Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:65]=[CH:64][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:60]([O:62]C)=[O:61])[CH2:59][CH2:58]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:65]=[CH:64][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:60]([OH:62])=[O:61])[CH2:58][CH2:59]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CC2)C3)cc1)c1ccc(Cl)cc1
Yield: 88 %

Procedure:
The compound of example 588 was prepared analogous to compound of example 98 by hydrolysis of compound of example 587.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[S:7][N:6]=1)(=O)=O.CS(C1N=C(C2C=CC=CC=2Cl)SN=1)=O.[CH2:32]([OH:37])[C:33]#[C:34][CH2:35][CH3:36].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[S:7][N:6]=[C:5]([O:37][CH2:32][C:33]#[C:34][CH2:35][CH3:36])[N:9]=1
Reactant: CS(=O)(=O)c1nsc(-c2ccccc2Cl)n1
Reactant: CCC#CCO
Agent: CS(=O)c1nsc(-c2ccccc2Cl)n1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCC#CCOc1nsc(-c2ccccc2Cl)n1
Reaction time: 1 h

Procedure:
In 3 ml of N,N-dimethylformamide, 400 mg of a mixture of 3-methylsulfonyl-5-(2-chlorophenyl)-1,2,4-thiadiazole and 3-methylsulfinyl-5-(2-chlorophenyl)-1,2,4-thiadiazole, and 136 mg of 2-pentyne-1-ol were dissolved, to the resulting solution was added 65 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 1 hour, and further stirred at room temperature for 1 hour. Then, the reaction mixture was added to an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 220 mg of 5-(2-chlorophenyl)-3-(2-pentynyloxy)-1,2,4-thiadiazole (the compound (77) of the present invention).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][C:33]([N:8]1[C:9]2[C:5](=[C:4]([F:3])[C:12]([C:13]3[C:21]4[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=4[N:15]([CH3:23])[CH:14]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:34]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Yield: 36 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), 2,5-difluorophenylacetic acid (48.3 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), and DIEA (0.196 mL, 1.123 mmol) was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and a precipitate formed. The precipitate was collected by filtration, and dried at the pump for 1 hour. The residue was adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtAc) to afford 5-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (44.2 mg, 36.0% yield) as a white solid. LC-MS (ES) m/z=438 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23-3.29 (m, 2H), 3.75 (s, 3H), 3.97 (s, 2H), 4.36 (t, J=8.34 Hz, 2H), 5.78-6.19 (m, 2H), 7.13-7.32 (m, 5H), 7.89 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC#Cc1cc(Cl)cnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Cl)cnc2[nH]1
Temperature: 85 °C
Yield: 84 %

Procedure:
5-Chloro-3-prop-1-ynyl-pyridin-2-ylamine (53.7 g, 0.32 mol) was treated with a 1M solution of potassium tert-butoxide in tert-butanol (515 mL) and the reaction mixture was heated at 85° C. for 1 hour. The mixture was then allowed to cool to ambient temperature and poured onto a 1:1 mixture of water/ice (ca. 1 L). The resultant precipitate was collected by filtration, washed with water and left to air dry. The resultant solid was dissolved in dichloromethane, dried (Na2SO4), filtered and evaporated then triturated with diethyl ether to afford the title compound as a grey solid (44.8 g, 83%). LCMS (Method B): RT=3.64 min, M+H+=167/169. 1H NMR (400 MHz, DMSO-d6): 8.02 (d, J=2.4 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 6.11 (d, J=1.1 Hz, 1H), 2.40 (d, J=1.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:14][OH:15])[NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCl.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:19][CH2:20][C:21]([N:10]1[CH:9]([CH2:14][OH:15])[CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC(CO)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1Cc2cc([N+](=O)[O-])ccc2CC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-methanol (1.648 g, 7.92 mmol), dichloromethane (60 ml) and triethylamine (1.1 ml), cooled in an ice bath, was added chloroacetyl chloride (0.651 ml). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with dilute hydrochloric acid and then with water. The organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to yield 2-chloro-1-(3-hydroxymethyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (2.08 g); MS 285 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1nc2ccccc2o1
Temperature: 0 °C

