Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([C:5]([OH:7])=[O:6])[C@@H:3]1[CH:8]=[C:9]([Cl:11])[Cl:10]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([C:5]([OH:7])=[O:6])[C@H:3]1[CH:8]=[C:9]([Cl:10])[Cl:11]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O

Procedure:
100 g. of dl-cis-trans-permethric acid (consisting of 40% cis and 60% trans isomer) were stirred with 400 ml. of benzene at 27° for one hour, then the suspension was filtered. The solid product, i.e. 31 g. of permethric acid consisting of 79% cis and 21% trans isomer was worked up according to the Example (4b) for obtaining racemic cis-permethric acid. The benzene solution was evaporated to give 67.2 g. of a mixture consisting of 23% cis and 77% trans isomer which was then stirred together with extraction petroleum ether at 30° C. for 5 hours. The suspension was filtered to give 26.8 g. of dl-trans-permethric acid as a solid product containing more than 95% trans isomer.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccncc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of the obtained methyl 5-(4-pyridyl)-2-thiophenecarboxylate (410 mg) in ethanol (20 ml) was added 1 N sodium hydroxide solution (4 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in water, to which was added 1 N hydrochloric acid (4 ml). The precipitate was filtered, washed with water and dried to give the title compound (363 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1CC=C[NH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](O)C>>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(OCc1ccccc1)C1=CNC=CC1
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-trifluoromethylbenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-'2'-trifluoromethylphenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 136° C (from ethanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C.[Pd]>[CH2:14]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COCOC1CCN(CCN)CC1
Agent: [Pd]
Solvent: CCO
Product: COCOC1CCN(CCNCc2ccccc2)CC1
Reaction time: 24 h
Yield: 64.8 %

Procedure:
27 g of 1-(2-aminoethyl)-4-methoxymethoxypiperidine was dropwise added to a solution of 15 g of benzaldehyde in 300 ml of ethanol, at room temperature. The mixture was stirred at the same temperature for 1 day. To the reaction mixture was added 5 g of 10% Pd-C, and the resulting mixture was allowed to absorb hydrogen at room temperature at atmospheric pressure. After a reaction was over, the catalyst was removed by filtration. The filtrate was diluted with ethyl acetate. The dilution was subjected to extraction with 10% hydrochloric acid. The aqueous layer was made alkaline with an aqueous potassium hydroxide solution and then subjected to extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 10% methanol-chloroform) to obtain 25.50 g of 1-(2-benzylaminoethyl)-4-methoxymethoxypiperidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:23][CH2:24][O:25][CH3:26])[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC.[OH-].[Na+]>CC1C=CC=CC=1C.C1(C)C=CC=CC=1>[CH3:26][O:25][CH2:24][CH2:23][N:16]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]2[NH:42][N:41]=[N:40][N:2]=2)=[CH:10][CH:11]=1
Reactant: CCCCC(=O)N(CCOC)Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(CCOC)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h

Procedure:
A solution of 1.6 g (4.5 mmol) of crude N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(2methoxyethyl)valeramide and 1.8 g (5.5 mmol) of tri-n-butyltin azide in 15 ml of o-xylene is heated under reflux for 20-24 hours while passing a gentle stream of nitrogen through. After cooling, the solution is diluted with about 30 ml of toluene, treated with 15 ml of 1N aqueous sodium hydroxide solution and intensively stirred for 2 hours. The aqueous phase is separated off and rendered acidic with 16 ml of 1N aqueous hydrochloric acid. The precipitated product is isolated by extraction with ethyl acetate. The crude title compound is thus obtained as an oil which crystallizes from a little ethyl acetate, m.p. 120°-122°.
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19](=[S:21])[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)C.[OH-].[Na+]>CO>[CH3:13][C:12]([CH:9]1[C:10]([C:7]([CH3:16])([CH3:8])[CH3:6])([OH:11])[CH:5]=[CH:6][C:7]([C:16]2[S:20][C:19](=[S:21])[NH:18][N:17]=2)=[CH:8]1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C1C=C(c2n[nH]c(=S)s2)C=CC1(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 213.2 %

Procedure:
To a 0° C. solution of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione (5.16 g, 0.0159 mole) in methanol (50 ml), is added aqueous 1.00M NaOH (15.9 ml, 0.0159 mole) dropwise. After the addition is complete the solution is stirred one hour at room temperature before concentrating in vacuo. The residue is slurried in toluene and concentrated. The product is transferred from the flask to a crystallizing dish and dried in vacuo at 80° C. for 48 hours to provide 5.5 g (5.5 g theor., 100%) of 5-[3,4-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, mono-sodium salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([CH2:7][CH2:8]O)[CH2:4][O:3]1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)Br>ClCCl>[Br:12][CH2:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]1
Reactant: CC1(C)OCC(CCO)O1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: BrC(Br)Br
Solvent: ClCCl
Product: CC1(C)OCC(CCBr)O1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol (292 mg, 2 mmol) in dichloromethane (20 mL) at 0° C. was added carbon tetrabromide (796 mg, 2.4 mmol) and polymer-supported triphenyl phosphine (1 g, 3 mmol). After stirring for 1.75 hours and slowly warming to room temperature, the reaction mixture was filtered through Celite and rinsed with additional dichloromethane. The filtrate was concentrated to give the product as a mixture of product and bromoform (2:1). MS (DCI) m/e 208 (M+NH4—H2O)+; 1H NMR (300 MHz, DMSO-d6) □ 4.15 (m, 1H), 4.02 (dd, J=8.1, 6.1 Hz, 1H), 3.47-3.62 (m, 3H), 1.94-2.09 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)[CH:7]=[CH:6]2.B(Br)(Br)Br>>[NH2:19][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: BrB(Br)Br
Product: Nc1cccc(-c2ccc3cc(O)ccc3c2)c1
Yield: 14 %

