Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](=[O:16])[N:14]=[N:15][C:11]3=[CH:10][C:9](=[O:17])[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](=[O:16])[N:14]=[N:15][C:11]3=[CH:10][C:9](=[O:17])[N:8]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:7]=2[CH:24]=1)=[O:26]
Reactant: CSc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)c1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
3.22 g of 8-(methylthio)-6-phenyl-1H-s-triazolo [4,3-a][1,5]benzodiazepine-1,5-dione and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromatographed on twenty silica gel (1000μ plates, 20 × 20 cm) using acetone-methanol (9:1) as eluting solvent. The band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[CH2:32][OH:33].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[C:23]([CH2:32][OH:33])=[CH:24]2)[CH:7]=1
Reactant: OCc1cnc2ccccc2c1O
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(CO)c(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C
Yield: 73.6 %

Procedure:
To a suspension of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (344 mg) and 4-hydroxy-3-hydroxymethylquinoline (412 mg) in anhydrous ethanol (2.5 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 439 μL). After heating at 85° C. for 17 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 80%-100% ethyl acetate-hexanes) to give the title compound as a white solid (405 mg), m.p. 183° C.-184° C.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:10][C:8]3[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=4[CH:12]4[CH2:21][CH2:20][C:19]5[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=5[CH2:13]4)=[CH:6][CH:7]=3)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 133.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:16]=[C:14]([CH:15]=1)[CH2:13][N:12](C(=O)C)[CH2:11][CH2:10][N:9](C(=O)C)[CH2:8][CH2:7][N:6](C(=O)C)[CH2:5]2.CC([O-])(C)C.[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:15]=[C:14]2[N:16]=[C:4]([CH:3]=1)[CH2:5][NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][CH2:13]2
Reactant: CC(=O)N1CCN(C(C)=O)Cc2cc(Cl)cc(n2)CN(C(C)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc2nc(c1)CNCCNCCNC2

Procedure:
5.1 g (13-9mmol) of the title compound of Example 5 (h) is dissolved under nitrogen in 50 ml of dioxane. To this mixture is added 6.24 g (55.6 mmol) of potassium tert-butylate, and the mixture is refluxed overnight, evaporated to dryness, taken up in 50 ml of water, and extracted 4 times with 100 ml of hot toluene. The combined toluene phases are dried over magnesium sulfate and evaporated under vacuum. The residue is purified by chromatography (silica gel/methanol/water/ammonia (aq. 33%) =10/1/1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazol-4-yl]propionate (505 mg), 3-picolyl chloride hydrochloride (476 mg), potassium carbonate (601 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (531 mg, yield: 83%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].C([Li])CCC.Br[CH:46]([OH:48])[CH3:47]>C1COCC1>[OH:48][CH2:46][CH2:47][CH2:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3]
Reactant: CC(O)Br
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCCO
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
834 mg of trans-2-[3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran dissolved in 8 ml of dry THF was cooled to -78° C. and to it was added 2 ml of n-butyllithium (1.6N solution in THF) in a nitrogen atmosphere. After 15 min. 140 mg of bromoethanol dissolved in 2 ml of THF was added to the reaction mixture. The yellow solution was warmed to room temperature and was quenched with a saturated NH4Cl solution. The title compound was obtained after workup and chromatography on silica gel: MS, m/z 600 M+ ; NMR (CDCl3, 200 MHz) δ 1.0 (t, OCH2CH2CH3), 1.82 (q, OCH2CH2CH3), 1.9-2.4(m, SO2CH2CH2CH2OH, H-4), 2.5(m, H-3), 3.58 (t, SO2CH2CH2CH2OH), 3.72(m, CH2OH), 3.86, 3.92(2s, 3 OCH3), 4.18 (t, OCH2CH2CH3), 5.18(s, OCH2Ar), 5.08-5.22 (m, H-2, H-5), 6.62(s, C5ArH), 7.28-7.54(m, ArH).
Reaction SMILES: [NH2:1][C:2]1([C:15]#[N:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=N)SC)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1>CC(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2([NH:1]/[C:36](=[N:35]\[C:33]([C:26]3[C:25]([NH2:24])=[N:30][C:29]([NH2:31])=[C:28]([Cl:32])[N:27]=3)=[O:34])/[NH:16][CH2:15]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC1(N)CCN(Cc2ccccc2)CC1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)/N=C2/NCC3(CCN(Cc4ccccc4)CC3)N2)nc1Cl
Temperature: 70 °C

