Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=O)[NH:8][S:9][C:5]=2[CH:4]=1.CN(C)C=O.S(Cl)([Cl:20])=O>ClC1C=CC=CC=1>[Cl:20][C:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]sc2c1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: COc1ccc2c(Cl)nsc2c1
Reaction time: 1 h
Yield: 88 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 90.6 g (0.5 mol) of 6-methoxy-1,2-benzisothiazol-3-one, 109.6 g (1.5 mol) of N,N-dimethylformamide and 150.0 g of chlorobenzene. While stirring, 89.2 g (0.75 mol) of thionyl chloride was added dropwise thereto at 80° to 90° C. over 1 hour, and the mixture was reacted at the same temperature for 5 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was recrystallized from cyclohexane to give 86.9 g (0.44 mol) of 3-chloro-6-methoxy-1,2-benzisothiazole. The yield based on 6-methoxy-1,2-benzisothiazol-3-one was 87%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (177 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) by refluxing in xylene according to the general procedure M. Obtained as a brown solid (269 mg).
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:39][O:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:21])([F:22])[F:20])=[N:17][CH:18]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)=[CH:37][N:36]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cnc(C(F)(F)F)nc4)cc3)nc2=O)cn1
Reaction time: 1 h
Yield: 3 %

Procedure:
The same procedure as E121 from 2-(4-{[2-(trifluoromethyl)-5-pyrimidinyl]oxy}phenyl)ethyl imidocarbamate (60 mg, 0.184 mmol), methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (49.5 mg, 0.221 mmol) and K2CO3 (102 mg, 0.736 mmol) in NMP (1 mL), except that the temperature was 130° C. and the reaction time was 1 h, to afford the title compound (2.8 mg, 5.60 μmol, 3.04% yield). LCMS: rt=1.29 min, [M+H+]=501
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[F:24][C:25]([F:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH2:27]>>[F:34][C:25]([F:24])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH:27][C:13](=[O:15])[CH2:12][N:7]1[C:8]([CH3:11])=[CH:9][N:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:6]1=[O:16]
Reactant: Cc1cnc(NCC(F)(F)c2ccncc2)c(=O)n1CC(=O)O
Reactant: NCC(F)(F)c1ccccn1
Product: Cc1cnc(NCC(F)(F)c2ccncc2)c(=O)n1CC(=O)NCC(F)(F)c1ccccn1

Procedure:
N-(2,2-Difluoro-2-pyridin-2-yl-ethyl)-2-[3-(2,2-difluoro-2-pyridin-4-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetamide (6-3) 6-3 was prepared from [3-(2,2-difluoro-2-pyridin-4-ylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 2,2-difluoro-2-(2-pyridyl)ethyl amine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1) 465.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([CH2:12]O)[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.CN(C=O)C.[N:31]([Si](C)(C)C)=[N+:32]=[N-:33]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:31]([CH2:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7])=[N+:32]=[N-:33]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CNC(=O)c1ccc(Cl)cc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccc(Cl)cc1CN=[N+]=[N-]
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-chloro-2-(hydroxymethyl)-N-methylbenzamide (5.81 g, 29.2 mmol) in methylene chloride (200 mL) cooled in an ice bath, was added triethylamine (5.10 mL, 36.6 mmol) and methanesulfonyl chloride (2.50 mL, 32.3 mmol). After 90 min, the reaction was diluted with chloroform and partitioned with aqueous sodium bicarbonate and brine. After extracting three times with chloroform, the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. To this residue was added DMF (50 mL) sodium azide (0.35 g, 5.4 mmol) and azidotrimethylsilane (2.6 mL, 19.6 mmol) portionwise with stirring at 40° C. for three days. The reaction was concentrated in vacuo and partitioned between chloroform and aqueous sodium bicarbonate. After extracting three times with chloroform, the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a 30-50% ethyl acetate/hexane gradient. Fractions were concentrated in vacuo to afford 2-(azidomethyl)-4-chloro-N-methylbenzamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([O:23][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCO[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To an ice cooled solution of (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 6.4 mmol) in dry CH2Cl2 (8 ml) was added N-ethyldiisopropylamine (1.7 ml, 9.5 mmol) and stirred for 10 minutes MEM-chloride (1.1 ml, 9.5 mmol) was added to the solution at 0° C. and stirred for 3 h at room temperature. The solvent was concentrated and the residue purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to yield (2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne (2.2 g, 85%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.5 1H NMR (CDCl3, 200 MHz): δ 2.65-2.75 (m, 2H), 3.39 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 3.78 (t, J=4.8 Hz, 2H), 4.11 (s, 2H), 4.16 (m, 3H), 4.56 (s, 2H), 4.89 (s, 2H), 6.8-7.02 (m, 4H), 7.3-7.35 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NC3CCN(C)CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 1-methylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=356).
Reaction SMILES: [C:1]12([CH2:11]OC3C=CC(C#N)=CC=3Br)CC3CC(CC(C3)[CH2:2]1)C2.[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1Br)[CH2:29]2>>[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[CH:11]1[CH2:1][CH2:2]1)[CH2:29]2
Reactant: N#Cc1ccc(OCC2C3CC4CC(C3)CC2C4)c(Br)c1
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Product: N#Cc1ccc(OCC2C3CC4CC(C3)CC2C4)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 39 step 1 and making variation as required to replace 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile with 4-(adamantan-2-ylmethoxy)-3-bromobenzonitrile the title compound was obtained as a colorless solid (0.68 g, 84%): MS (ES+) m/z 308.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:21]([O-])=O)[N:7]=1>O1CCOCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:21])[N:7]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3cccs3)c(-c3cccs3)nc12
Solvent: C1COCCO1
Product: Nc1cccc2nc(-c3cccs3)c(-c3cccs3)nc12