Procedure:
The compound is prepared by reaction of 3-(6-methoxynaphthalene-2-yl)phenylamine (87.9 mg, 0.35 mmol, 1 eq) with boron tribromide (5 eq) according to method G. Purification by column chromatography with hexane/ethyl acetate 9/1 as the eluent yields the desired product in a yield of 14%, 12 mg.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:24].O[NH:38]/[C:39](=[N:56]\[H])/[C:40]1[CH:48]=[C:47]2[C:43]([C:44]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:45][NH:46]2)=[CH:42][CH:41]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:56]=[C:39]([C:40]3[CH:48]=[C:47]4[C:43]([C:44]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:45][NH:46]4)=[CH:42][CH:41]=3)[N:38]=2)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:22]
Reactant: COc1cc(C(=O)O)cnc1OC(C)C
Reactant: [H]/N=C(\NO)c1ccc2c(CCC(=O)OCC)c[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)ccc12
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
EDCI (281 mg) and HOBT (219 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinecarboxylic acid (152 mg) in THF (3 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D107) (261 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (0.91 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (30% EtOAc in hexane) to afford ethyl 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D112) (258 mg) as a pale yellow solid. MS (ES): C24H26N4O5 requires 450; found 451.2 (M+H+).
Reaction SMILES: Cl.[Cl-].[S:3]1[C:15]2[C:14]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[S+]1.S(=O)(=O)(O)O.[N:21]([O-])=O.[Na+].C>O>[S:3]1[C:15]2[C:14]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[N:21]1
Reactant: O=N[O-]
Reactant: c1cc2ccc3n[s+]sc3c2cn1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: c1cc2ccc3nnsc3c2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2.4 g. (0.009 mole) of the above hydrochloride in 50 ml. of 50% aqueous sulfuric acid was cooled to 0° C. and treated with a solution of 0.97 g. (0.014 mole) of sodium nitrite in 10 ml. of water. The mixture was stirred at 0° C. for two hours, poured into ice water, treated with charcoal, filtered, basified with ammonium hydroxide and extracted with ether. The combined ether extracts were dried, treated with charcoal, filtered and partly concentrated to yield [1,2,3]thiadiazolo[4,5-h]isoquinoline, melting point 150°-153° C.
Reaction SMILES: [Cl-:1].[Cl-].[CH:3]1([Zr+2:8][C:9]2([CH2:14][CH2:15][O:16][Si](C)(C)C)[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4]1>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH:3]1([Zr+2:8][C:9]2([CH2:14][CH2:15][OH:16])[CH:10]=[CH:11][CH:12]=[CH:13]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: C[Si](C)(C)OCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: OCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
2.16 g (5.69 mmol) of the organocomplex (cyclopentadienyl)(trimethylsiloxyethylcyclopentadienyl) zirconium dichloride was added to a suspension of 2.9 g of Silica XPO 2407 in 75 ml of dry toluene at room temperature; the suspension immediately acquired a greenish-yellow color. The sample was maintained under continuous stirring at room temperature for 48 hours. The yellow solution was separated from the solid by filtration. The solution was brought to dryness and, after washing with three fractions of 15 ml of hexane, a dusty white solid was obtained. (0.57 g Yield: 30%) 1H-NMR: (Cl3CD): 1.65 (m,1H), 2.95 (t,2H), 4.05 (m,2H), 6.32 (m,2H), 6.35 (m,2H), 6.5 (s,5H).
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=[CH:47][C:48](N2CCSC2=S)=[O:49])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38]OCCOC>O1CCCC1>[CH3:29][O:30][CH2:31][CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=[CH:47][C:48]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:49])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:36][O:37][CH3:38]
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Reactant: COCCOCOc1ccc(C=CC=CC(=O)N2CCSC2=S)cc1OCOCCOC
Solvent: C1CCOC1
Product: COCCOc1ccc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OCCOC
Yield: 160 %

