Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[C:7]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:13]#[C:14][CH2:15][CH3:16])=[O:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC.CC(C)=O>[C:20]([O:19][C:17]([C:7]1([CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])[CH:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][CH:8]1[OH:11])=[O:18])([CH3:21])([CH3:23])[CH3:22]
Reactant: [H][H]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC

Procedure:
A 1.4 g quantity of 3-methoxycarbonylmethyl-2-methoxycarbonyl-2-(2-pentynyl)-cyclopentanol (compound (1-a)) and 2.2 g of Lindlar catalyst are dissolved in a mixture of 50 ml of n-hexane and 5 ml of acetone. The starting compound is thus reduced at room temperature and atmospheric pressure with use of hydrogen gas. The reaction is completed when the solution has absorbed the theoretical amount of the gas, whereupon the catalyst is filtered off. The filtrate is concentrated in vacuo, and the residue dissolved in benzene-ethyl acetate and purified with a silica gel column. The product is distilled in a vacuum, giving 2-methoxycarbonyl-3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (1-b), R1 =R2 =CH3) in a yield of 87%, b.p. 74°-78° C./0.01 mm Hg.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=O)[CH2:20]Br)=[CH:17][CH:16]=1.CN(C)C=O>C(O)C>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:20]=2)=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)co2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of methyl 4-carbamoylbenzoate (4.67 g), 4-chlorophenacyl bromide (6.50 g) and N,N-dimethylformamide (5 ml) was stirred at 130° C. for 2 hours. Hot ethanol was added to the reaction mixture, which was filtered. The filtrate was cooled to obtain crystals of methyl 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoate (1.45 g, Yield: 18%). The product was recrystallized from ethanol. Pale yellow prisms. Melting Point: 183 to 184° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4]([OH:7])(=[O:6])=[O:5].[Na].O.[Cl-].[C:13]1([S+:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[C:26]1([S+:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(O)C(F)(F)CO
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=S(=O)([O-])C(F)(F)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2 L reactor was charged with 183.7 g (38% purity, 0.38 mole) of sodium 2-hydroxy-1,1-difluoroethanesulfonic acid, 300 mL of water, 450 mL of chloroform and an aqueous solution of triphenylsulfonium chloride [142.8 g (0.49 mole/1.25 equivalents) of triphenylsulfonium chloride and 150 mL of water], followed by stirring at room temperature for 1 hour. A reaction solution was analyzed by using nuclear magnetic resonance (NMR), by which there was found almost half the raw material sodium 2-hydroxy-1,1-difluoroethanesulfonic acid remaining. Accordingly, the reactor was further charged with the aqueous solution of triphenylsulfonium chloride [142.8 g (0.49 mole/1.25 equivalents) of triphenylsulfonium chloride and 150 mL of water], followed by stirring at room temperature for 0.5 hour (triphenylsulfonium chloride was used in an amount of 285.7 g (0.96 mole/2.5 equivalents) in total and the reaction time was 1.5 hours in total). The reaction solution was analyzed by using nuclear magnetic resonance (NMR), by which the raw material was detected being consumed. Thereafter, the reaction solution was separated. The obtained water layer was extracted with 100 mL of chloroform three times while distilling a solvent out of the obtained organic layer, thereby obtaining 328.2 g of the target triphenylsulfonium 2-hydroxy-1,1-difluoroethanesulfonate. In this case, the purity was 48% and the yield was 97%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:35])=[CH:32][CH:31]=1)#[N:29]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cc1

Procedure:
The title compound, off-white solid (111 mg, 97%), MS (ISP) m/z=460.5 [(M+H)+], mp 262.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:12]=1>O1CCCC1>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:12]=1)[CH3:7]
Reactant: Clc1ccc(CNc2cc(Cl)nc(Cl)n2)cc1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
To 4.2 g. of ethyl glycolate in 50 ml. of anhydrous tetrahydrofuran was added 1.7 g. of sodium hydride oil dispersion (57 percent) with stirring. There was added after 20 minutes 11.5 g. of 2,4-dichloro-6-(p-chlorobenzylamino)pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([O-])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH:28]=[CH:27][N:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:2][C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][C@@H:9]1[C:21]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[CH2:30][CH2:29][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:22])=[O:7])([CH3:4])[CH3:3]
Reactant: c1cn(CCC2CCCCN2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCCCC2CCn2ccnc2)C1
Temperature: 25 °C
Reaction time: 122 h
Yield: 30.3 %

