>[NH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC(N)C2)nc1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Add trifluoroacetic acid (30 mL) to [1-(5-cyanopyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (7.95 g, 27.6 mmol) in dichloromethane (200 mL) and stir for 2 h. Concentrate, add toluene (100 mL) and reconcentrate to give a residue. Partition the residue between dichloromethane and an saturated aqueous solution of sodium bicarbonate and separate the layers. Extract the aqueous layer 5 times with 15:85 isopropyl alcohol:chloroform, combine the organic layers, dry (sodium sulfate), filter, and concentrate to give the title compound as a yellow oil (5.25 g). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H, J=2.5 Hz), 7.53-7.50 (m, 1H), 6.29 (d, 1H, J=8.8 Hz), 3.80-3.10 (m, 5H), 2.25-2.15 (m, 1H), 1.90-1.75 (m, 3H); MS (ES): m/z=189 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: Cc1c(F)c(Cl)nc(Cl)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(Cl)nc(Cl)c1C(=O)Cl
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A slurry of 30.8 g (0.147 moles) of 2,6-dichloro-4-methyl-5-fluoronicotinic acid in 200 mL of dichloromethane, containing a catalytic amount of dimethyl formamide, was treated dropwise over a 1-hour period with 19.2 mL (0.22 moles) oxalyl chloride. After 1 hour, the homogenous solution was evaporated in vacuo, diluted with an equal volume of dichloromethane, and evaporated in vacuo to yield 31.6 g of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1cc(Br)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1sc(C(=O)O)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1 g, 3.5 mmol) in dioxane/H2O (5:1, 18 mL) was added K2CO3 (1.9 g, 13.98 mmol), tetrakistriphenylphosphine Pd(0) (201 mg, 0.175 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (678 mg, 3.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜1 g, quant.): LC-MS (ES) m/z=288 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[N:14]=[C:15]=[O:16]>CN(C=O)C.C1(C)C=CC=CC=1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[NH:14][C:15]([N:8]=[C:7]1[NH:6][C:4](=[O:5])[CH2:3][N:2]1[CH3:1])=[O:16]
Reactant: O=C=Nc1ccco1
Reactant: CN1CC(=O)N=C1N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccco1
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a stirred mixture of 6.9 g (60 mM) of creatinine in 100 ml of anhydrous DMF was added a solution of 6.5 g (60 mM) of 2-furanyl isocyanate in 75 ml of toluene. After stirring the mixture 1 hr. at 25° C. and then 1 hr. at 55° C., the solvents were removed in vacuo and the residue taken up in ethyl acetate and washed with water. The solvent was removed and the residue chromatographed over silica gel using ether-ethyl acetate (4:1) as the eluant. The fractions containing the product were combined and concentrated to leave 1.1 g of the above urea as an off-white solid, m.p. 173°-175° C. (dec.)
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:32])[C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:11][CH:10]=[CH:9][C:8]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)C>CO>[CH2:21]1[O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[C:7]=3[C:6]([OH:32])=[O:5])=[CH:15][C:16]=2[O:22]1
Reactant: CCOC(=O)c1c(Oc2cccc(OC)c2)cccc1Oc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Oc2cccc(Oc3ccc4c(c3)OCO4)c2C(=O)O)c1
Yield: 67.3 %

Procedure:
KOH (371 mg, 5.7 mmol) that was dissolved in methanol was added to a solution of ethyl-2-(3-methoxyphenoxy)-6-[3,4-(methylenedioxy)phenoxy]benzoate (200 mg, 0.57 mmol) in methanol (5 ml). The mixture was heated under reflux for approximately 20 hours at which time TLL had indicated the formation of a polar material. The solvent was evaporated and the remaining residue was diluted with water (7 ml, pH≈7.5) and extracted with EtOAc (2×10 ml). The aqueous fraction was then acidified to pH˜2.5 using concentrated HCl and then extracted with ethyl acetate (2×10 ml). Evaporation of solvents gave an off-white solid which was recrystallized from methanol/H2O to give 146 mg (67%) of a white solid, mp 146-148° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Yield: 50.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (80 mg, 210 μmol, 1 eq.) and morpholine (54.8 μl, 629 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (48 mg, 50.8%) as white solid. mp: 267-269° C., MS: m/z=451.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13](Cl)(Cl)=[S:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[N:4]=[C:13]=[S:14]
Reactant: Cc1c(N)ccc([N+](=O)[O-])c1C
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(N=C=S)ccc([N+](=O)[O-])c1C
Yield: 48 %

