Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]=[C:2]1[N:7]([CH3:16])[C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: COc1ccc2c(c1)OCC(=O)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)OCC(=O)N2C
Yield: 92 %

Procedure:
Following the procedure of Example 1, 21.7 g of 3-oxo-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine and 19.88 g of methyl iodide were reacted in 600 ml of acetone in the presence of 19.32 g of solid potassium carbonate. The reaction was carried out, and the product isolated and purified by the procedure of Example 1 to yield 3-oxo-4-methyl-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine; yield=92%; molecular ion by mass spectrum=193.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]>C(O)(=O)C.Br.CCOCC.C([O-])(O)=O.[Na+]>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(F)c1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 1.09 g (5.96 mmol) 1-(2-fluoro-4-methoxy-3-methyl-phenyl)-ethanone was dissolved in 12 ml acetic acid and 6 ml 62% aqueous HBr. The reaction mixture was stirred 2 h at room temperature and heated to 120° C. for 6 h, cooled, diluted with ether and neutralized carefully with aqueous saturated NaHCO3 (pH=8). Extraction of the water phase with ether (two times), washing with aqueous 10% NaCl, drying (Na2SO4) and evaporation gave 0.78 g of the crude product as a dark red gum.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:28]4([CH3:33])[O:32][CH2:31][CH2:30][O:29]4)[CH:27]=3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CC1(c2cncc(Br)c2)OCCO1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(C4(C)OCCO4)c3)ccc21
Temperature: 105 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (109 mg, 0.4 mmol), prepared as described in Example 3a, was added 3-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (CAS#59936-01-5, 107 mg, 0.44 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (182 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 105° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-5-[5-(2-methyl-[1,3]-dioxolan-2-yl)-pyridin-3-yl]-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 311.1395 (M+H)+; 1H NMR (400 MHz, CDCl3) δppm 1.73 (s, 3H), 3.28 (s, 3H), 3.62 (s, 2H), 3.82-3.88 (m, 2H), 4.08-4.16 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 7.49-7.58 (m, 2H), 7.97 (s, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(Cl)Cl.[OH:34][CH:35]([CH2:40][CH3:41])[C:36]([O:38][CH3:39])=[O:37].CN(C)C>CCOCC>[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:34][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH3:41])=[O:25])=[CH:22][CH:21]=1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[15-(trifluoromethyl)-pentadecylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. trimethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield the product as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:23]=[O:24])[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:12][CH:13]=1)([CH3:4])[CH3:3].[C:27]([Mg]Br)([CH3:29])=[CH2:28]>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([OH:24])[C:27]([CH3:29])=[CH2:28])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: C=C(C)[Mg]Br
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C=O)c1
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cc(CO[Si](C)(C)C(C)(C)C)ccc1-c1cc(OC)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 250 mL round bottom flask was charged with 83.18C (1.05 g, 2.80 mmol) and THF (15 mL) and cooled to −78° C. under N2. To the cold solution was added isopropenylmagnesium bromide (0.5 M in THF) (available from Aldrich) (11.2 mL, 5.61 mmol) dropwise. The mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 83.18D (1.05 g, 90% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[CH:11]1[CH:16]=[C:15]([CH:17](O)[C:18](O)=[O:19])[C:14]([Cl:22])=[CH:13][CH:12]=1>>[Cl:22][C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[CH:17]1[C:9]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:10]=2)[NH:8][C:18]1=[O:19]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)C(O)c1ccccc1Cl
Product: CCOc1ccc2c(c1)C(c1ccccc1Cl)C(=O)N2

Procedure:
This compound is prepared according to the procedure described in step B of Preparation 66 from N-4-ethoxyphenyl-DL-2-chloromandelamide (120°-130° C.), itself obtained according to the procedure described in step A of Preparation 2 from 4-ethoxyaniline and DL-2-chloromandelic acid. This gives the expected product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH2:7][C:5]4[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=4)[C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Reactant: Cn1cnc(CC(=O)O)c1
Product: COc1ccc(N2CCN(C(=O)Cc3cn(C)cn3)[C@@H](CC(C)C)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1-methyl-1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 34, Compound 122) as starting materials. Product as an oil (13.5%). LC/MS (Method B) 2.6 min, [M+1]+ 441.1. Potency class B.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:27]=[CH:26][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]3[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:26][CH:27]=1
Reactant: Clc1nccnc1Cl
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Product: Cc1ccc(COC(=O)N2CCC(CNc3nccnc3Cl)CC2)cc1

Procedure:
The title compound was prepared as described in EXAMPLE 47, reacting 2,3-dichloropyrazine with INTERMEDIATE 2a to give the title compound. M.S.(M+1): 375.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: CC(Cl)c1ccc(F)cn1
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2ccc(F)cn2)nc2nc(N)sc12
Yield: 19.7 %