Procedure:
1,4-Di-N-tert-butoxycarbonylpiperazine-2(R)-carboxylate (prepared as described in Preparative Example 2) (0.6946 g, 2.1 mmoles), 2(R/S)-[2-(1H-imidazol-1-yl)ethyl]piperidine (0.49 g, 2.73 mmoles) (prepared as described in Preparative Example 57, Step D) (INO972). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.524 g, 2.73 mmoles), 1-hydroxybenzotriazole (0.3693 g, 2.73 mmoles) and 4-methylmorpholine (0.2765 g, 0.3005 mL, 2.73 mmoles) were dissolved in anhydrous DMF (3 mL) and the mixture was stirred under argon at 25° C. for 122 h. The mixture was evaporated to dryness and chromatographed on silica gel using 2-3%(10% conc. ammonium hydroxide in methanol)dichloromethane as the eluant to give the title compound (0.3127 g, 30%): CIMS: m/z 492.4 (MH+): δ11 (CDCl3) 1.47 (18H, s, CH3), 7.01 (1H, s, Im-H,), 7.05 (1H, s, Im-H4) and 7.63 ppm (1H, s, Im-H2); δC (CDCl3) CH3: 28.2, 28.2, 28.2, 28.4, 28.4, 28.4: CH2: 19.1, 25.9, 26.2, 31.9, 40.8/41.3, 41.7, 43.0, 44.0: CH: 46.0, ˜52.1, 128.4, 137.2: C:˜80.4, 80.6, ˜154.3, ˜154.3 and 169.8.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:17][CH2:18][CH2:19][C:20]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=1)=[O:21]
Reactant: O=C(Cl)CCCl
Reactant: COC(=O)COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)COc1ccc(C(=O)CCCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (33.35 g) was added portionwise to a stirred cooled (<0° C.) solution of methyl phenoxyacetate (14.46 ml) and 3-chloropropionyl chloride (9.55 ml) in dichloromethane (500 ml). After the addition the ice-bath was removed and the mixture stirred for 1 hour when it was poured into ice-water (500 ml). The organic phase was separated and the aqueous portion extracted two times with dichloromethane. The combined dichloromethane extracts were washed with water, then brine and dried (MgSO4). The residue, after removal of the solvent in vacuo and trituration with ether gave methyl 4-[3-chloropropanoyl]phenoxyacetate, 22.3 g, as a solid: m.p. 89°-90° C.; NMR (d6DMSO) δ 7.95(2H,d), 7.05(2H,d), 4.92(2H,s), 3.91(2H,t), 3.71(3H,s), 3.49(2H,t); m/e 257(M+H)+ ; calculated for C12H13ClO4 : C, 56.1; H, 5.0. found: C, 55.8; H, 5.1%.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][CH:9]([CH2:11][OH:12])[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl.NC1C(CC2C=CC(Cl)=C(Cl)C=2)C2C=C(CN[S:36]([CH2:39]CC)(=[O:38])=[O:37])C=CC=2CC1>>[CH2:1]([S:4]([N:7]1[CH2:8][CH:9]([CH2:11][O:12][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:10]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CC(CO)C1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Agent: Cl
Product: CCCS(=O)(=O)N1CC(COS(C)(=O)=O)C1

Procedure:
Prepared by standard procedure from [1-(propane-1-sulfonyl)-azetidin-3-yl]methanol and methan-1-sulfonyl chloride (e.g. example 40)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]([OH:17])[C:14]([OH:16])=[O:15])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:17][CH:13]([C:9]1([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]1)[C:14]([OH:16])=[O:15])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)C1(NC(=O)OC(C)(C)C)CCC1

