Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13]C)[CH:9]=[CH:8]2)[CH3:2].Br.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH2:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1c(F)cnc2ccc(OC)nc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1c(F)cnc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A suspension of 8-ethyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (1.045 g, 5.07 mmol) in glacial acetic acid (10 ml) at rt under argon, was treated with 33% HBr in acetic acid (10 mL). After stirring at rt for 18 h, the solvents were evaporated under reduced pressure. More glacial acetic acid (10 ml) was added to the reaction mixture and the solvent was removed to give a yellow solid. As this residue was placed in water (ca. 50 ml) a white precipitate came out of solution. The pH was adjusted to pH 6-7 by addition of solid sodium hydrogen carbonate. The mixture was then stirred at rt for 2 h, after which the solid was isolated by filtration with suction to give a white damp solid. This product was dried on the sinter with suction for 2 h then dried in a vacuum oven over 18 h at 40° C. to give the title compound as an white solid (0.81 g, 83%).
Reaction SMILES: [Fe:1].[NH2:2][CH2:3][C:4]([OH:6])=[O:5]>O>[NH2:2][CH2:3][C:4]([O-:6])=[O:5].[Fe+2:1].[NH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: NCC(=O)O
Reactant: [Fe]
Solvent: O
Product: NCC(=O)[O-]
Product: [Fe+2]

Procedure:
The water is heated to 60° C., and the iron II sulfate heptahydrate and the glycine are then introduced into the water in a mixer.
Reaction SMILES: C(OC([N:6]1[CH2:30][C@:29]2([C:31](=[O:35])[CH2:32][S:33][CH3:34])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:36])[CH2:7]1)=O)=C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[F:27][C@@:14]12[C@:15]3([CH3:26])[C:20](=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]3)[C@@H:21]([F:24])[CH2:22][C@H:23]1[C@@H:10]1[CH2:9][C@@H:8]3[C@:29]([C:31](=[O:35])[CH2:32][S:33][CH3:34])([C@@:11]1([CH3:36])[CH2:12][C@@H:13]2[OH:28])[CH2:30][NH:6][CH2:7]3
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CSC)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of compound 185 (122 mg, 0.234 mmol) and HCl 4M in Dioxane (2 ml, 8.00 mmol) in DCM (10 ml) is stirred at RT for 2 hours, then the solvent is evaporated and the crude is dried in vacuo for 16 hours. MeOH (15 ml) is added and the solution is stirred at 45° C. for 20 minutes. The solvent is evaporated to afford the title compound (106 mg, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]2[CH2:27][O:26]C(C)(C)[O:24]2)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)(=O)C>[OH2:16].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]([OH:24])[CH2:27][OH:26])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]([OH:24])[CH2:27][OH:26])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1=C(COCC2COC(C)(C)O2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(COCC(O)CO)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Product: O
Yield: 62.2 %

