Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:2].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>N1C=CC=CC=1>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][S:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])(=[O:13])=[O:12])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: CCc1cccc(CC)c1S(=O)(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.2 %

Procedure:
2,6-Diethylbenzenesulfonyl chloride (0.100 g, 0.430 mmol) was added to a solution of 3,5-bis(trifluoromethyl)aniline (0.099 g, 0.434 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was triturated with hexanes (2×10 mL) to afford the title compound (0.037 g, 20% yield). LCMS (M+Na) 447.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(N)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A mixture of diethyl (4-nitrophenyl)phosphonate (150 mg, 0.58 mmol), EtOH (40 ml) and 10% Pd/C (30 mg) was hydrogenated under 50 psi of hydrogen pressure at 40° C. for 6 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate concentrated in vacuo to afford 130 mg of desired diethyl (4-aminophenyl)phosphonate (yield: 98%), which was used directly in further chemistries without purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: O=C1CCCN1
Reactant: Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NCCCc1nc2ccccc2[nH]1

Procedure:
162 g (1.5 mols) of o-phenylene diamine, 85 g (1 mol) of pyrrolidone and 8 g of p-toluene sulphonic acid are melted, while stirring, in a nitrogen atmosphere and the water which is gradually eliminated is distilled off over a period of 5 hours at a sump temperature of 150° to 250°C. The reaction mixture is then subjected to fractional distillation under reduced pressure. 150 g (85.5 % of the theoretical) of 2-(3'-aminopropyl)-benzimidazole are obtained at a pressure of 0.1 Torr and a boiling temperature of 190° to 196°C in the form of a brownish-yellow crystalline mass melting at 118°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>ClCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ncc(OCc2ccccc2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ncc(OCc2ccccc2)cn1
Yield: 96982.2 %

Procedure:
A solution of 5-(benzyloxy)pyrimidin-2-amine (60.0 g, 0.30 mmol) in dichloromethane (400 mL) was added with pyridine (30 mL, 0.37 mmol), the mixture was added dropwise with a solution of hexanoyl chloride (46 g, 0.34 mmol) in dichloromethane (100 mL) with stirring on an ice bath, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with 1 M hydrochloric acid (500 mL), and extracted with chloroform, and the organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was recrystallized froth chloroform-hexane to obtain N-[5-(benzyloxy)pyrimidin-2-yl]hexanamide (87.1 g, 98%) as colorless acicular crystals.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)=[CH:3]C=1.Cl.C(Cl)(=O)C1C=CC=[N:20][CH:19]=1>>[N:20]1[CH:19]=[CH:6][CH:5]=[C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Agent: Cl
Product: c1cncc(-c2nnc3n2CCCN3)c1

Procedure:
The title compound is prepared according to the procedure for 3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (example 17a) from nicotinoyl chloride hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:44])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1CN(c2c(N)cnn2C)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
To a solution of tert-butyl (±)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (400 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (630 mg, 2.46 mmol), HATU (0.83 g, 8.19 mmol) in DMF (15 mL) was added TEA (1.5 mL). The reaction mixture was stirred at 25° C. for 20 hours and poured into water (100 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (280 mg, 52%) as white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 10.32 (s, 1H), 8.70 (s, 1H), 7.80 (s, 1H), 7.38-7.35 (m, 1H), 7.06-7.03 (m, 2H), 4.34 (s, 1H), 3.94-3.97 (m, 1H), 3.81 (s, 3H), 3.67-3.40 (m, 1H), 3.20-3.25 (m, 2H), 3.04-3.06 (m, 1H), 2.88-2.90 (m, 1H), 1.55 (s, 9H), 1.47 (s, 9H), 1.34-1.36 (d, J=6.4 Hz, 3H); MS (ESI) m/z=434 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2noc(-c3ccccc3)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2noc(-c3ccccc3)c2c1
Yield: 59 %

Procedure:
A mixture of 11.7 g (0.05 g mole) of 5-methyl-3-phenyl-2,1-benzisoxazole, 10.0 g (0.056 mole) of N-bromosuccinimide and 0.1 g of dibenzoylperoxide in 200 ml of carbon tetrachloride was heated at reflux under illumination by a flood lamp for 2.5 hr. The mixture was filtered and the filtrate was washed with 5% sodium hydroxide, dried over sodium sulfate and concentrated to give a solid as residue. This solid was recrystallized twice from 2-propanol to yield 9.5 g (59%) of crystals, m.p. 130° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](Cl)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:19][NH2:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Cl:17][C:15]1[N:14]=[C:13]([NH:20][CH3:19])[CH:12]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:16]=1
Reactant: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(Cl)n1