Procedure:
4-Amino-1-benzyl-piperidine-4-carbonitrile (Intermediate G) (200 mg, 0.91 mmol) in dry propan-2-ol (10 ml) is treated with triethylamine (0.25 ml) followed by 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (355 mg, 0.91 mmol). The mixture is heated at 70° C. for 5 hours and then allowed to cool to room temperature. The precipitate is collected and washed with methanol to afford the title compound as a light yellow solid, 190 mg; [M+H]+ 415
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH2:27]([O:26][C:24]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CC1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred mixture of 175.4 parts of ethyl 4-piperidineacetate, 116.6 parts of sodium carbonate and 2250 parts of trichloromethane there were added dropwise 119.4 parts of ethyl chloroformate. After stirring for 4 hours at room temperature, the reaction mixture was diluted with 400 parts of water. The organic layer was separated, dried, filtered and evaporated, yielding 277 parts (100%) of ethyl 1-(ethoxycarbonyl)-4-piperidineacetate (interm 18).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=2)[N:7]=1.[CH3:18][NH:19][CH3:20].C(O)(C)(C)C.Cl>O>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=2)[N:7]=1
Reactant: CCCc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CCCc1nc2ccc(N(C)C)nn2c1S(N)(=O)=O
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-2-n-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.50 g, 1.81 mmol), 50% aqueous dimethylamine (1.0 ml) and t-butanol (5.0 ml) was heated at 100° C. for 8 hours with stirring in a sealed tube reactor. The reaction solution was left and cooled to room temperature, poured into water (50.0 ml) and adjusted to pH 6 with dilute hydrochloric acid, to precipitate crystals which were then filtered and washed with water, to give the title compound as pale yellow crystals. The yield was 0.38 g (74.0%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(tetrahydropyran-4-yl)-ethanol (1.5 g, 11.5 mmol) in 10 mL of CH2Cl2 and 7 mL of pyridine was added p-toluenesulfonyl chloride (2.4 g, 12.7 mmol) portion wise over 15 minutes. The mixture stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 302 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:25])=[N+:7]2[O-].C(OC(=O)C)(=[O:28])C.CO>C(O)(=O)C>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:25][OH:28])=[N:7]2
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1Br
Temperature: 110 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A solution of S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline 1-oxide (497 mg, 1.21 mmol) in acetic acid (12 mL) was heated at 80° C. for 15 minutes. To the solution was added acetic anhydride (1.37 mL, 14.5 mmol) and the resulting solution was heated at 110° C. for 2 hours. The reaction mixture was cooled to 50° C. and methanol (6 mL) was added and stirred for 1 hour. The reaction was cooled to room temperature and concentrated. The resultant oil was taken up in tetrahydrofuran (20 mL) to which was added 6 M potassium hydroxide (20 mL) and stirred for 1 hour. The product was extracted with ethyl acetate and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (366 mg, 74%). LCMS-ESI+ (m/z):
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29](=[S:31])[NH2:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.CCO.Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[S:31][CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(C(N)=S)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-8-carbothioamide (Intermediate 575, 54 mg, 0.128 mmol) in mixture of EtOH:DMF (1 mL: 0.5 mL) were added ethyl bromopyruvate (47 mg, 0.24 mmol) and molecular sieves, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography to give product as solid. Yield: 13 mg (20%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCNC(=O)c4ccccc4)c(=O)c1n23