Procedure:
The title compound was prepared according to General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (21 mg, 0.072 mmol) and 2-(1-chloroethyl)-5-fluoropyridine (8 mg, 0.048 mmol). Purification by preparative HPLC yielded 4 mg (21% yield) of the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[Na].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])CCl>C(O)C>[CH3:13][C:14]1[CH:15]=[C:16]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1ccc(CCl)cc1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(CCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metallic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0° C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred at a room temperature for another 1 hour, heated at the boiling temperature for 4 hours and concentrated under a reduced pressure. The residue was dissolved in ethyl ether and the solution was washed with water. After further concentration under a reduced pressure, the organic phase was combined with 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. The mixture was concentrated under a reduced pressure to about one half volume; then 200 ml of 98% sulfuric acid was added slowly thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl acetate. The organic solvent was distilled off under a reduced pressure and the residue was recrystallized from boiling hexane to obtain 42.1 g of the title compound as a white solid(yield: 55%).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4]/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:25][C@@H:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27](O)=[O:28]>C1(C)C=CC=CC=1>[N:17]1([CH2:16][CH2:15][NH:14][C:8]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]2[N:5]([CH2:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:27](=[O:28])[C@H:26]([CH2:30][C:31]([OH:33])=[O:32])[S:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCCCC1
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cccc(F)c1NCCN1CCCCC1

Procedure:
2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-(piperidin-1-yl)ethyl)benzenamine (457 mg, 1.370 mmol) and (S)-2-mercaptosuccinic acid (224 mg, 1.492 mmol) were stirred in toluene (14 mL) at 80° C. for 24 hours. The solvent was removed on a rotary evaporator under high vacuum at 35° C. Crude 2-((5S)-2-(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid was obtained as a brown foam and carried on to the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[Cl:23])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[Cl:24])[CH3:2].C=O.[C:28]([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[Cl:23])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[Cl:24])[CH3:28])[CH3:2]
Reactant: CCOC(=O)CNc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)CN(C)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a yellow mixture of (2-chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamino)-acetic acid ethyl ester (0.360 g, 0.903 mmol), paraformaldehyde (0.271 g, 9.03 mmol) and glacial acetic acid (4.5 mL) was added sodium cyanoborohydride (0.284 g, 4.51 mmol) in small portions over 5 min. The yellow mixture became a white suspension and was stirred overnight at room temperature. The white suspension was added to a 25% NaOH(aq) solution at 0° C. The aqueous layer was extracted with dichloromethane (50 mL), washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The clear oil was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:5) to yield 0.362 g (96%) of the title compound as a white solid. 1H NMR (CDCl3): 7.94 (d, 1H, J=1.7 Hz), 7.73 (td, 1H, J=8.2, 1.9 and 1.7 Hz), 7.61 (dd, 1H, J=5.5, 5.2, 1.6 and 1.4 Hz), 7.45 (dd, 1H, J=8.5 and 1.4 Hz), 7.13 (dd, 1H, J=5.5, 5.2, 1.6 and 1.4 Hz), 4.18 (q, 2H, J=7.1 Hz), 4.04 (s, 2H), 3.07 (s, 3H), 1.26 (t, 3H, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:5]2[S:10][C:9]([Cl:11])=[CH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1>C(O)CCC>[Cl:11][C:9]1[S:10][C:5]2[C:4]([C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[O:13])=[N:3][C:2]([NH:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: NCc1cccnc1
Reactant: O=C(c1cccs1)c1nc(Cl)nc2cc(Cl)sc12
Solvent: CCCCO
Product: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Temperature: 100 °C
Yield: 38 %

Procedure:
A stirred solution of Example 4 (5 g, 16 mmol) in n-butanol (120 ml) was treated with 3-picolylamine (8.1 ml, 80 mmol) and heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature, reduced in vacuo and the residue purified by silica gel (100 g) column chromatography (3% MeOH/DCM) affording the title compound in 38% yield, >95% purity. LC-MS m/z=387.0 [M+H]+; RT=3.30 min; LC-MS method 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:33])=[C:15]([CH:32]=2)[C:16]([NH:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=2)=[O:17])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-:35].[K+].[K+].OO.Cl>CS(C)=O.O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:33])=[C:15]([CH:32]=2)[C:16]([NH:18][C:19]2[N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:22]=[C:21]([C:30]([NH2:31])=[O:35])[CH:20]=2)=[O:17])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.2 %