Procedure:
A solution of 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxymethyl}-2,2-dimethyl-1,3-dioxolane (5.9 g) in 60% aqueous acetic acid was stirred at room temperature for 27 hours and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (60 g) using toluene plus 0-100% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ether to give the title compound (2.3 g) as a hemihydrate, m.p. 115°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2C=CC[NH:9][CH2:8][C@H:7]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]1=[O:28].C(N(CC)CC)C.[C:37]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:14]2[CH:13]=[CH:18][CH:17]=[CH:16][C:15]=2[N:9]([C:45](=[O:46])[CH2:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][C@H:7]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:6]1=[O:28]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CNCC=Cc2ccccc21
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of (3S)-2-oxo-3-(benzoylamino)-2,3,4,5-tetrahydro-1H-1,5-benzodiazecine-1-acetic acid methyl ester 200 mg, 0.57 mmol) in CH2Cl2(10 ml) was treated with triethylamine (1-9 mg, 1.13 mmol) and 3-phenylpropionyl chloride (114 mg, 0.68 mmol). The reaction was stirred at RT for 30 min and diluted with CH2Cl2. The solution was washed wIth*. aq. 10% HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo to give 240 mg (87%) of 602a as a white foam.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH:23]=[CH:22][CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=1)=[O:7])[CH3:4]>CCOCC.C1COCC1.[Cu]I>[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH2:23][CH:22]([CH3:2])[CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Reactant: [Li]C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CC(C)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MeLi (1.4M in ether, 2 ml) is added dropwise to a stirred suspension of CuI (268 mg, 1.40 mmol) in Et2O at 0° C. The reaction mixture is kept at 0° C. for 15 min. 4-oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (300 mg, 0.94 mmol) in THF is added slowly to the solution at 0° C., the reaction mixture is allowed to warm up to room temperature over a period of 30 min and then quenched with saturated NH4Cl(aq., 30 ml). 50 ml Et2O is added and stirring is continued for 5 min. The layers are separated; the organic layer is washed with water (20 ml), dried (Na2SO4), and evaporated. Flash chromatography (30% EtOAc/hexanes) provides the title compound as white powder. 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, d), 1.28 (3H, t), 1.56 (9H+1H, s+m), 1.92 (1H, m), 2.15 (1H, m), 2.48 (1H, q), 2.80 (1H, q), 3.15-3.25 (2H, m), 4.24 (2H, q), 7.57 (1H, s). MS (ES+) 336 (M+1) Step 2: 6-Methyl-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[H-].[Na+]>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:9][OH:10])=[CH:2][CH:3]=1
Reactant: OCc1ccc(CO)cc1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1ccc(COc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 1,4-benzenedimethanol (5.5 g, 40 mmol), 2-fluoropyridine (1.3 g, 13 mmol) and N,N-dimethylformamide (15 mL) was added sodium hydride (1.4 g, 40 mmol, 66% in oil) at 0° C., which was stirred for 20 minutes at room temperature and for 1 hour at 70° C. To the reaction mixture was added water, and extraction was performed with ethyl acetate. The organic layer was washed with saturated saline, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the titled compound (1.9 g, 66%).
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH:9]([CH3:11])[CH3:10])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.ClCCl>[C:12]([O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH:9]([CH3:10])[CH3:11])(=[O:14])[CH3:13]
Reactant: CCC(/C=C/CO)=C\C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(/C=C/COC(C)=O)=C\C(C)C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of (E,E)-4-ethyl-6-methyl-2,4-heptadien-1-ol (23.8 g) in pyridine (61.4 g) at 0° C. was added dropwise acetic anhydride (50.9 g). After two hours, the reaction mixture was diluted with dichloromethane. The solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% ethyl acetate-hexane) to give (E,E)-1-acetoxy-4-ethyl-6-methyl-2,4-heptadiene (24.11 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: Clc1ccccc1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.86 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and chlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87-89/9-13. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.86 to 0.88%].
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:9]1[S:13][CH2:12][N:11]([CH3:14])[CH:10]=1)[O:7][CH3:8].CN(C)C=O.[CH3:24][CH:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CCOCC>[CH3:8][O:7][CH:6]([C:9]1[S:13][CH2:12][N:11]([CH3:14])[CH:10]=1)[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH:3]=[N:2][O:1][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=NO
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(C1=CN(C)CS1)c1ccccc1C=NOC(C)c1ccccc1
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a mixture of 0.25 g (1 mmol) of 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylthiazole, 3 ml of N,N-dimethylformamide and 0.24 g (1.3 mmol) of α-methylbenzyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-(4-phenyl-2-aza-3-oxa-1-pentenyl)benzyl]-3-methylthiazole (0.32 g, 91.3%) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:15][CH:12]([CH3:14])[CH3:13])[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=1
Reactant: NC(=O)c1ncc(Cl)cc1Cl
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)cnc1C(N)=O
Temperature: 200 °C
Yield: 55.8 %

Procedure:
3,5-Dichloropicolinamide (50 mg, 0.26 mmol, 1.0 equiv) and isopropylamine (225 uL, 2.6 mmol, 1.0 equiv) were combined in a microwave vial equipped with a stirbar, sealed and heated to 200° C. for 30 min. The mixture was then dissolved in dichloromethane and loaded onto a Biotage caplet. Purification by silica gel MPLC (13%-68% Et2O/Hexanes) provided the desired compound as a white solid (31 mg, 56%). m/z=214.1 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:33])=[O:32])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(O[N:42]1N=N[C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(N)C.Cl>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:32])=[O:33])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:42][CH2:43][CH3:44])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 0.08 h