Procedure:
1.01 g (3.0 mmol) of 2,3-dithienyl-5-nitroquinoxaline was dissolved in 30 g of dioxane and the system was fully purged with argon. Thereafter, 0.3 g of 5% Pd/C (hydrous) was added, followed by purging satisfactorily with argon again. This system was purged with a hydrogen gas and reacted at room temperature for 24 hours. After completion of the reaction, the system was filtered. The resulting filtration residue was washed with acetone and then with dioxane, and was filtered again. The solvent was removed from the resulting filtrate, and a reaction product was extracted with a silica gel column.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)=[CH:4][CH:3]=1.[S:16]1[CH2:22][C:20](=[O:21])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:17]1=[S:18].[Cl-].[NH4+].N>C(O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:22]3[S:16][C:17](=[S:18])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:20]3=[O:21])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1csc(Nc2ccc(F)cc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccc(F)cc3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 1 g of 2-(p-fluoroanilino)thiazole-4-carbaldehyde, 0.85 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia, and 10 ml of ethanol, giving the title compound as an orange powder.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C@@:8]2([CH3:33])[N:12]3[C:13]([C:16]([NH:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:9]2=[O:32])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:37][C@H:38]([CH3:42])[C:39]([NH2:41])=[S:40].C(N(C(C)C)CC)(C)C.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:39]([C@H:38]([NH:37][C:20]([C@@H:19]([NH:18][C:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:35][CH:34]=3)([CH3:33])[C:9](=[O:32])[N:10]([C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)[C:11]2=[N:15][CH:14]=1)=[O:17])[CH3:23])=[O:22])[CH3:42])(=[S:40])[NH2:41]
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: C[C@@H](N)C(N)=S
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@H](C)C(N)=S
Temperature: 0 °C
Yield: 102.9 %

Procedure:
A solution of (S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid, (129 mg, 0.25 mmol), (R)-2-amino-thiopropionamide hydrochloride (53 mg, 0.38 mmol) and diisopropylethylamine (0.175 mL, 1.01 mmol) in DMF (1 mL) was stirred at room temperature for 10 min. After cooling to 0° C., HOAt (69 mg, 0.50 mmol) and HATU (105 mg, 0.25 mmol) were added. The clear yellow reaction mixture was allowed to warm to room temperature slowly overnight. The reaction mixture was partitioned between ethyl acetate (35 mL) and 1 M HCl (10 mL). The organic phase was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-10% MeOH in dichloromethane) to afford 154 mg of the title compound as a white foam, m/z 598.4 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C([O-])(=O)C.[Na+].[Br:19]Br.O>C(O)(=O)C>[Br:19][C:8]1[CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c2ncccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VI) (0.177 g, 1 mmol), sodium acetate (0.492 g, 6 mmol) and bromine (0.308 mL, 6 mmol) in glacial acetic acid (5 mL) was heated overnight at 120° C. in a sealed tube. The solution was cooled and poured into water. The solids formed were filtered, washed with water and dried at room temperature under vacuum. The crude product was purified on a flash silica gel column (100% DCM→100:2 DCM:MeOH) to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) as a white solid (78 mg, 0.31 mmol, 30% yield). 1H NMR (CDCl3) δ ppm 3.95 (s, 3H), 8.62 (d, J=3.01 Hz, 1H), 8.73 (d, J=3.01 Hz, 1H); ESIMS found for C8H6BrN3O2 m/z 256.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6]1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C1(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(C(=O)O)CC3)c(Cl)cc2F)c1=O
Temperature: 0 °C
Yield: 62 %

Procedure:
2.0 g of methyl 1-[2-chloro-4-fluoro-5-{3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl}phenoxy]cyclopropanecarboxylate was dissolved in a solution consisting of 10 ml of 1,4-dioxane and 10 ml of conc. hydrochloric acid, and the obtained solution was heated under reflux for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution in turn, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure. The produced crystals was washed with a mixted solution of hexane and t-butyl methyl ether to give 1.2 g of 1-[2-chloro-4-fluoro-5-{3-methyl-2,6-dioxo-4-(trifluoro-methyl)-1,2,3,6-tetrahydropyrimidin-1-yl}phenoxy]cyclo-propanecarboxylic acid (Compound 1-1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 29.1 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). 1H NMR (CDCl3, HMDSO),δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1H, br s); 6.92-7.89 (10H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH:15]1[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:17][CH2:16]1
Reactant: ClCC1CC1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(OCC2CC2)cc1C
Temperature: 80 °C
Yield: 99.7 %