Procedure:
22.3 g (0.16 mole) of glycine ethyl ester hydrochloride were stirred in small portions into a mixture of 23.0 g (0.15 mole) of 2-chlorobenzoxazole, 250 ml of absolute acetonitrile and 44.2 g (0.32 mole) of anhydrous K2CO3 at 50° C. in the course of 3 hours, with stirring. The mixture was subsequently stirred under gentle reflux (80°-82° C.) for a further 4 hours, cooled in an ice-water bath and poured into about 750 ml of ice-water.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[O:22]=[C:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:23]3([OH:22])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (17.29 g, 81 mmol) was dissolved in THF (214 mL) under argon at room temperature. Chlorotrimethylsilane (20.60 mL, 17.63 g, 162 mmol, 2 eq.) was added, and the mixture was stirred at room temperature for 3 h. Then, it was cooled to 0° C., and 2-propyl magnesium chloride (170 mL of a 2.0 M solution in THF, 340 mmol, 4.2 eq.) was added. The mixture was stirred for further 3 h while warming up to room temperature. Then, tert-butyl 3-oxopiperidine-1-carboxylate (25.00 g, 121 mmol, 1.5 eq.) was added, and stirring was continued for another 16 h. The reaction was quenched with a 1:1 mixture of concentrated aqueous ammonium chloride solution and ice until the pH value reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The title compound crystallized upon trituration of the residue with diethyl ether (50 mL). The crystals were washed with diethyl ether and dried to give 17.20 g (64% of th.).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH3:33])(=[O:31])=[O:30])[C:19]([Cl:34])=[CH:18][N:17]=1.Cl.O1CCOCC1>COCCO>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH3:33])(=[O:31])=[O:30])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 14 %

Procedure:
7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (160 mg, 0.84 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (280 mg, 0.84 mmol) and 4N HCl in dioxane (0.21 ml, 0.84 mmol) were dissolved in 2-methoxyethanol (4 ml) and heated to 120° C. for 5 hours. The mixture was concentrated to a brown solid. Preparative TLC (5% MeOH/CH2Cl2) gave a brown residue which was triturated with MeOH/CH2Cl2 to 2-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamideas a white solid, 58 mg. (14% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.23 (s, 1H), 8.32-8.58 (m, 1H), 8.27 (s, 1H), 7.45-7.90 (m, 5H), 7.23-7.37 (m, 1H), 7.14-7.22 (m, 1H), 3.22 (s, 3H), 2.39-2.60 (m, 5H), 1.92-2.18 (m, 4H); MS (m/e) 487 (M+1); retention time 7.65 minute; mp 175-177° C.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(OC([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=O)C.C1(S([O-])(=O)=O)C=CC=CC=1.C(OC(OC1C=CC(S([O-])(=O)=O)=CC=1)=O)C.[OH-].[K+]>C(O)C.C1C=CC=CC=1>[O:1]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([OH:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: CCOC(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: c1ccccc1
Product: O=S(=O)(Oc1ccccc1)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Sodium phenoxide, 9.0 g. (0.078 mole) is added in portions to a solution of 20 g. (0.076 mole) of 4-ethoxycarbonyloxybenzenesulfonyl chloride in 250 ml. of dry benzene. The slurry is brought to reflux (80° C.) for 1.5 hours and then allowed to stir at room temperature overnight. The reaction is followed by thin layer chromatography, additional sodium phenoxide is added as needed, and the reaction is refluxed until complete. The slurry is then cooled to room temperature and filtered to remove sodium chloride. The filtrate is concentrated to give 22.3 g. (88%) of the desired benzene sulfonate as an oil of suitable purity for the next reaction. The 4-ethoxycarbonyloxybenzene sulfonate (22.3 g., 0.069 mole) is taken up in 120 ml. of ethanol and stirred at 20° C. while a solution of 5.3 g. (0.08 mole) of potassium hydroxide in 50 ml. of ethanol is added dropwise. After two hours at room temperature, the solution is brought to 40° C. for 30 minutes and then concentrated in vacuo. The residue is taken up in 250 ml. of water (pH=10), extracted once with ether, acidified to pH 1 with 10 ml. of concentrated hydrochloric acid and then extracted three times with 200 ml. portions of chloroform. The chloroform extracts are combined, dried over sodium sulfate and concentrated in vacuo to give 15.9 g. (91%) of the phenol as an oil which crystallizes on standing; m.p.=114°-116.5° after recrystallization from xylene.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:32])=[N:22]1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[N:3]=3)[CH2:35][CH2:34]2)=[O:32])=[N:22]1
Reactant: Fc1ccc(-c2nsc(Cl)n2)cc1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccc(F)cc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of 5-chloro-3-(4-fluorophenyl)-1,2,4-thiadiazole (119 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 114 mg (48.5%) of the desired product.
Reaction SMILES: [CH:1]1([C:5]2[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11][CH:12]([CH:15]=O)[CH:13]=O>>[Br:11][C:12]1[CH:13]=[N:10][C:7]2[N:8]([N:9]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:6]=2)[CH:15]=1
Reactant: Nc1cc(C2CCC2)[nH]n1
Reactant: O=CC(Br)C=O
Product: Brc1cnc2cc(C3CCC3)nn2c1

