Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:4]=2[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:4]2[NH:3][CH2:2][CH2:7][O:6][C:5]=2[CH:8]=1
Reactant: O=C1COc2cc(F)ccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)OCCN2
Yield: 64.8 %

Procedure:
3-Oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.2 g, 1 eq, 13.1 mmol) obtained in step (ii) in dry THF (10 ml) was added drop wise to a refluxing THF (60 ml) containing LAH (1.5 g, 3 eq, 39.5 mmol). It was further refluxed for 3 h and quenched with ethyl acetate. To this water (1.5 ml), 15% sodium hydroxide (1.5 ml) and water (4.5 ml) were added sequentially. Once Al(OH)3.H2O precipitated out, it was filtered though celite. The filtrate was condensed on rotavapour and chromatographed (ethyl acetate and hexane) to yield 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, yield 65%) as yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][S:8]([CH2:11][S:12]([O-:15])(=O)=[O:13])(=[O:10])=[O:9].[Na+].Cl.CS([Cl:21])=O>P(Cl)(Cl)(Cl)=O>[CH3:7][S:8]([CH2:11][S:12]([Cl:21])(=[O:15])=[O:13])(=[O:10])=[O:9]
Reactant: CS(=O)Cl
Reactant: CS(=O)(=O)CS(=O)(=O)[O-]
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)CS(=O)(=O)Cl
Temperature: 70 °C

Procedure:
Phosphorus pentachloride (79.3 g, 0.381 mole) and sodium (methylsulfonyl)methanesulfonate (Formula II with Y=Na, X=H and R=CH3 ; 70 g, 0.359 mole) were stirred with 150 ml of phosphorus oxychloride. As the mixture was warmed to 70° C. in an oil bath, hydrogen chloride was slowly evolved, and the slurry thinned enough to be stirred with a magnetic stirrer. The mixture was heated for 18 hours in an oil bath at 80°-90° C., cooled, and filtered, and the residue was washed with dry chloroform. The chloroform caused the product to precipitate in the filtrate. The precipitate was collected, washed with a small amount of chloroform, and dried over sodium hydroxide pellets: yield, 28.5 g (41%); mp 109°-111° C.; MS (direct-probe temperature, 20° C.) m/e 193 (M+H), 192 (M), 177 (M-CH3), 157 (CH3SO2CH2SO2), 143, 141, 113 (CH2SO2Cl), 98 (CH3SOCl), 94, 93 (CH3SO2CH2), 79 (CH3SO2), 78, 64, 63 (CH3SO); IR (cm-1, strong and medium bands) 3045, 3025, 2995 s, 2930 s, 1405, 1390 s, 1380 s, 1360, 1335 s, 1325 sh, 1315 s, 1225, 1175 s, 1160 s, 1110 s, 980 s, 965, 860 s, 760 s, 695, 595 s, 515 s, 495 s, 460 s.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:13]3[S:18][C:17]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][C:14]=3[N:15]=2)[C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[N:33](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:9]=[N:33][NH:8]2)=[C:4]([C:10]2[N:11]=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:13]3[S:18][C:17]([CH2:19][N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:16][C:14]=3[N:15]=2)[CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cc(F)cc1-c1nc(N2CCOCC2)c2sc(CN3CCN(C)CC3)cc2n1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc3nc(-c4cc(F)cc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared by treatment of 5-fluoro-2-methyl-3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenylamine with isoamyl nitrite in chloroform and acetic acid.
Reaction SMILES: C(O)COCCOCCO.[FH:11].[F-].[K+].[C:14]([O:18][CH2:19][CH:20]1[CH2:22][O:21]1)([CH3:17])([CH3:16])[CH3:15].O>COC(C)(C)C>[C:14]([O:18][CH2:19][CH:20]([OH:21])[CH2:22][F:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: F
Reactant: CC(C)(C)OCC1CO1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCOCCO
Solvent: COC(C)(C)C
Product: CC(C)(C)OCC(O)CF
Temperature: 130 °C
Reaction time: 7.5 h
Yield: 61 %