Procedure:
A vigorously stirred mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 1.00 g, 10.9 mmol), chloromethylcyclopropane (4-1, 1.22 g, 7.4 mmol), and powdered potassium carbonate (1.54 g, 11.1 mmol) in DMF (10.0 mL) was heated at 80° C. for 16 h under N2. The mixture was allowed to cool and was filtered through Diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium carbonate and dried over Na2SO4. The solution was concentrated under reduced pressure to provide 1-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)ethanone (4-3, 1.61 g) as off-white solids in 99% yield: 1H NMR (500 MHz, CDCl3) δ 6.55 (s, 2 H), 3.77 (d, J=6.9 Hz, 2 H), 2.45 (s, 3 H), 2.27 (s, 6 H), 1.19 (s, 1 H), 0.64 (m, 2 H), 0.33 (m, 2 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH2:8].N1C=CC=CC=1.[CH3:21][CH:22]([CH2:26][S:27][CH3:28])[C:23](Cl)=[O:24].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH:8][C:23](=[O:24])[CH:22]([CH3:21])[CH2:26][S:27][CH3:28]
Reactant: CSCC(C)C(=O)Cl
Reactant: Nc1sc(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1Cl
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was charged 7.5 g (30.2 mmoles) of 4-chloro-2-(pyridine-3-yl)-1,3-thiazol-5-amine hydrochloride and 200 mLs of anhydrous methylene chloride. The resulting suspension was cooled to 15° C., and 5.98 g (76 mmoles) of pyridine was added at a rate that maintained the temperature below 20° C. 1.85 g (15.11 mmoles) of N,N-dimethylpyridin-4-amine was added in one portion and the resulting yellow solution was stirred at 5° C. for 10 minutes. A solution of 2-methyl-3-(methylthio)propanoyl chloride (5.54 g 36.3 mmoles) in 25 mLs of methylene chloride was added dropwise at a rate that maintained the temperature below 15° C. The reaction was stirred at ambient temperature for 12 hours, than poured into 200 mLs of water. The target was extracted with methylene chloride (3×100 mLs) and the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes to yield a yellow oil (5.4 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.3, 0.8 Hz, 1H), 9.00 (s, 1H), 8.64 (dd, J=4.8, 1.6 Hz, 1H), 8.17 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.37 (ddd, J=8.0, 4.9, 0.8 Hz, 1H), 3.00-2.57 (m, 3H), 2.17 (s, 3H), 1.38 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.68, 155.24, 150.55, 146.75, 132.81, 129.26, 127.62, 124.99, 123.80, 40.85, 37.98, 17.46, 16.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][OH:31])([CH3:4])([CH3:3])[CH3:2].[CH3:33]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A 15 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.10 g, 0.23 mmol) and methyl iodide (0.21 mL, 2.3 mmol) in anhydrous DMF (1 mL) under a nitrogen atmosphere. The mixture was cooled in an ice bath and treated in one portion with NaH (0.018 g, 0.25 mmol, 60% oil dispersion). The reaction mixture was stirred for 2 h, concentrated, and diluted with EtOAc (40 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 10:90 to 25:75) to give a yellow oil (0.060 g, 58%). MS (ES) m/e 648 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[CH3:18]>>[CH3:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 60 °C

Procedure:
Using phenol and 2-fluoro-5-nitrotoluene and the procedures described in Example 52A, except the reaction was heated to 60° C. overnight and vacuum distilled at 4.5 mm Hg, 174°-5° C., provided 3-methyl-4-phenoxynitrobenzene. 1H NMR (CDCl3) δ 8.16 (dd, 1H), 8.00 (dd, 1H), 7.42 (m, 2H), 7.23 (m, 1H), 7.05 (m, 2H), 6.78 (d, 1H),2.42 (s, 3H). MS (DCl/NH3) role 247 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[C:8](=[O:9])[C:7]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:6]=2[O:5]1.C([O-])(=O)C.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[Br:1][C:11]1[C:12]([CH3:14])=[CH:13][C:6]2[O:5][C:4]([CH3:16])([CH3:3])[C:8](=[O:9])[C:7]=2[C:10]=1[CH3:15]
Reactant: Cc1cc(C)c2c(c1)OC(C)(C)C2=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc2c(c(C)c1Br)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Bromine (8.7 mL, 169 mmol) was added to a mixture of acetonitrile (200 mL) containing 2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (30.7 g, 161 mmol) synthesized in Reference Example 118 and sodium acetate (14.5 g, 177 mmol), and the mixture was stirred at room temperature for 2 hours. After that, the reaction solution was poured into 5% sodium sulfite aqueous solution, and extraction was performed using ethyl acetate. The extract was washed with water and saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 50:1-9/1), and crystallization was performed using methanol to give 26.2 g of the title compound (yield: 61%).