Procedure:
The title compound, yellow solid, MS: m/e=254.0/252.1 (M+H+), can be prepared in accordance with the general method of example 9, step 1 from 5-cyclobutyl-1H-pyrazol-3-ylamine and 2-bromomalonaldehyde.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3cc(C(F)(F)F)cnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]methyl}amino)benzoate (775 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred for 1 day with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (671 mg, 87%) as a pale-brown solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[C-:23]#[N:24].[K+]>CS(C)=O>[C:23]([CH2:11][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14]1)#[N:24]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3O2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCCC1Cc2ccccc2O1
Yield: 92.6 %

Procedure:
Starting from 15.2 g (48 mmol) of 2-p-toluenesulfonyloxyethyl-2,3-dihydrobenzofuran (compound described in the U.S. Pat. No. 4,129,655) and 3.4 g (52 mmol) of potassium cyanide in 170 ml of dimethyl sulfoxide treated under the conditions described in step 5 of Example 7, 7.7 g of product were obtained in oil form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16]2/[C:17](=[O:22])NC(=S)[S:20]/2)=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[SH:20])/[C:17]([OH:25])=[O:22])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COc1cc(/C=C2\SC(=S)NC2=O)ccc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Product: COc1cc(/C=C(\S)C(=O)O)ccc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-[1-(4-Benzyloxy-3-methoxy-phenyl)-meth-(Z)-ylidene]-2-thioxo thiazolidin-4-one (38 g) and 2.5M NaOH were warmed at 80° C. for one hour. Next the solution was cooled to 10° C. and poured slowly into 6M HCl-solution (200 ml). The reaction mixture was stirred at room temperature for one hour. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]([S:13](Cl)(=[O:15])=[O:14])([CH3:12])[CH3:11]>N1C=CC=CC=1.Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:13]([CH:10]([CH3:12])[CH3:11])(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccc(NS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 4-methylsulfanyl-phenylamine (1.1 eq) in pyridine (1.3M) at 0° C. was added iso-propylsulfonyl chloride (1.5 eq). The mixture was stirred at room temperature for 12 h, poured in HCl (1N) and extracted with EtOAc. The combined organic extracts were washed with HCl (1N; 2×), water (2×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc 0 to 50% in 15 min) and a suspension-filtration sequence in Hex/CH2Cl2 afforded the desired compound as a white solid.
Reaction SMILES: F[B-](F)(F)F.[H+].Br[CH:8]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9]1.C([O-])(O)=[O:17].[Na+].[OH-].[K+]>O1CCOCC1.[Hg]=O>[C:8]1([OH:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: O=C([O-])O
Reactant: BrC1Cc2ccccc21
Agent: F[B-](F)(F)F
Agent: O=[Hg]
Agent: [H+]
Solvent: C1COCCO1
Product: OC1=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of mercury(II) oxide (591.3 mg, 2.73 mmol) and 35% aqueous tetrafluoroboric acid (TFBA) (999.4 mg, 5.46 mmol) in 1,4-dioxane (10.9 mL), 1-bromobenzocyclobutene (1.0 g, 5.46 mmol) was added. The reaction stirred at room temperature for 2 h and was then treated successively with NaHCO3 and 3N KOH until the solution remained basic. The precipitated mercury(II) oxide was filtered off and the filtrate extracted with CH2Cl2 (3×300 mL), dried with anhydrous Na2SO4, filtered, and concentrated to yield white crystals that were purified via column chromatography using a 3:2 Hexanes:EtOAc solvent system.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17]COC)=[C:5]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[CH:6]=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(O)(=O)C.C(O)C.ClCCl.[C].[Pd]>[OH:17][C:4]1[C:5]([CH3:6])=[CH:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COCOc1c(C=O)cc(N2CCCC2=O)cc1OC