Procedure:
A 1.5 L 4-necked sulfonation flask equipped with magnetic stirring bar, reflux condenser, thermometer and an argon in/outlet, was charged with 333.3 mL triethylene glycol, 235.2 g (3.012 mol) finely ground potassium hydrogendifluoride and 200 g (1.536 mol) 2-tert-butoxymethyl-oxirane. The suspension was heated under stirring at an internal temperature of 130° C. for 7.5 h. The mixture was allowed to cool to RT over night, treated with 670 mL water and 350 mL tert-butyl methyl ether, the phases were separated and the aqueous phase was extracted with 350 ml tert-butyl methyl ether. The combined organic phases were washed with 350 mL brine, dried over sodium sulfate, filtered and evaporated. The brown oily residue (286 g) was distilled to provide 141 g (61%) 1-tert-butoxy-3-fluoro-propan-2-ol as colorless liquid, b.p. 80-93° C./70-40 mbar. GC composition: 1.1% 2-tert-butoxymethyl-oxirane, 95.1% 1-tert-butoxy-3-fluoro-propan-2-ol and 3.8% of 3-tert-butoxy-2-fluoro-propan-1-ol. 1H-NMR (CDCl3, 300 MHz): 4.45 (dxm, JH,F=46, —CH2—F); 3.93 (m, br, H—C(2); 3.45 (m, —CH2—O); 2.55 (d, br, J=6, OH); 1.20 (s, C(CH3)3).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.[Li+].[OH-].CC(O)=O>CO>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccc4cn(C)nc4c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1cc2ccc(-c3ncnc4c3c(C(=O)O)cn4COCC[Si](C)(C)C)cc2n1
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate in MeOH (2.0 mL) was added 2 M aqueous LiOH (1.1 mL) and the reaction mixture was heated at 60° C. for 17 hours. The reaction mixture was then acidified with AcOH and extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid. No further purification was carried out. LRMS (ESI) calc'd for C21H26SiN5O3 [M+H]+: 424, found 424.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:3]1=[O:18].S(Cl)([Cl:22])(=O)=O.N>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:22])=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:3]1=[O:18]
Reactant: Cc1csc2c1c(-c1ccccc1)nc(=O)n2C
Reactant: O=S(=O)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)sc2c1c(-c1ccccc1)nc(=O)n2C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.33 g of 1-methyl-4-phenyl-5-methyl-1,2-dihyrothieno[2,3-d] -pyrimidin-2-one in 35 of chloroform is added dropwise 1.62 g of sulfuryl chloride in 6 ml of chloroform. After stirring the reaction mixture for 5 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia and then extracted with chloroform. The chloroform extracts are washed with water, dried, evaporated under reduced pressure to a residue to give crystals of 1-methyl-4-phenyl-5-methyl-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one, which are recrystallized from ethanol-ether to give crystals having a melting point of 190° - 191.5°C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([N:20]2[C:24]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[N:23][N:22]=[N:21]2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:34][O:35][C:36](=[O:57])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[O:48])=[CH:42][CH:41]=1)[NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:34][O:35][C:36](=[O:57])[C@H:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[O:48])=[CH:44][CH:45]=1)[NH:38][C:13]([C:12]1[CH:16]=[CH:17][C:18]([N:20]2[C:24]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[N:23][N:22]=[N:21]2)=[CH:19][C:11]=1[Cl:10])=[O:15]
Reactant: O=C(O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.8 %