Procedure:
To a solution of {2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid (40 mg, 0.86 mmol) in DMSO (0.7 mL) is added HATU (49 mg, 0.129 mmol) and diisopropylethylamine (0.045 mL, 0.256 mmol). The mixture is stirred for 5 min then ethylamine (0.086 mL, 2M in THF) is added dropwise. Upon completion of the reaction, the mixture is acidified with 1N HCl and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)=[O:5].[NH4+].[OH-].[NH2:26]C1C=C(F)C([N+]([O-])=O)=CC=1C(NC1C=C2C(C=NN2)=CC=1)=O.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>O1CCOCC1>[NH2:26][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]([C:4]([NH:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[O:5])=[C:2]([N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)[CH:19]=1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Reactant: CN1CCNCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-fluoro-N-(1H-indazol-5-yl)-5-nitrobenzamide (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, the reaction mixture was charged with N-methylpiperazine (8 mmol). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-(1H-indazol-5-yl)-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](C)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC(Cl)(Cl)C(O[C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([Cl:28])[C:20]=1[Cl:29])=O.[CH2:32]([N:34](CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:34][CH3:32])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([Cl:28])[C:20]=1[Cl:29])=[O:8]
Reactant: O=C(Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(Cl)(Cl)Cl
Reactant: COc1cc(C)c(Cl)cc1C(=O)O
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1cc(OC)c(C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-chloro-2-methoxy-4-methyl benzoic acid (2 g., 0.0093 mol) in dimethylformamide (50 ml) was treated with pentachlorophenyl trichloroacetate (4.5 g., 0.11 mol) and triethylamine (1.5 ml). The mixture was stirred at room temperature for one hour. The dimethylformamide was stripped off in vacuo, and the residue recrystallised from acetone/petroleum to give pentachlorophenyl 5-chloro-2-methoxy-4-methylaminobenzoate, m.pt 217°-219° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>N1C=CC=CC=1>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][C:2]=1[N:1]([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)c1cc(OC)c(N)s1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-amino-4-methoxythiophene-2-carboxylate (Int. 69) (261 mg, 1.297 mmol) (prepared as described in Step 5 hereabove reported) in pyridine (10 ml) cooled to 0° C., methanesulfonyl chloride (0.131 ml, 1.686 mmol) was added, and the reaction was allowed to warm to RT and stirred overnight. The solvent was removed under vacuum and the residue was portioned between EtOAc and 10% HCl; the organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under vacuum and the residue was dissolved in dry DMF (10 ml); K2CO3 (448 mg, 3.24 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (362 mg, 1.946 mmol) were added in one portion, and the resulting mixture was heated to 80° C. and stirred at this temperature for 3 hours. The solvent was removed under vacuum, and the residue was dissolved in EtOAc and washed with brine. The organic phase was dried over sodium sulfate, filtered evaporated. The residue was purified by filtration on silica gel cartridge (DCM/EtOAc=8/2 to EtOAc) to afford ethyl 4-methoxy-5-(N-(2-morpholinoethyl)-methylsulfonamido)thiophene-2-carboxylate (Int. 70) in a mixture with approximately 30% of corresponding methyl ester (375 mg, 0.955 mmol, MS/ESI+392.8 [MH]+). This intermediate was used as such in the following step considering it was a single product.
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][S:14][C:15]3[NH:16][N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:3][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][S:14][C:15]3[N:16]([CH3:26])[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc2nc(CSc3nc(-c4ccccc4)n[nH]3)nn12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cccc2nc(CSc3nc(-c4ccccc4)nn3C)nn12
Reaction time: 3 h

Procedure:
Methyl iodide (142 mg, 1.00 mmol) dissolved in DMF (0.5 ml) was added to a stirred suspension of 5-Methyl-2-(5-phenyl-2H-1,2,4-triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyridine (322 mg, 1.00 mmol) and Potassium carbonate (276 mg, 2.0 mmol) in N,N-Dimethylformamide (3.5 mL) at rt, under Ar. The solution was stirred at 3 h and then quenched by adding Sat bicarbonate sol and extracting with EtOAc. The Organic phase was dried (MgSO4) and was rotovaped. The crude product was purified by HPLC. This afforded 10 mg of the title compound. LC-MS: m/z=337.1 (MH+), tR=0.63 min, Method B. 1H NMR (600 MHz, DMSO-d6): δ 7.96 (d, 2H), 7.63 (d, 1H), 7.60 (t, 1H) 7.50-7.40 (m, 3H), 7.07 (d, 1H), 4.68 (s, 2H), 2.66 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH:15]=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:17][NH2:18].CC([O-])=O.[Na+].C(OC(C)C)(=O)C>O.C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH:15]=[N:18][OH:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(-c2ncc(C=O)cc2C)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Cc1cc(-c2ncc(C=NO)cc2C)ccn1

Procedure:
To a 5-L four-necked flask equipped with an overhead stirrer, and a thermocouple was charged with 2′,3-dimethyl-[2,4′-bipyridine]-5-carbaldehyde (34d, 1120 mmol), hydrochloro hydroxyamine (34e, 140.1 g, 2016 mmol), and ethanol (1600 mL). The mixture was stirred at 23° C. for 2 h before the addition of NaOAc (183.8 g, 2240 mmol, 2 eq) and iso-propyl acetate (2 L)/water (2 L). The aqueous layer was back-extracted with iso-propyl acetate (2 L) after the layer separation. The combined organic layers were concentrated to almost dryness to afford the crude 2′,3-dimethyl-[2,4′-bipyridine]-5-carbaldehyde oxime (34f) as a brown oil.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1>C1COCC1>[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:1])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Add methylmagnesium bromide (3 M in ether, 12 mL, 36 mmol) at 0° C. under nitrogen to a solution of 6-fluoro-pyridine-3-carbaldehyde (3 g, 24 mmol) in THF (20 mL). Continue to stir the mixture overnight at RT. Quench the mixture with 1 N HCl, followed by basification with diluted ammonium hydroxide to ˜pH 9. Extract the product with chloroform/IPA (3/1). Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10% methanol in DCM) to give the title compound as a colorless oil (2.3 g, 68%). MS (ES) m/z 142 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][C:18]#N.[OH-:20].[Na+].CCO.[OH2:25]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][C:18]([OH:25])=[O:20]
Reactant: O
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CC#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CC(=O)O

Procedure:
8.69 g of the above prepared [5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetonitrile (32.6 mmol) was dissolved in 100 ml EtOH/water=1/1 and treated with 10 eq. of NaOH-pellets (13 g). Hydrolysis was allowed to proceed over night at 85° C. Pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing with water, drying over magnesium sulfate, evaporation of the solvents, followed by recrystallization from AcOEt/hexane, yielded 7.35 g of the title acid as off-white crystals.