Procedure:
(1-Tert-butoxycarbonylaminocyclobutyl)-hydroxyacetic acid (201.5 mg, 0.822 mmol) was stirred with acetic anhydride (95 mL) in pyridine (1.5 mL) for 24 h. The mixture was first concentrated under vacuum, and then diluted with 5 mL EtOAc. The organic solution was washed with 1N HCl (2 mL) followed by saturated aqueous NaCl (2 mL), dried (Na2SO4), and evaporated under vacuum which gave the title compound. LC-UV/MS API-ES− m/z 286 [M−H]−
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (12.46 g; compound B7) in DCM (100 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (15 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[ClH:19].Br[C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH2:31][C:32]3[N:33]=[CH:34][NH:35][CH:36]=3)[CH2:29][CH2:28][N:27]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)=[O:38])[CH2:26][C:25]=2[CH:49]=1>>[ClH:19].[ClH:19].[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH2:31][C:32]3[N:33]=[CH:34][NH:35][CH:36]=3)[CH2:29][CH2:28][N:27]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)=[O:38])[CH2:26][C:25]=2[CH:49]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccco3)cc2C1
Yield: 11 %

Procedure:
Example 38 was prepared as a green solid in 11% yield from Compound A of Example 37 and 2-(tributylstannyl)furan as described for Compound B of Example 37.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[Cl-].[Ca+2].[Cl-].[CH3:29]I>CC(C)=O>[CH3:29][O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13]
Reactant: CI
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: COc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Yield: 79.7 %

Procedure:
34 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) was dissolved in 50 ml of acetone and 27.6 g of anhydrous calcium chloride was added to this solution. 15 g of methyl iodide was slowly added dropwise thereto while stirring under reflux. After stirring for 6 hours, the reaction mixture was cooled and solid matter was filtered off. The filtrate was poured into ice-water and the formed crystals were filtered off. The crystals were recrystallized from water-containing methanol to obtain 28.2 g of compound (59).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH2:4]Br.[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10]>>[CH3:1][NH:2][C:3](=[O:6])[CH2:4][NH:10][C:9]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:8]=1[CH3:7]
Reactant: CNC(=O)CBr
Reactant: Cc1cccc(C)c1N
Product: CNC(=O)CNc1c(C)cccc1C
Reaction time: 8 h

