Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH2:20][CH:21]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:32].[Na+].[BH4-].[Na+]>O1CCOCC1.O.CC(C)=O.C(OCC)(=O)C.O.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH2:20][CH2:21][OH:32])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(O[Si](C)(C)C(C)(C)C)c(CCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-(tert-butyldimethylsilyloxy)-3-allyl-5-methylbenzoate (0.239 g, 0.742 mmol) in dioxane/water (3:1, 16 mL) was treated with 2,6-lutidine (173 uL, 1.484 mmol), osmium tetroxide (3.8 mg, 0.0148 mmol) which was added as solution in acetone (1 mL) followed by sodium periodate (635 mg, 2.97 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere. After 2 hours, TLC analysis showed mostly product. the reaction was then diluted with ethyl acetate (20 mL) and water (10 mL). The ethyl acetate layer was separated and the aqueous layer was extracted once more with ethyl acetate (10 mL). The combined ethyl acetate extracts were washed with brine. They were then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. A brown oil (0.255 g) was recovered. The very unstable aldehyde was then reduced immediately by first dissolving it in methanol (5 mL) and after cooling in an ice-bath, adding sodium borohydride (50 mg, 2 equivalents). This reaction was stirred in the ice-bath and after 10 minutes TLC analysis indicated complete conversion to the alcohol. The reaction was then quenched with acetone (2 mL) and stirred for 10 minutes. The reaction mixture was then evaporated to dryness and the residue was dissolved in ethyl acetate (30 mL) and then washed once with saturated aqueous ammonium chloride and then saturated aqueous sodium bicarbonate. The ethyl acetate solution was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. A dark brown viscous oil was recovered which was purified by preparative TLC on silica using 25% ethyl acetate.hexanes. The product was obtained as a clear, viscous oil. Yield 138 mg (58%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=O.[Cl-].C([O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][CH2:11][C:10]2[O:9][C:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:7][C:6]=2[CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:30][CH:29]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Reactant: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde (3.00 g), 4-benzyloxybenzyltriphenylphosphonium chloride (6.58 g), potassium carbonate (1.84 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). A mixture of the obtained colorless oil, 5% palladium on carbon (5.00 g) and tetrahydrofuran (200 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hrs. After removing palladium on carbon by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to give 5-[2-(4-hydroxyphenyl)ethyl]-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole (3.24 g, yield 79%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 102-103° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.CO.C(Cl)Cl>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CCN2C(=O)c3ccccc3C2=O)n(Cc2ccccc2)n1
Agent: NN
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(CCN)n(Cc2ccccc2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
2-[2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethyl]-isoindole-1,3-dione (80 mg, 0.233 mmol) was dissolved in ethanol (2 ml) followed by the addition of an 1M solution of hydrazine in methanol (0.34 ml, 0.34 mmol). The reaction mixture was stirred at 90° C. for 16 h, cooled to rt and DCM (3 ml) was added and the suspension was filtered. The filtrate was concentrated under reduced pressure to give 40 mg (80%) 2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethylamine. LC-MS: tR=0.58 min; [M+H]+=216.38.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:25][CH3:26])=[CH:37][CH:36]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 9.1 %

Procedure:
A mixture of 2.55 g (6.6 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 7 g (34 mmol) of 4-[2-(diethylamino)ethoxy]-aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using firstly 5% methanol in dichloromethane and then dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 150 ml of dichloromethane. The solution was washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 1.18 g (35%) of crude product. Purification by crystallisation from cyclohexane/ethyl acetate gave 310 mg (9%) of pure 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 123-124° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:18][CH3:19])[CH2:15][O:14]C(C)(C)[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO>[CH2:1]([O:8][CH2:9][C:10]([CH2:15][OH:14])([CH2:18][CH3:19])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1(COCc2ccccc2)COC(C)(C)OC1
Solvent: O
Solvent: CO
Product: CCC(CO)(CO)COCc1ccccc1
Reaction time: 3 h

