Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=C)[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[C:5]2[C:21]#[N:22].C[N+]1([O-])CC[O:27]CC1.C1COCC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:27])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[C:5]2[C:21]#[N:22]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c2cc(Cl)cc(C=O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Osmium tetroxide (0.1 mL, 0.013 mmol) (4% in water) was added to a solution of 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indole-3-carbonitrile (385 mg, 1.157 mmol) and NMO (271 mg, 2.313 mmol) in Acetone (20 mL) and Water (5 mL). The reaction was stirred at ambient temperature for 2 hours and then THF (10 mL) and sodium periodate (742 mg, 3.47 mmol) were added. The reaction was stirred for 1 hour, and precipitate formed. The solvent was evaporated and the residue was taken up in water (100 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 10% to 15% ethyl acetate/hexanes to give 5-chloro-7-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (310 mg, 0.926 mmol, 80% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 10.22 (s, 1H), 8.0 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 5.80 (s, 2H), 3.43 (app T, J=8.2 Hz, 2H), 0.84 (app t, J=8.2 Hz, 2H), −0.07 (s, 9H). LC (HPLC method 4): tR=3.68 min.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1COCC1.CC(C)([O-])C.[K+].F[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>C(OCC)(=O)C>[CH2:1]([O:9][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:34])[F:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 75 °C
Yield: 99.3 %

Procedure:
1-octanol (315 μL, 2.0 mmol), THF (5 mL), potassium t-butoxide (5 mL, 1M solution in THF), 4-Fluoro-3-trifluoromethylbenzoic acid (417 mg, 2.0 mmol) were mixed and heated at 75° C. for 3-4 hrs. The reaction mixture was then diluted with ethyl acetate and washed with water. The water layer was acidified and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated to afford the title compound (632 mg, HPLC purity >95%), which was used for next reaction without further purification. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was 3.28 min with gradient 50-98% acetonitrile-H2O (0.1% trifluoroacetic acid (TFA)) in 3.5 min as mobile phase.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.N1[CH:39]=[CH:38]C=CC=1>C1(C)C=CC=CC=1.C(O)CO.C(OCC)C>[CH2:39]1[CH2:38][O:30][C:13]2([CH2:14][C@H:15]([CH3:21])[C@@:16]3([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]4[C@@H:18]3[CH2:19][CH2:20][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])[CH2:12]2)[O:22]1
Reactant: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: CCOCC
Product: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Reaction time: 6 h

Procedure:
A solution of 30 g of 17β-hydroxy-1α-methyl-5α-androstan-3-one in 300 ml of toluene and 90 ml of ethylene glycol is combined with 900 mg of p-toluenesulfonic acid and stirred for 6 hours with gradual removal by distillation. After cooling, the reaction solution is mixed with 3 ml of pyridine, diluted with diethyl ether, and washed with water. After evaporation, 35 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17β-ol is obtained.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CO>C(Cl)(Cl)Cl>[Br:1][CH2:15][C:14]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (35 ml) in chloroform (150 ml) was added dropwise over 3 hours to a stirred mixture of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (150 g), chloroform (50 ml) and methanol (235 ml). When the addition was complete, the mixture was stirred at ambient temperature for a further 3 hours, then it was diluted with ice-cold water (750 ml). The product was extracted into dichloromethane (3×200 ml), and the combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (3×100 ml) and water (100 ml), dried (MgSO4), and the solvents removed in vacuo, to leave 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone as an oil which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[OH:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CCCCC(O)(CCl)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 94.4 %