Procedure:
7-Chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (1.0 eq, 0.64 mmol, 190 mg), methyl amine (8M in EtOH, 3.5 eq, 2.2 mmol, 0.28 ml) and Cs2CO3 (2.5 eq, 1.59 mmol, 518 mg) are dissolved in DMF (2 ml) and the reaction mixture is heated using microwave radiation at 160° C. for 30 min, it is diluted with CH2Cl2. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford [6-chloro-4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-pyridin-2-yl]-methyl-amine as a brown solid; [M+H]+=294
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1)([CH3:17])([CH3:16])[CH3:15]>CCO>[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:2]2[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(CNc2ncc([N+](=O)[O-])c(SC#N)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 2-chloro-5-nitro-4-thiocyanato-pyrimidine (1.31 g, 6.05 mmol) in EtOH (10 mL) at 0° C. was added a solution of (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (1.43 g, 6.05 mmol) dropwise over 45 min. The reaction was allowed to stir at room temperature overnight and the resulting precipitate filtered and washed with EtOH. The crude material was purified by column chromatography (silica gel, 10:90 to 12:88 EtOAc/hexane) to afford {3-[(5-nitro-4-thiocyanato-pyrimidin-2-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (1.43 g, 56%) as a yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(N(CC)CC)C.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][CH:49]([OH:52])[CH:50]=[CH2:51])[CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:51][CH2:50][C:49](=[O:52])[CH2:48][CH2:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: C=CC(O)CCc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCc1cccnc1)CCc1ccc2ccccc2c1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
Palladium(II) acetate (0.056 g), tri-o-tolylphosphine (0.148 g), 2-bromonaphthalene (0.49 g) and triethylamine (10 ml) were added to a solution of (±)-5-(3-pyridyl)-1-penten-3-ol (0.40 g) in acetonitrile (30 ml) and the mixture heated at 100° C. for 24 hours. The solvents were removed under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (2:1) to give the sub-title ketone as a brown oil (0.327 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[Li]CCCC.[CH:25](=[O:28])[CH2:26][CH3:27]>C1COCC1>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH:25]([OH:28])[CH2:26][CH3:27]
Reactant: CCC=O
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Br)c2C)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine in dry THF was added nBuLi and stirred at that temperature for 20 minutes. Excess propionaldehyde was added and stirred for 2 hours at −78° C. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. After column chromatography, an off-white solid was obtained, mp. 119–120° C. 1H NMR(CDCl3) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H), 2.21(s,3H), 2.02(s,6H), 1.65–1.8(m,2H), 1.00(t,3H) ppm.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:7][O:8][C:9]([C:11]1[C:16]([NH:17][C:24](=[O:25])[C:23]2[CH:27]=[C:19]([Br:18])[CH:20]=[CH:21][C:22]=2[F:28])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: O=C(Cl)c1cc(Br)ccc1F
Reactant: COC(=O)c1nccnc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Temperature: 40 °C
Yield: 74.9 %

Procedure:
Pyridine (7.75 g, 98.0 mmol) was added at 0° C. under N2 to a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester 101 (1.5 g, 9.80 mmol) and 5-bromo-2-fluorobenzoylchloride (9.45 g, 49.0 mmol) in CH2Cl2. The reaction mixture was warmed at 40° C. for 4 h, then cooled down at room temperature. The reaction mixture was quenched with 20 mL of ethanol, evaporated, partitioned between CH2Cl2 and 1N NaHCO3, dried (Na2SO4) and evaporated. The crude material was triturated in EtOH, filtered, washed with EtOH and ether to give 2.6 g of 3-(5-bromo-2-fluorobenzoyl-amino)pyrazine-2-carboxylic acid methyl ester 102 as a white powder (LCMS analysis).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[CH:20]=[CH:19]4)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH:39]=[C:38]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1.CN(C=O)C>[CH2:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:35]4[CH2:36][CH:37]=[C:38]([C:41]5[C:49]6[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=6)[NH:43][CH:42]=5)[CH2:39][CH2:40]4)[O:28][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: CCc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C