Procedure:
5-Benzyloxymethyl-2,2-dimethyl-5-ethyl-1,3-dioxane (15.0 g.) and Dowex 50×8-200 ion exchange resin (H+ form) (2.0 g.) in methanol (250ml.) containing water (50 ml.) was refluxed, with stirring, for three hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Benzyloxymethyl-2-hydroxymethyl-butan-1-ol was obtained as a yellow oil (9.7 g.).
Reaction SMILES: Br[CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(#N)C>[N:16]1([CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CCCCC(Br)C(=O)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CCCCC(C(=O)c1ccc(Cl)cc1)n1cncn1

Procedure:
2-Bromo-4'-chlorohexanophenone (0.02 mol), 1,2,4-triazole (0.10 mol) and acetonitrile (50 ml) were refluxed for 48 hours. The acetonitrile was removed in vacuo and the residue extracted with chloroform (150 ml), washed with water (5×100 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo to leave an oil which crystallised on trituration with petroleum ether (5×50 ml). Recrystallisation from petroleum ether gave 2-(1,2,4-triazol-1-yl)-2-n-butyl-4'-chloroacetophenone, m.p. 81°-83°.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[CH3:9][O:8][C:1](/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])=[O:5])=[O:7]
Reactant: CC(C)(C)OC(=O)CCCNC(=O)CCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCCCC(=O)O
Yield: 45.6 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.56 g, 4.33 mmol) dissolved in NMP was reacted at ca. 55° C. with tert-butyl 4-(2-chloroacetylamino)butanoate (0.85 g, 3.61 mmol) in the presence of CsHCO3 (0.98 g, 5.05 mmol) of the tert-butyl-protected intermediate and then purified by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. The purified product was treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal of solvents afforded 0.45 g (46% yield) of the title compound (7). 1H NMR (CD3OD, 400 MHz): δ 6.94-6.91 (m, 2H), 4.65 (s, 2H), 3.81 (s, 3H), 3.28 (t, J=6.8 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H), 1.81 (p, J=7.1 Hz, 2H). MS (ESI): m/z 274.03 (M+H)+272.06 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)=[N:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[O:9])=[CH:6][C:5]([C:36]2[CH:37]=[CH:38][C:32]3[O:31][CH2:30][CH2:29][N:28]([C:22]4[C:21]5[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=5)[N:25]=[CH:24][N:23]=4)[CH2:34][C:33]=3[CH:35]=2)=[CH:4][N:3]=1
Reactant: C[C@@H](CO)CS(=O)c1cc(Br)cnc1N
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(N)c(S(=O)C[C@@H](C)CO)c5)cc4C3)ncnc2c1