Procedure:
A mixture of 40 g (0.14 m) of 1-chloro-2-(2,4-dichlorophenyl)hexan-2-ol and 38.6 g (0.57 m) of imidazole in 10 ml of dimethyl formamide is heated at 160° for one hour. The reaction mixture is cooled, poured into 300 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated sodium chloride solution and dried over MgSO4. Solvent is evaporated to give 42 g of a gummy brown solid, mp 78°-80°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2C=CC=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)C>CN(C=O)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:51][CH2:52][CH3:53])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and ethylamine (41.3 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26.2 mg, 78%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:49](=O)[CH2:50][CH3:51]>O.ClCCCl.C(O)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:14]([CH2:49][CH2:50][CH3:51])[C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(N)cc2)cc1
Reactant: CCC=O
Reactant: O=Cc1nc(-c2ccccc2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a mixture of 4-phenyl-1,3-thiazole-2-carbaldehyde (380 mg, 2.0 mmol), methyl 3-{4-[(4-aminobenzyl)oxy]phenyl}-propanoate (570 mg, 2.0 mmol), acetic acid (0.1 mL), and 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.6 g, 2.8 mmol) under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hr. Propanal (120 mg, 2.1 mmol) and sodium triacetoxyborohydride (0.4 g, 1.9 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:2 in volume ratio) to give the title compound (340 mg, yield 68%) as a yellow oil.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH:16](Br)[Br:17])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20](=[O:24])[CH:21](Br)[Br:22].CCN(CC)CC.P([O-])(OCC)OCC>C1COCC1>[S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH2:16][Br:17])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20](=[O:24])[CH2:21][Br:22]
Reactant: O=C(c1ccc2c(c1)OCCc1cc(C(=O)C(Br)Br)sc1-2)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)OCCc1cc(C(=O)CBr)sc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(2,2-dibromoethanone) (2d) (0.65 g, 1.08 mmol) in 20 ml THF at 0° C. was added Et3N (0.45 ml, 3.24 mmol) and diethyl phosphite (0.42 ml, 3.24 mmol). The reaction mixture was gradually warmed to room temperature and the mixture was stirred for 1 hr. The volatiles were removed under reduced pressure and the crude residue was washed with n-pentane to yield an yellow solid (2e) that was used in the next step without purification (0.42 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a stirred solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.29 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.05 g, 1.25 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then 2-(bromomethyl)-5-(trifluoromethyl)furan (0.25 mL, 1.80 mmol) was added. The mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 40% gradient) to afford 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 80%): mp 111-112° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=9.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.15-7.12 (m, 1H), 7.06-7.01 (m, 3H), 6.77-6.76 (m, 1H), 6.55-6.52 (m, 1H), 5.20-4.85 (m, 4H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ175.7, 163.9, 158.1, 154.9, 151.6, 141.4, 130.2, 129.5, 123.9, 123.1, 120.7, 117.9, 117.1, 112.9, 109.3, 108.9, 108.8, 107.9, 81.2, 56.2, 37.5, 9.8; MS (ES+) m/z 462.9 (M+23).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=2[CH3:14])[CH:2]=1.CI.[O-][CH2:20]C.[Na+]>C(O)C>[CH3:20][S:15][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([CH3:14])[N:12]=1
Reactant: CC[O-]
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1cccnc1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nc(C)c(Cc2cccnc2)c(=O)[nH]1

Procedure:
Treatment of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil with methyl iodide and sodium ethoxide in ethanol at 0° followed by acidification gave 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 208°-211°.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:21])[O:12][CH2:13][C:14]2[O:15][C:16](=[O:20])[O:17][C:18]=2[CH3:19])=CC=1)([O-])=O.[NH2:22][C:23]1[S:27][N:26]=[C:25](/[C:28](=[N:56]/[OH:57])/[C:29]([NH:31][C@@H:32]2[C:39](=[O:40])[N:38]3[C@@H:33]2[S:34][CH2:35][C:36](/[CH:44]=[C:45]2/[C:46](=[O:55])[N:47]([C@@H:50]4[CH2:54][CH2:53][NH:52][CH2:51]4)[CH2:48][CH2:49]/2)=[C:37]3[C:41]([OH:43])=[O:42])=[O:30])[N:24]=1.CC(C)=O>CS(C)=O>[NH2:22][C:23]1[S:27][N:26]=[C:25](/[C:28](=[N:56]/[OH:57])/[C:29]([NH:31][C@@H:32]2[C:39](=[O:40])[N:38]3[C@@H:33]2[S:34][CH2:35][C:36](/[CH:44]=[C:45]2/[C:46](=[O:55])[N:47]([C@@H:50]4[CH2:54][CH2:53][N:52]([C:11]([O:12][CH2:13][C:14]5[O:15][C:16](=[O:20])[O:17][C:18]=5[CH3:19])=[O:21])[CH2:51]4)[CH2:48][CH2:49]/2)=[C:37]3[C:41]([OH:43])=[O:42])=[O:30])[N:24]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Reactant: Cc1oc(=O)oc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of 13.2 g (44.72 mmol) of carbonic acid 5-methyl-2-oxo-[1,3]dioxol4-ylmethyl ester 4-nitro-phenyl ester in 200 ml of dimethylsulfoxide are added 20.0 g of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The mixture is stirred under argon at room temperature for 4 hours and 1000 ml of acetone are added. The slightly turbid solution is clarified by filtration over a fluted filter. To the clear motherliquour are added 34.0 ml (34 mmol) of a 1N solution of sodium-2-ethylcaproate in acetone at room temperature during 20 minutes. The slightly yellow suspension is stirred for 10 minutes at room temperature, the solid is collected by filtration, washed with 1000 ml of acetone and 1000 ml of n-pentane and dried under high vacuum. The product is suspended in 600 ml of acetone and stirred at room temperature for 2 hours. The product is collected by filtration and dried under high vacuum to yield 23.94 g of the title compound as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:13]2[CH:12]=[C:11]([CH3:10])[NH:15][N:14]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)ncc2C)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (1.25 g, 7.8 mmol) in EtOH (30 ml) was added 5-methyl-1H-pyrazol-3-ylamine (756 mg, 7.8 mmol) and DIPEA (2.8 mL). The mixture was heated at 70° C. overnight. LC/MS showed the completion of the reaction. The title compound was obtained by filtration under vacuum as a white solid (700 mg). m/z 224.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN1CCOCC1.ClC(OCC)=O.S(O)(C1C=CC(C)=CC=1)(=O)=O.[NH2:57][C@H:58]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61]>O1CCCC1.CN(C)C=O>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20]([NH:57][C@H:58]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)OCc2ccccc2)cc1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
In 500 ml of tetrahydrofuran is dissolved 46.2 g (100 millimoles) of Z-Arg(Tos)-OH, and 11 ml of N-methylmorpholine is added to the solution and the mixture is stirred at -5° C. for 5 minutes. Then, 9.6 ml of ethyl chloroformate is added to the mixture, and a cooled solution of 39.4 g (100 millimoles) of Tos-OH.H-Leu-OBzl and 11 ml of N-methylmorpholine in dimethylformamide is added to the above mixture. The resulting mixture is stirred at -5° to 0° C. for 4 hours and concentrated under reduced pressure. The residue is dissolved in 700 ml of ethyl acetate, and the solution is washed with 0.1 N aqueous hydrochloric acid, 1 N aqueous NaHCO3 and water and concentrated under reduced pressure. Ether is added to the residue and the formed precipitate is recovered by filtration to obtain 58 g of intended Z-Arg(Tos)-Leu-OBzl (the yield being 87%).
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:26])=[CH:7]/[CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][C:17](=[O:19])[CH3:18])[C:12]([CH3:20])=[C:11]([CH3:21])[C:10]=1[O:22][C:23](=[O:25])[CH3:24])(=O)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>CO>[C:23]([O:22][C:10]1[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]([O:16][C:17](=[O:19])[CH3:18])=[C:14]([CH3:15])[C:9]=1[CH2:8]/[CH:7]=[C:6](\[CH3:26])/[CH2:5][OH:4])(=[O:25])[CH3:24]
Reactant: CC(=O)OC/C(C)=C/Cc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(C/C=C(\C)CO)c1C
Temperature: 25 °C
Yield: 90.5 %