Procedure:
83 g of bromoacetic acid methyl amide and 169 ml of 2,6-dimethyl aniline are stirred for 10 hours at 140° C bath temperature. The reaction mixture is left to stand overnight at room temperature. Next morning the contents of the flask are crystallised right through. The contents are filtered off and the precipitate is washed with benzene. The precipitate is subsequently dissolved in a small amount of water, the solution is brought to a pH of 10 to 11 with 30% sodium hydroxide solution and extracted with ether. The ethereal extract is dried over sodium sulphate, the ether distilled off in vacuo, and the residue is distilled in a high vacuum to yield 55 g of 2,6-dimethylanilinoacetic acid methyl amide (b.p. 152°-154° C/0.1 Torr). After recrystallisation from diisopropyl ether the product melts at 71°-73° C. 2,6-dimethylanilinoacetic acid dimethyl amide was manufactured in analogous manner: b.p. 132° C/0.3 Torr; m.p. 52°-54° C (recyrstallisation from diisopropyl ether/petroleum ether).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.Cl[C:32](OC)=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([O:33][CH3:32])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: COC(=O)Cl
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting methyl chloroformate and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:9])=[O:8].Cl>C(O)C.[Pd].O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nccs2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(S(=O)(=O)Nc2nccs2)c1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a suspension of 1-(thiazol-2-ylaminosulphonyl )-3-nitrobenzene (0.5 g, 1.8 mmol) in ethanol (50 ml) was added 10% palladium on carbon. (0.25 g, 50% (w/w)) in water (2 ml) and 5M hydrochloric acid (1 ml, 5 mmol). The mixture was hydrogenated at 45 psi for 3 h. The catalyst was filtered off and washed with ethanol. The solvents were evaporated in vacuo and the residue chromatographed on silica gel using 10% methanol in dichloromethane as the eluant to afford the product (0.34 g, 76%) as a pale yellow solid. mp 187°-190° C. 1H NMR (360 MHz, D6 -DMSO) δ 5.49 (2H, brs), 6.66-6.73 (1H, m), 6.80 (1H, d, J=4.6 Hz), 6.85-6.90 (1H, m), 6.98-7.02 (1H, m), 7.11 (1H, dd, J=7.9 and 7.9 Hz), 7.22 (1H, d, J=4.7 Hz), 12.59 (1H, brs).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14].O1CCCC1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of 16.3 g (100 mmol) of isatoic anhydride in 100 mL of H2O is added portionwise 100 mL of 2N methylamine-tetrahydrofuran solution (200 mmol) at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic layer is washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give 13.79 g of desired product, 2-amino-N-methyl-benzamide (92 mmol, 92%) as colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:21]=[C:20]([O:22][C:23]2[CH:24]=[N:25][C:26]([CH:30]3[CH2:32][CH2:31]3)=[C:27]([Cl:29])[CH:28]=2)[C:19]([Cl:33])=[CH:18][C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12]>ClCCl>[Cl:8][C:9]1[CH:21]=[C:20]([O:22][C:23]2[CH:24]=[N:25][C:26]([CH:30]3[CH2:32][CH2:31]3)=[C:27]([Cl:29])[CH:28]=2)[C:19]([Cl:33])=[CH:18][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
Trifluoroacetic acid (42 μL, 0.56 mmol) was added to a solution of tert-butyl 2,5-dichloro-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)benzoate (Preparation 219, 116 mg, 0.28 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 4 hours then concentrated in vacuo. The residue was dissolved in methanol (10 mL) then concentrated in vacuo to afford the title compound as colourless solid (100 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[C:2]1([NH:1][C:19](=[O:20])[CH2:18][Br:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at −50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed 40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:14].[F:15][C:16]([F:27])([F:26])[S:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5]/[C:6](=[CH:22]\[C:21]1[CH:24]=[CH:25][C:18]([S:17][C:16]([F:27])([F:15])[F:26])=[CH:19][CH:20]=1)/[C:7]2=[O:14]
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1ccc2c(c1OC)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1OC)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 4,5-dimethoxy-2,3-dihydro-1H-inden-1-one (165) (100 mg, 0.520 mmol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde (72) (118.4 mg, 0.572 mmol) and PTSA (178.9 mg, 1.414 mmol). The reaction was stirred at 120° C. for 6 h. The resulting reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 25% ethyl acetate in hexane to afford yellow coloured solid of (E)-4,5-dimethoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one intermediate 166.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16].Cl>CO>[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][CH:14]([CH2:15][OH:16])[CH2:20][OH:21]
Reactant: CCOC(=O)C(Cc1cccc(Br)c1)C(=O)OCC
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCC(CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To an ice-cooled 94 ml of 1.0 M diisobutylalminium hydride toluene solution was added dropwise 5.41 g of diethyl (3-bromobenzyl)malonate at 15° C. or less under argon flow. The mixture was stirred for 30 minutes under ice-cooling, warmed to room temperature and stirred for 2 hours. The reaction solution was ice-cooled, and 21 ml of methanol was added dropwise slowly, then 41 ml of 2 N hydrochloric acid was added dropwise. The mixture was stirred for 20 minutes at room temperature. The reaction solution was filtered to remove insolubles, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform:methanol=10:1) to provide 1.96 g of the objective compound as white crystals. M.p 61–63° C.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][N:6]=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(OCC)(OCC)[CH3:20]>>[CH3:19][C:20]1[N:4]2[CH:5]=[N:6][CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1ncncc1-c1cccc(C(F)(F)F)c1
Product: Cc1nnc2c(-c3cccc(C(F)(F)F)c3)cncn12
Reaction time: 0.17 h

Procedure:
A mixture of 1.0 g. of 4-hydrazino-5-(3-trifluoromethylphenyl)pyrimidine and 10-12 ml. of triethyl orthoacetate is stirred at room temperature. Complete solution is effected in about 10 minutes and stirring is continued for an additional 30-40 minutes until a new precipitate begins to form. This precipitate is collected in 3 crops over a 4 hour period to yield 0.85 g. (77%) of product. The product is recrystallized from chloroform-hexane to give the title compound, m.p. 157°-159° C.