Procedure:
Prepared according to the method of example 5 by using (2S)-3-[(2-amino-5-bromopyridin-3-yl)sulfinyl]-2-methylpropan-1-ol (reagent preparation 41) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.42 (s, 1H), 8.36 (br, 1H), 8.02 (br, 1H), 7.93 (d, 1H), 7.52 (br, 1H), 7.40 (d, 1H), 7.08 (m, 2H), 7.01 (d, 1H), 5.03 (s, 2H), 4.43 (m, 2H), 4.22 (m, 2H), 3.90 (s, 3H), 3.64 (dd, 0.5H), 3.57 to 3.46 (m, 1.5H), 3.40 (dd, 0.5H), 3.14 (dd, 0.5H), 3.01 (dd, 0.5H), 2.82 (dd, 0.5H), 2.15 (m, 1H), 1.12 (dd, 3H); MS (EI) for C27H29N5O4S: 520 (MH+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O1CCCCC1OC1CCCCO1.[CH3:43][C:44]([CH:48]=O)([CH2:46][OH:47])[CH3:45].C([Li])CCC>CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH3:43][C:44]([CH3:45])(/[CH:48]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:46][OH:47]
Reactant: CC(C)(C=O)CO
Reactant: CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCC/C=C\C(C)(C)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A 5.6 g (11.9 mmoles) sample of (n-nonyl)triphenylphosphonium bromide was coupled with 1.86 g (10 mmoles) of the tetrahydropyranyl ether of hydroxypivaldehyde using the Wittig reaction conditions described in the previous examples (THF:HMPT, 2:1; 7 ml of 1.6 M n-butyllithium in hexane; -78° C.). The crude product (3.4 g) was chromatographed on silica gel. Hexane-ether (7:3) eluted 2.8 g (95%) of (Z)-2,2-dimethyl-3-dodecen-1-ol tetrahydropyranyl ether, which was dissolved in 28 ml of methanol and subsequently treated with 0.3 ml of 2 N HCl. After stirring for 3 hours at room temperature, most of the solvent (about 20 ml) was removed in vacuo, and the residue was extracted with ether. The ethereal solution was washed with brine, saturated NaHCO3 solution, brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The crude alcohol (2.2 g) was chromatographed on silica gel to afford 1.8 g (85%) of (Z)-2,2-dimethyl- 3-dodecen-1-ol as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]2)=[CH:3][CH:4]=1
Reactant: COC(=O)C1CC(=O)C1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Yield: 274.7 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tetrahydrofuran (12 L), 1,4-dibromobenzene (2020 g, 8.56 mol, 1.03 equiv), followed by the addition of n-BuLi (3566 mL, 1.03 equiv, 2.4 M) dropwise with stirring at −78° C. The mixture was stirred at −78° C. for 1 h. Into another 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 3-oxocyclobutane-1-carboxylate (1064 g, 8.30 mol, 1.00 equiv) in tetrahydrofuran (4 L). To this was added the resulting solution in the first flask dropwise with stirring at −78° C. The resulting solution was stirred overnight at 25° C. This reaction was repeated for 2 more times. The reaction was then quenched by the addition of 15 L of saturated aqueous NH4Cl, concentrated under vacuum, diluted with 15 L of H2O and extracted with 2×5 L of ethyl acetate. The organic layers were combined, washed with 1×8 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 6500 g (92%) of methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate as a dark red oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].ClCCCl>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:18](=[O:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1ccc2cc(I)ccc21
Yield: 96.5 %

Procedure:
A solution of 5-iodo-1H-indole (530 mg, 2.18 mmol), DMAP (53 mg, 0.43 mmol), triethylamine (0.46 mL, 3.30 mmol), acetic anhydride (0.81 mL, 8.57 mmol), and 1,2-dichloroethane (5.5 mL) was heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed (50 mL saturated NH4Cl then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as a white solid (600 mg, 96%). 1H NMR (300 MHz, DMSO-d6): δ 8.17 (d, 1H), 8.01 (d, 1H), 7.87 (d, 1H), 7.58 (dd, 1H), 6.70 (d, 1H), 2.64 (s, 3H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccncc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10 g, 48.1 mmol) in toluene (250 ml) at 0° C., trimethylaluminum (2M solution in toluene, 36.1 ml, 72.2 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-cyanopyridine (10 g, 96.2 mmol) in toluene (250 ml) was added over 10 minutes and the mixture was heated to 70° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate and filtered. The pale yellow solid (4.8 g, 36%) was used in the next reaction without further purification. Anal. Calc'd. for C13H14N3SClO2H2O: C, 47.34, H, 4.89, N, 12.74, S, 9.72. Found: C, 47.69, H, 4.35, N, 12.77, S, 9.74.
Reaction SMILES: [NH2:1][C:2](=[S:16])[CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[F:15].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=O>C(O)C>[F:15][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:4]=1[CH2:3][C:2]1[S:16][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[N:1]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(CC(N)=S)c(F)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c(F)c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution (4 mL) of the compound (400 mg, 1.7 mmol) obtained in Example 189c in ethanol was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (530 mg, 2.0 mmol), and the mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (540 mg, 80%) as colorless crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C1COCC1>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([CH2:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][CH:8]=[CH:9]3)[CH2:23][CH2:22]1
Reactant: CN1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C