Procedure:
To a solution of 5-(6-acetamidopyridin-2-yl)-2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)benzamide (Example 88, 100 mg, 0.22 mmol) in dimethylsulfoxide (3 mL) was added potassium carbonate (60 mg, 0.44 mmol) followed by hydrogen peroxide (30% w/w solution in water, 441 μL, 4.4 mmol) and the reaction was stirred at room temperature for 2.5 hours. Additional hydrogen peroxide was added (882 μL, 8.8 mmol) and the reaction was stirred for 1 hour. The reaction was diluted with water (5 mL) then neutralised with 2M aqueous hydrochloric acid and extracted into ethyl acetate (3×10 mL). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 80% ethyl acetate in heptanes to furnish the title compound as a colourless solid (65 mg, 62%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH2:17]([O:19][C:20](=[O:22])C)[CH3:18]>C(Cl)(Cl)Cl.CCCCCC>[CH2:17]([O:19][C:20](=[O:22])[NH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:18]
Reactant: CCOC(C)=O
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)NCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
Chloro ethyl formate (1.92 mL) and 2N Na2CO3 solution (20 mL) were added to a stirred solution of 2-(4-chloro-phenyl)-ethylamine (I-1b: 2.6 g, 0.01667 mmol) in chloroform (20 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (20% ethylacetate in hexane). The reaction mixture was partitioned between water and chloroform. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% ethylacetate in hexane) afforded 2 g of the product (52.6% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+]>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:12]=2)[C:22](=[O:23])[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[N:13]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2ccc(-c3ccccc3)cn12
Temperature: 140 °C
Yield: 28.6 %

Procedure:
To a mixture of 0.20 g (1.17 mmol) of 5-phenylpyridin-2-amine and 0.227 g (1.17 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added 0.180 g (2.34 mmol) of ammonium acetate. The reaction mixture was heated at 140° C. for 12 hours. After cooling, water was added and the mixture was extracted with chloroform. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and evaporated. The resulting solid was dissolved in methanol and purified on preparative thin layer chromatography eluting with a mixture of ethylacetate/ethanol in the proportions 95/5 to afford 0.10 g (28%) of the desired compound which was transformed into the oxalate salt in the usual manner to give the pure product as a solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)Br.[F:25][C:26]1[CH:31]=[C:30]([O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:29]=[C:28]([F:43])[C:27]=1[CH2:44]CO>C(Cl)Cl>[Br:24][CH2:20][CH2:44][C:27]1[C:26]([F:25])=[CH:31][C:30]([O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:38])[CH3:39])=[CH:29][C:28]=1[F:43]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)[Si](Oc1cc(F)c(CCO)c(F)c1)(C(C)C)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc(F)c(CCBr)c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
PPh3 (1.11 g, 4.24 mmol) was added to a cooled (0° C.) solution of CBr4 (0.92 g, 237 mmol) in DCM (15 mL). After stirring for 15 minutes, a solution of PMW04155 (0.70 g, 2.12 mmol) in DCM (5 mL) was added and the reaction mixture was stirred for 1 h, then allowed to warm to room temperature and stirred for 2 h. The solvent was removed in vacuo and the residue was purified using the Combiflash system (EtOAc/PE) to give the title compound (0.56 g, 67%) as a colourless oil; 1H NMR (270 MHz, CDCl3) 1.05-1.32 (21H, m, 6×CH3,3×CH), 3.13 (2H, t, J=7.7, CH2), 3.48 (2H, t, J=7.7, CH2), 6.34-6.45 (2H, m, ArH).
Reaction SMILES: [Cl:1][C:2](=[CH2:5])[CH2:3][NH2:4].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C(O)C>[Cl:1][C:2](=[CH2:5])[CH2:3][NH:4][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]([C:20]([F:21])([F:22])[F:23])=[C:7]([Cl:6])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: C=C(Cl)CN
Solvent: CCO
Product: C=C(Cl)CNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting 2-chloroallylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in ethanol. After recrystallization from ethanol, the compound melts at 78°-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1
Yield: 86.2 %

Procedure:
The title compound was synthesized by reacting 2-amino-5-methylbenzoic acid (0.25 g, 1.65 mmol), 4-fluoro-benzenesulfonyl chloride (0.39 g, 1.98 mmol) and sodium carbonate (0.36 g, 3.39 mmol) in 3 mL of water, following the reaction procedure of 10. The white solid obtained after acidification of reaction mixture was filtered, washed with water and dried to give 12 (0.44 g, 85.42%). Crystallization with EtOH gave (0.3 g) white amorphous solid, mp: 159-160° C.; IR (CHCl3) 3177, 1662, 1342, 1148, 667 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.31 (s, 3H, CH3), 7.08-7.86 (m, 7H, aromatic), 9.32 (br, 1H, NH), and 10.18 (s, 1H, COOH). HRMS calcd 332.0363 (C14H12FNO4S.Na+), found 332.0372.