Procedure:
To a solution of (2R)-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.60 g, 1.5 mmole) and potassium carbonate (0.65 g, 4.70 mmole) in 30 mL of 1:1 THF/DMF was added 0.90 g (4.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The mixture was heated at reflux under nitrogen for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness under vacuum and the residue column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum and the residue recrystallized from ethanol to give 0.42 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 190° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7])(=[O:34])=[O:33]
Reactant: O=C(OCCCO)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A suspension of 3.3 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid 3-hydroxypropyl ester in a mixture of 60 ml. of methylene chloride and 5 ml. of triethylamine is treated dropwise at 15°-20° C. with a solution of 2.4 ml. of methanesulfonyl chloride in 10 ml. of methylene chloride and the mixture is stirred at room temperature for 1 hour. After dilution with 60 ml. of methylene chloride, the suspension is removed by filtration and the filtrate washed successively with water, 0.5-N hydrochloric acid, 5% sodium bicarbonate solution and again with water. After drying over sodium sulfate and evaporation of the solution, there is obtained a solid crude product which is chromatographed on 100 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The uniform fractions yield 5-chloro-3-phenylisoindole-1-carboxylic acid 3-[(methylsulfonyl)oxy]propyl ester having a melting point of 155°-158° C. which can be used in the process without further purification. An analytical sample is obtained by recrystallization from ethanol, and there are obtained greenish crystals having a melting point of 159°-161° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:8]=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2].[CH3:20][O:21][C:22]([N:24]=[C:25]=[S:26])=[O:23]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:8]=[CH:7][C:6]=1[NH:19][C:25]([NH:24][C:22]([O:21][CH3:20])=[O:23])=[S:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(S(=O)c2ccccc2)ccc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1NC(C)=O

Procedure:
1 G. of 2-acetamido-1-amino4-phenylsulfinylbenzene in 30 ml. acetone is treated overnight with 2 g. methoxycarbonyl isothiocyanate. The solution is concentrated and the residue triturated with ether. Recrystallization yields 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-4-phenylsulfinylbenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]([F:36])([F:35])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1.[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:22]([F:36])([F:21])[F:35])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CS1
Reactant: C[Sn](C)(C)c1ccc(OCC(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OCC(F)(F)F)nc3)cc2)CS1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)thiazoline (0.90 g, 2.5 mmol, obtained from precursor VP3 and Lawesson's Reagent in toluene) was mixed with 2-trifluoroethoxy-5-trimethylstannylpyridine (1.21 g, 3.6 mmol), Pd(PPh3)4 (0.15 g) and lithium chloride (0.16 g) in dioxane (10 ml) and the mixture was refluxed for 8 hours. After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-trifluoroethoxypyridin-5-yl)phenyl]thiazoline was obtained, 0.46 g, beige solid; MS: M+ 450.
Reaction SMILES: [C:1]([C:5]1[C:14]([OH:15])=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C=O>[C:1]([C:5]1[C:14]([O:15][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cc(O)c(C(C)(C)C)cc2o1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc2nc(C)oc2cc1C(C)(C)C

Procedure:
6.9 g of the benzoxazole derivative obtained in Step (c) above was dissolved in 50 ml of dimethylformamide and the solution was stirred at 80° to 90° C. for 6 hours together with 8 g of anhydrous potassium carbonate and 11 g of hexadecyl bromide. After the completion of the reaction, the insoluble material was removed by filtration. To the filtrate was added 150 ml of methanol and the mixture was cooled with ice to precipitate crystals. The crystals were collected by filtration, thus obtained 8.8 g (62%) yield) of 6-tert-butyl-5-hexadecyloxy-2-methylbenzoxazole.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:16][CH:15]=[CH2:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: C=CCBr
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1ccc(C=O)cc1

Procedure:
3.8 g (12 mmol) of sodium hydride (80% in oil) and 100 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 15 g (10 mmol) of 4-formylbenzoic acid in 100 ml of DMF is added dropwise and the mixture is stirred until the evolution of gas has ceased. 10 ml (12 mmol) of allyl bromide are then added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 17.2 g (90%) of the expected allyl ester are collected in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A quantity of 5.2 g of 5-bromo-3-chloro-2,4-difluorobenzoic acid is suspended in 30 ml of dichloromethane; then 2.92 g of oxalyl chloride is added, and 3 drops of dry DMF are added. The mixture is stirred at room temperature for 3 hours and the desired compound is isolated after evaporation of the solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13]([C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[O:31])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccnc2c(Sc3nc4ccccc4[nH]3)cccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccnc2c(S(=O)c3nc4ccccc4[nH]3)cccc12

Procedure:
The product of step (b) above (390 mg) in ethyl acetate (20 ml) was cooled to -5° and treated with m-chloroperbenzoic acid (273 mg of 85% pure material). The temperature was allowed to rise to ambient. The reaction mixture was then diluted with ethyl acetate and methylene chloride, and then washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The solution was dried and evaporated. Column chromatography (SiO2 /ethyl acetate) gave the title compound 140 mg, mp 178°-9° (d).