Procedure:
Lithium aluminium hydride (2.4691 mmol, 0.0938 gram) was taken in a 25 mL two necked round bottom flask provided with a condenser, under nitrogen atmosphere. To this (1H-Indol-5-yl)-(4-methylpiperazin-1-yl)methanone (2.0576 mmol, 0.5 grams) (obtained from step (iii)) dissolved in 5 mL of THF was added and refluxed the mass for a period of 2 hours. After the completion of reaction, the reaction mixture was cooled to 25° C. and quenched by addition of ice-cold water slowly, to decompose the excess of LAH. The resultant precipitate of aluminium hydroxide was removed by filtration over hy-flow. THF was distilled off from this emulsion and the concentrate was diluted with water (20 mL), basified with 20% sodium hydroxide solution to pH: 10 and the mixture was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extracts were then washed with water (2×20 mL), brine 20 mL and dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to obtain thick syrupy mass. This syrupy compound was purified over silica gel column, eluent being ethyl acetate and triethylamine (0.2 to 1.0%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]3)=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NC1CCCCC1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CCCCC1

Procedure:
Following the procedure of Example 5, making variations only as required to use cyclohexylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as white powder (34% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.05, 7.82, 7.74, 7.65, 7.55, 7.52, 7.35, 3.69-3.79, 3.44-3.58, 3.35-3.42, 3.20-3.26, 3.11-3.18, 1.75-1.84, 1.58-1.67, 1.47-1.55, 1.10-1.35.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH2:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C([O-])(=O)C.[NH4+:18]>CO>[NH2:18][C:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH2:8])[C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CC1CCC(=O)C1C(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: C=CC1CCC(N)=C1C(=O)OCC
Temperature: 50 °C
Yield: 37.6 %

Procedure:
Ethyl 2-oxo-5-vinylcyclopentanecarboxylate (0.48 g, 2.79 mmol) was mixed with ammonium acetate (2.15 g, 27.9 mmol) in MeOH (10 mL). The mixture was heated to 50° C. for 2 hours. The contents were concentrated. The residue was partitioned between DCM and water. The DCM layer was separated, and the aqueous layer was extracted with DCM. The combined DCM solutions were dried (Na2SO4). The crude was purified with flash chromatography to give ethyl 2-amino-5-vinylcyclopent-1-enecarboxylate (0.19 g, 41% for 2 steps). 1H NMR (CDCl3, 400 MHz) δ (ppm): 5.59-5.58 (m, 1H), 5.05-4.88 (m, 2H), 3.68 (s, 3H), 3.52-3.46 (m, 1H), 2.66-2.56 m, 1H), 2.38-2.30 (m, 1H), 2.13-2.03 (m, 1H), 1.70-1.62 (m, 1H), 1.61 (br s, 2H). MS: 168.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:46]([O:48][C:49](=[O:58])[CH2:50][C:51]1[N:52]=[C:53]([NH2:57])[S:54][C:55]=1[CH3:56])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:46]([O:48][C:49](=[O:58])[CH2:50][C:51]1[N:52]=[C:53]([NH:57][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:54][C:55]=1[CH3:56])[CH3:47]
Reactant: CCOC(=O)Cc1nc(N)sc1C
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1nc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)sc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (200 mg, 0.67 mmol) in a mixture of dry methylene chloride (5 mL) and dry DMF (1 mL) were added HOBT (20 mg) and DCC (155 mg, 0.75 mmol), and the mixture was stirred at room temperature for 2 h. A solution of (2-amino-5-methyl-thiazol-4-yl)-acetic acid ethyl ester (220 mg, 0.78 mmol) and DIPEA (135 μl, 102 mg, 0.79 mmol) in dry DMF (1 mL) was added to the reaction mixture and stirring was continued for 18 h at room temperature. The mixture was evaporated in vacuo and the residue purified on a silica gel column (heptan:ethyl acetate (7:3)) to give {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic acid ethyl ester. Yield: 120 mg (37%). 1H-NMR (CDCl3): δ 8.86 (broad s, 1H), 7.91 (d, 2H), 7.52 (d, 2H), 4.14 (q, 2H), 3.66 (t, 1H), 3.57 (s, 2H), 3.07 (s, 3H), 2.32 (s, 3H), 2.25-2.18 (m, 1H), 1.93-1.86 (m, 1H), 1.81-1.43 (m, 7H), 1.24 (t, 3H), 1.16-1.06 (m, 2H); HPLC-MS: m/z=480 (M+1); Rt=4.09 min.