Procedure:
To a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 equiv.) in toluene (50 mL) was added thiophosgene (0.3 mL, 1.3 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (25% CH2Cl2/hex) to afford 2,3-dimethyl-4-nitrophenyl isothiocyanate as a light yellow solid (0.30 g, 48%): 1H NMR (CDCl3) δ2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J=8.4 Hz, 1H); CI-MS m/z 200 ((M+H)+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(F)cc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccnc(-c2nc(=O)c3ccc(F)cc3s2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
tert-Butyl 3-[2-(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.92 g, 2.3 mmol) was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether-methanol to give the titled compound (0.56 g, 71%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1>CO.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCc2cccnc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(OCc2cccnc2)c1
Reaction time: 12 h
Yield: 97 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 4-nitro-3-(pyridin-3-ylmethoxy)-benzoic acid methyl ester (288 mg, 1.0 mmol) in methanol (2 mL) and saturated aqueous ammonium chloride (1 mL) was added zinc dust (131 mg, 2.0 mmol). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to yield the desired product as a yellow solid (97% yield). 1H-NMR (400 MHz, CDCl3) δ8.78 (s, 1H), 8.61 (d, 1H, 7.79 (d, 1H), 7.59 (m, 2H), 7.39 (m, 1H), 6.71 (d, 1H), 5.18 (s, 2H), 4.28 (br s, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(CBr)c1
Temperature: 90 °C
Reaction time: 96 h
Yield: 104.9 %

Procedure:
To a solution of 2-methyl-4-nitrobenzotrifluoride (5.05 g, 24.6 mmol, synthesised according to Journal of medicinal chemistry (1996), 39(23), 4608-4621) in carbon tetrachloride (50 ml) was added NBS (4.77 g, 26.8 mmol, Aldrich) and then benzoyl peroxide (0.110 g, 0.454 mmol, Acros). The mixture was heated to 90° C. overnight, cooled to ambient temperature and the allowed to stand for 4 days. The suspension was filtered and the residue washed with carbon tetrachloride (10 ml). The solvent was removed in vacuo to give 2-(bromomethyl)-4-nitro-1-(trifluoromethyl)benzene as a mobile orange oil (7.33 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[O:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])c(C=O)c(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)c(C=O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
6-Nitro-2,3,4-trimethoxybenzaldehyde (4.0 g) was dissolved in methanol (40 mL) and THF (20 mL), 10% palladium on carbon was added to the solution, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4 to 1:3) to obtain 6-amino-2,3,4-trimethoxybenzaldehyde (3.1 g). This product was immediately dissolved in dichloromethane (35 mL), and triethylamine (4.2 mL) was added thereto. Chloroacetyl chloride (1.78 mL) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with chloroform, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the extract under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4 to 1:3) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([N:12]([CH3:38])[CH2:13][CH2:14][N:15]([CH3:37])[C:16]([C:18]1[O:19][C:20]2[C:26](F)=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([CH3:34])=[C:23]([C:35]#[N:36])[C:21]=2[N:22]=1)=[O:17])(=[O:11])[CH3:10].C(N(CC)CC)C>CS(C)=O>[C:9]([N:12]([CH3:38])[CH2:13][CH2:14][N:15]([CH3:37])[C:16]([C:18]1[O:19][C:20]2[C:26]([N:5]3[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]([CH3:34])=[C:23]([C:35]#[N:36])[C:21]=2[N:22]=1)=[O:17])(=[O:11])[CH3:10]
Reactant: CC(=O)N(C)CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 0.75 h
Yield: 43.9 %

Procedure:
Under nitrogen atmosphere at 140 to 150° C., a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidin (32 μl, 256 μmol) was added to a dimethyl sulfoxide (3 ml) solution of N-{2-[acetyl(methyl)amino]ethyl}-4-cyano-N,5-dimethyl-7-fluoro-6-phenyl-1,3-benzoxazole-2-carboxamide (I-204) (87 mg, 213 μmol) and triethylamine (39 μl, 277 μmol), followed by stirring at the same temperature for 45 minutes. After cooling, the solvent was evaporated away under reduced pressure, the residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (47 mg, 44%) as an amorphous substance.