Procedure:
5.0 g of (E)-4-(2',5'-diacetoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenyl acetate are dissolved in 50 ml of methanol and treated with 0.2 g of boron trifluoride etherate. The mixture is boiled at reflux for 4 hours, then cooled to room temperature and poured into aqueous sodium bicarbonate solution. The aqueous solution is extracted with diethyl ether, and the ether phase is washed in sequence with sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to dryness. From the residue (4.6 g) there are obtained by column chromatography (silica gel, diethyl ether/n-hexane/methanol) 4.0 g of (E)-4-(2',5'-diacetoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenol in the form of white crystals, m.p. 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21](OC)=[O:22])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylate (0.15 g, 0.41 mmol) in 1 ml of THF at −78° C. was added 1M DIBAL-H in toluene (1.03 ml, 1.03 mmol) dropwise. After 5 min, the reaction was allowed to warm to room temperature and stirred for 4 h. Water (0.1 ml), 10% NaOH (0.1 ml) and celite were added to the reaction solution and the mixture was filtered. Washed with THF and the filtrate was dried over Na2SO4, filtered, concentrated and purified by flash chromatography (silica, 20-50% EtOAc/hexanes) to provide {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol as white solid: 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.5 Hz, 1H), 8.05 (m, 2H), 7.56 (dd, J=8.4, 2.5 Hz, 1H), 7.13 (m, 3H), 4.72 (d, J=6.2 Hz, 2H), 2.98 (d, J=6.2 Hz, 1H); LCMS [M+H]+=337.3.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[C:20]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:19]=3[CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH:8]=[CH:7][C:6]=1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2].[Br:32]Br>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[C:20]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:19]=3[C:18]([Br:32])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH:8]=[CH:7][C:6]=1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1OC(C)=O
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1OC(C)=O

Procedure:
Prepared from acetic acid 2-acetoxy-4-(benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (Example 36) according to the procedure of Example 37. White solid: mp 178-179° C.: MS (EI): [M+], 1 bromine isotope pattern, 504, 506; Anal. Calc. for C26H17BrO4S: C, 61.79, H, 3.39, N, 0.00. Found: C, 61.37, H, 3.32, N, 0.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1F.[NH2:13][C:14]1[CH:19]=[N:18][C:17]([Cl:20])=[CH:16][N:15]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][C:3]4[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[N:15][CH:16]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Product: CS(=O)(=O)c1cccc(F)c1Oc1ccc2ncnc(Nc3cnc(Cl)cn3)c2c1

Procedure:
The compound of Example 144 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-difluoro-3-(methylsulfonyl)benzene, 2-amino-5-chloropyrazine and 4-chloro-6-hydroxy-quinazoline.