Procedure:
In an argon atmosphere, DIPEA (0.102 mL; 0.585 mmol) was added to a stirred solution of 2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]benzoic acid (51 mg; 0.15 mmol), 4-[[(2,6-dichlorophenyl]carbonyl]amino]-L-phenylalanine methyl ester (60 mg; 0.15 mmol) and HBTU (59 mg; 0.1555 mmol) in dimethylformamide (3 mL). The reaction mixture was stirred for 17 hr at room temperature, then was concentrated under reduced pressure. The residual oil was taken up in dichloromethane (25 mL) and washed in turn with 0.5 N HCl (10 mL) and water (10 mL). The aqueous layers were backwashed in turn with dichloromethane. The combined organic layers were dried (Na2SO4) and evaporated to give 85 mg of crude product. This material was crystallized from dichloromethane-diethyl ether to furnish 79 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine methyl ester as a colorless solid, mp 155-158° C. FAB HRMS: (C32H26Cl3N7O5) Obs. Mass 694.1158 Calcd. Mass 694.1139 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([CH3:22])=[C:20]([C:23]#[N:24])[C:11]3[N:12]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[O:14][C:10]=3[C:9]=2F)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:33][NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([CH3:22])=[C:20]([C:23]#[N:24])[C:11]3[N:12]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[O:14][C:10]=3[C:9]=2[N:37]2[CH2:38][CH2:39][C@H:35]([NH:34][CH3:33])[CH2:36]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CCNC1
Reactant: Cc1c(-c2cccc(Cl)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3cccc(Cl)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
6-(3-Chlorophenyl)-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-311) (500 mg, 1.40 mmol) was dissolved in dimethyl sulfoxide (20 ml), and at room temperature, triethylamine (215 μl, 1.54 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (164 μl, 1.54 mmol) dissolved in dimethyl sulfoxide (3 ml) was added all at a time. After stirred at the same temperature for 30 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was first roughly purified by middle-pressure liquid chromatography using an eluent of chloroform:methanol=95:5 (v/v), and then the roughly-purified product was purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and further the obtained solid was purified in slurry with diisopropyl ether to obtain the entitled compound (250 mg, 41%) as a pale yellow solid.
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[C:42]=1[C:43](Cl)=[O:44]>ClCCl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:43](=[O:44])[C:42]3[C:46]([O:50][CH3:51])=[CH:47][CH:48]=[CH:49][C:41]=3[O:40][CH3:39])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4c(OC)cccc4OC)ccc3c2O)cc1
Reaction time: 14 h

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 6, 200 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL) and diisopropylethylamine (160 μL, 114 mg, 0.96 mmol) under nitrogen. 2,6-dimethoxybenzoyl chloride (120 mg, 0.60 mmol) was added and the solution was allowed to stir for 14 h. The resulting suspension was filtered to provide the title -compound (100 mg, 0.17 mmol, 36%) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 10.81 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=9 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 7.82 (s, 1H), 7.73 (d, J=9 Hz, 2H), 7.21 (t, J=9 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 6.67 (d, J=9 Hz, 2H), 4.72 (m, 1H), 3.87 (s, 3H), 3.82 (s, 6H), 1.32 (d, J=3 Hz, 6H); Analytical HPLC: 88% pure; MS (ES-NEG): [M−H] 578; Anal. Calc. for C29H29N3O8S: C, 60.09, H, 5.04, N, 7.25. Found: C, 57.26, H, 4.82, N, 7.09.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:14](=[O:15])[N:13]2[C:8]([S:9][CH2:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[CH3:16].[CH3:17][C:18]1[C:26]2[O:25][N:24]=[C:23]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:16][C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:15])[C:5]=1[CH2:4][CH2:3][N:30]1[CH2:31][CH2:32][N:27]([C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[C:26]=4[O:25][N:24]=3)[CH2:28][CH2:29]1)[CH2:12][CH2:11][CH2:10][S:9]2
Reactant: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reactant: Cc1cccc2c(N3CCNCC3)noc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCN(c3noc4c(C)cccc34)CC1)CCCS2
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A mixture of 7.4 parts of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido-[2,1-b][1,3]thiazin-6-one monohydrobromide, 4.4 parts of 7-methyl-3-(1-piperazinyl)-1,2-benzisoxazole, 10 parts of sodium carbonate and 94 parts of N,N-dimethylformamide was stirred overnight at 90° C. After cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.8 parts (44.6%) of 3,4-dihydro-8-methyl-7-[2-[4-(7-methyl-1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl]-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one; mp. 170.0° C. (compound 2).
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:25])[CH:21]([CH2:22][CH2:23][OH:24])[O:20]3)[CH:12]2[O:26][CH3:27])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)C>[C:28]([O:24][CH2:23][CH2:22][CH:21]1[O:20][C:19]1([CH:13]1[CH:12]([O:26][CH3:27])[CH:11]([O:10][C:8](=[O:9])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:18][CH2:17][C:14]21[O:16][CH2:15]2)[CH3:25])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCOC(C)=O
Temperature: 25 °C
Reaction time: 1.1 h