Procedure:
To a solution of 2.44 g (10.0 mmol) of 1-[4-(amino)butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 2.09 ml (15.0 mmol) of triethylamine in 80 ml of methylene chloride was added, while stirring under ice-cooling, 1.39 ml (12.0 mmol) of benzoyl chloride. The mixture was stirred for 0.5 hour at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([F:9])([F:8])[F:7].[NH2:14][C:15]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:17][N:16]=1>C(O)(=O)C>[CH2:21]([S:20][C:18]1[N:19]=[C:15]2[N:14]=[C:5]([C:6]([F:9])([F:8])[F:7])[CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[N:16]2[N:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(C(F)(F)F)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 20.8 g (0.100 mol) of 1,1,1,5,5,5-hexafluoro-2,4-pentanedione and 20.6 g (0.100 mol) of 3-amino-5-benzylthio-1,2,4-triazole in 150 ml of glacial acetic acid was heated at reflux for 14 hours. The solution was cooled to room temperature and poured over ice. The solid which separated was collected by filtration, washed with water and dried in vacuo to yield 35.5 g (94%) of the desired product as a pale yellow solid, m.p. 78.5°-80.5° C. IR, 1H NMR and 19F NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCCCNc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
A mixture of 99.8 g (0.670 mol) 2,4-dichloropyrimidine, 52.8 g (0.703 mol) 3-amino-propan-1-ol and 135.6 g (1.34 mol) triethylamine was stirred at room temperature for 12 h. The residue was treated with a mixture of 500 ml saturated sodium carbonate solution and 1000 ml ethyl acetate. The organic phase dried (sodium sulphate) and evaporated to give an oil that solidified in the refrigerator overnight. The material was extracted with 200 ml ethyl acetate and the soluble fraction containing the 2-isomer evaporated (the 4-isomer remains insoluble in ethyl acetate). Chromatography on silica (ethyl acetate) gave 28.9 g (23%) of 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15]O)[C:4]=2[CH:3]=[CH:2]1.S(Cl)([Cl:19])=O.CN(C)C=O>C(Cl)Cl>[Cl:19][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCOCCc1cccc2sccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCCCOCCc1cccc2sccc12

Procedure:
In 7.0 mL of methylene chloride was dissolved 1.40 g of 3-[2-(1-benzothiophen-4-yl)ethoxy]-1-propanol, followed by adding thereto 1.10 mL of thionyl chloride and 0.05 mL of N,N-dimethylformamide, and the resulting mixture was heated under reflux for 5 hours. Then, the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography (eluent; hexane:ethyl acetate=20:1) to obtain 1.43 g of 4-[2-(3-chloropropoxy)ethyl]-1-benzothiophene as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([O:28]CC)=O)=[O:7])=[CH:4][CH:3]=1.[NH3:33].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([NH2:33])=[O:28])=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1nc(N(C)c2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1ccc2ncccc2c1)c1nc(C(N)=O)c(NC(=O)c2ccc(F)cc2)s1
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of ethyl 5-(4-fluorobenzamido)-2-[methyl(quinolin-6-yl)-amino]thiazole-4-carboxylate (0.14 g, 0.31 mmol) in THF (5 mL) was added 7N NH3-MeOH (5mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were purified by silica gel chromatography eluted with EtOAc to give 110 mg (84% yield) of the titled compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:19]([NH:21][C@H:22]([C:31]([NH:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:19]([NH:21][C@H:22]([C:31]([NH:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C

Procedure:
4.3 g of Z-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH3 in 300 ml of methanol are hydrogenated with 1 g of 10 % strength palladium on charcoal catalyst in the usual manner and after completion of the hydrogen uptake the mixture is filtered and the filtrate evaporated. The evaporation residue, a solid colourless foam, is employed for the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:6]2.C(Cl)(=O)C([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([Cl:20])=[O:16])[CH:7]=[CH:6]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2cc(CC(=O)O)ccc2c1
Product: COc1ccc2cc(CC(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution dissolved 21.3 g (0.1 mol) of (6-methoxy-2-naphthyl)acetic acid in tetrahydrofuran anhydride (200 ml) was slowly added 19.0 g (0.15 mol) of oxalyl chloride and 1 ml of dimethylformamic at 0° C. After stirring at the room temperature for 15 hours, solvent and an excess of oxalyl chloride were removed to nearly quantitatively yield (6-methoxy-2-naphthyl)-acetyl chloride as product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)([Cl:18])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[C:6]([Cl:18])[C:7]=1[OH:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CCc1ccc(O)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1cc(Cl)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of Intermediate 5 (516 mg) in chloroform (5 ml) was added with sulfuryl chloride (177 μl), and stirred at room temperature for 21 hours. The reaction mixture was poured into aqueous saturated sodium hydrogencarbonate (20 ml), and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 6, 290 mg).