Procedure:
To a solution of 650 mg (1.2 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added a solution of 966 mg (2.0 mmol) of N-[5-[3,4-di(β-methoxyethoxymethoxy)phenyl]2,4-pentadienoyl]thiazolidine-2-thione in dry tetrahydrofuran (6 ml), and the mixture was reacted at room temperature for 14 hours. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed, in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 1% methanol in chloroform, to give 1.09 g (1.6 mmol) of N-[5-[3,4-di(β-methoxyethoxy)phenyl)-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>C(N(CC)CC)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCC(O)CO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCC(O)CO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 9.6 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.41 g of 3-amino-1,2-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 0.28 g of 3-(4-nitro-3-methylphenylamino)propane-1,2-diol (9) was obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22]>>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([NH:22][CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)=[N:11][CH:2]=[N:3]2)=[CH:8][CH:7]=1
Reactant: NCCc1ccccn1
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Product: Clc1ccc2c(NCCc3ccccn3)ncnc2c1

Procedure:
Analogously to example 17, 2,4,7-trichloro-quinazoline is reacted with 2-pyridin-2-yl-ethylamine to give (7-chloro-quinazolin-4-yl)-(2-pyridin-2-yl-ethyl)-amine and is further reacted
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[C:10]([O:13][CH2:14][C:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH:16]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(C)C=CC=CC=1>C1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]3[C:15]4([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[CH2:14][O:13][C:10]=3[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Br)c(OCC3=CCN(C)CC3)cc21
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2cc3c(cc21)OCC31CCN(C)CC1

Procedure:
The title compound was prepared from 1-acetyl-5-bromo-6-[(1-methyl-1,2,5,6-tetrahydropyridine-4-yl)methoxy]indoline (D65) using a similar procedure to Description 8b in WO96/19477, but with toluene at 80° C. in place of refluxing benzene. The product was obtained from the acid/base purification as a beige solid (94%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cncnc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.49 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.132 g, 1.25 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatograph y (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.050 g, 32.6% yield). 2,8-Dimethyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.13 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.046 g, 90% yield).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:36][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To a 0° C. solution of amine from Step 1 above (200 mg, 0.4 mmol) in 6 mL of CH2Cl2 was added 0.28 mL (2.0 mmol) of Et3N followed by 0.11 mL (1.4 mmol) of methylsulfonyl chloride. The solution was stirred at 0° C. for 1.5 h, quenched with water and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in 10 mL of a 1:1:1 mixture of THF:MeOH: 1 N K2CO3, stirred for 3.5 h at room temperature, quenched with a saturated aqueous NH4Cl solution and diluted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (100% ethyl acetate) to afford the methyl sulfonamide as a foam (114 mg, 51%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1.CO.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH:10]5[CH2:9][N:8]([CH3:2])[CH2:11]5)=[C:14]([O:36][CH3:37])[CH:15]=4)[CH:24]=[CH:23][C:22]=3[CH:25]=2)=[CH:33][CH:32]=1
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C)C1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
Mix 6-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one trifluoroacetic acid salt (210 mg, 0.48 mmol) with methanol (10 mL) and acetic acid (0.3 mL). Add a solution of formaldehyde (0.20 mL, 2.66 mmol, 37% aqueous solution) and stir the mixture for 15 min. Add sodium cyanoborohydride (110 mg, 1.75 mmol) and stir the mixture at RT overnight. Concentrate the mixture in vacuo and partition the crude material between saturated NaHCO3 (25 mL) and CH2Cl2 (25 mL). Remove the organic solution and extract the aqueous phase with additional CH2Cl2 (2×25 mL). Combine the organic solutions and concentrate in vacuo. Purify the crude material by flash chromatography, using 5% MeOH (2N NH3) in CH2Cl2 as eluent, to give 133 mg (61%) of 2-(4-chloro-phenyl)-6-[3-methoxy-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one as a white solid.
Reaction SMILES: C1(SCC(OCC)=O)C=CC=CC=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC[O-].[Na+]>[CH2:21]([S:28][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CBr
Reactant: SCc1ccccc1
Agent: CCOC(=O)CSc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)CSCc1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate starting with ethyl bromoacetate (16.7 g), a 2M ethanolic solution of sodium ethylate (50 cc) and benzylmercaptan (11.7 cc). Ethyl (benzylthio)acetate (19.4 g) is thereby obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[OH-].[K+].[CH3:18]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:18]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl

Procedure:
26.3 g (0.1 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 8.1 g (0.12 M as 100%) of potassium hydroxide, 7.7 ml (0.12 M) of methyliodide and 250 ml of ethanol are mixed and are heated in a water bath at 50°-60° for 5 hours. The ethanol is distilled off. The residue in the flask is washed with water and filtered. After recrystallization from isopropanol 14.0 g (50.5 % of the theoretical yield) of N-(2,6 -dichlorophenyl)-N'-acetyl-S-methylisothiourea are isolated.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])[CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Cl:26][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCOCC2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
To a solution of 66.46G (39.3 mg, 0.13 mmol) in dry DCM (1.0 mL) and dry DMF (0.010 mL) was added thionyl chloride (0.020 mL, 0.27 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.46H (39.5 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (3H, m), 7.02 (1H, t, J=8.8 Hz), 6.85 (2H, m), 5.57 (1H, s), 4.64 (2H, s), 4.13 (2H, q, J=2.7 Hz), 3.80 (3H, s), 3.70 (2H, t, J=5.3 Hz), 2.14 (2H, dd, J=4.5, 2.5 Hz).