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(N2CCCC2=O)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
3-methoxy-2-methoxymethoxy-5-(2-oxopyrrolidin-1-yl)benzaldehyde (0.72 g, 2.56 mmol) was dissolved in a solvent mixture of acetic acid (5 ml) and ethanol (7 ml) and 10% palladium carbon (70 mg) was added thereto to perform catalytic reduction at 50° C. for 10 hours. The reaction solution was cooled to room temperature and filtrated by cerite. The filtered cake was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (2.0 ml, 25.6 mmol) and triethylsilane (2.0 ml, 12.8 mmol) were added thereto under ice cooling. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→ethyl acetate). The purified product was concentrated under reduced pressure to obtain 1-(4-hydroxy-3-methoxy-5-methylphenyl)pyrrolidin-2-one (0.41 g) as light yellow oil.
Reaction SMILES: I(OC(=O)C1C=CC=CC=1)(=O)=O.CS(C)=O.[F:17][C:18]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[C:24]2[C:19]=1[C:20](=[O:49])[C:21]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)=[CH:22][N:23]2[CH2:32][CH2:33][S:34]([CH2:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35].O>C(OCC)(=O)C>[F:17][C:18]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[C:24]2[C:19]=1[C:20](=[O:49])[C:21]([C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)=[CH:22][N:23]2[CH2:32][CH2:33][S:34]([CH2:37][CH2:38][CH:39]=[O:40])(=[O:35])=[O:36]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCS(=O)(=O)CCCO)c12
Agent: O=C(O[I+2]([O-])[O-])c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCS(=O)(=O)CCC=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
O-iodoxybenzoic acid (IBX, 1.9 g, 6.78 mmol) was added to a dimethyl sulfoxide (DMSO) solution (3 ml) of 5-fluoro-1-[2-(3-hydroxypropane-1-sulfonyl)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (2.7 g, 5.65 mmol) and stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture. Subsequently, insoluble matter was filtered off, and the filtrate was then separated. The thus-obtained organic layer was washed with water and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified material was concentrated to dryness under reduced pressure, giving a white powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionaldehyde (1.8 g, yield: 67%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2ccc(C(F)(F)F)cc2)c(=O)c1=O
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure for example 1step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 4-trifluoromethyl-benzylamine was used in place of 4-fluoro-benzylamine. Yield: 63%; mp: 306-308° C.; 1H NMR (300 MHz, DMSO-d6): δ1.37 (m, 9H), 4.81-4.87 (m 2H), 7.57 (d, J=7.9 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.81 (brm, 1H), one N--H proton not seen; IR (KBr, cm-1): 3291s, 3244s, 3061w, 2980m, 1794m, 1656s, 1567s, 1540s, 1471s, 1327s, 1162s, 1127s; MS (ES) m/z (relative intensity): 349 (M+ +Na, 20), 327 (M+ +H, 100); Anal. Calcd. for C16H17F3 N2O2 : C, 58.89; H, 5.25; N, 8.58. Found: C, 59.07; H, 5.34; N, 8.31.