Procedure:
A mixture of 6-cyclohexylcarbamoyloxy-4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (5 mg), acetic anhydride (12 μl), pyridine (11 μl), and 4-dimethylaminopyridine (1 mg) in dichloromethane (1 ml) was stirred for 1.1 hours at ambient temperature. The mixture was diluted with diethyl ether and washed with brine (4×). The organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel to yield 4-[3-(2-acetoxyethyl)-2-methyloxiranyl]-6-cyclohexylcarbamoyloxy-5-methoxy-1-oxaspiro[2,5]octane as an oil (3.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH3:11].CS(O)(=O)=O.[CH2:23]([SH:26])[CH2:24][SH:25].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH3:11])[S:26][CH2:23][CH2:24][S:25]1
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)n1ccnc1
Reactant: SCCS
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(n1ccnc1)C1(c2ccc(Cl)cc2Cl)SCCS1

Procedure:
A mixture of 6 parts of 1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)-1-propanone and 30 parts of methanesulfonic acid was stirred till all solid entered solution. After cooling, 5.5 parts of 1,2-ethanedithiol were added while nitrogen gas was introduced. The whole was stirred overnight at room temperature. The reaction mixture was diluted with trichloromethane till a volume of 150 parts. This solution was added dropwise to a vigorously stirred solution of potassium carbonate in water. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was converted into the nitrate salt in 2-propanol. 2,2'-Oxybispropane was added till turbid and the formed salt was allowed to crystallize. It was filtered off and dried, yielding 6 parts of 2-(2,4-dichlorophenyl)-2-[1-(1H-imidazol-1-yl)ethyl]-1,3-dithiolane; mp. 141.9° C. (compound 29).
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([C:27]([OH:29])=[O:28])=[CH:16]1>CC(C)=O>[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([C:27]([O:29][CH3:4])=[O:28])=[CH:16]1
Reactant: O=C1C=C(C(=O)O)C(c2ccccc2)CC1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1=CC(=O)CCC1c1ccccc1
Temperature: 10 °C
Yield: 92.8 %

Procedure:
358 g (2.52 mol) of methyl iodide and 361 g (2.38 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were successively added to a solution of 428 g (1.98 mol) of (RS)-3-oxo-6-phenylcyclohex-1-ene-1-carboxylic acid, which was obtained according to J. Org. Chem., 1971, 36, 3707, in 4.5 cm3 of acetone and then the reaction mixture was brought to reflux for five hours. The acetone was subsequently distilled off and then the residue was stirred with 2.5 dm3 of water. After cooling to 10° C., the precipitate formed was filtered off, washed with ice-cold water and then dried at 30° C. 423 g (93%) of methyl (RS)-3-oxo-6-phenylcyclohex-1-ene-1-carboxylate were thus obtained in the form of a yellow powder, the characteristics of which were as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[C:6](=[O:16])[N:5]([CH3:17])[N:4]=1.[CH3:18][O:19][N:20]=[C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:22](=[N:24][NH2:25])[CH3:23]>CO>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[N:25][N:24]=[C:22]([CH3:23])[C:21](=[N:20][O:19][CH3:18])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:6](=[O:16])[N:5]([CH3:17])[N:4]=1
Reactant: CON=C(C(C)=NN)c1cccc(C(F)(F)F)c1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1C=O
Solvent: CO
Product: CON=C(C(C)=NN=Cc1ccccc1-n1c(OC)nn(C)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 5 °C

Procedure:
A solution of 1.17 g of 2-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzaldehyde and 1.43 g of 2-hydrazono-1-(3-trifluoromethyl-phenyl)-propan-1-one-O-methyl-oxime in 10 ml of methanol is held at reflux temperature for 4 hours. After cooling to 5° C., filtration takes place, and the filtrate is concentrated by evaporation on a rotary evaporator. The residue is chromatographed on silica gel using ethyl acetate/hexane (1:1). The title compound is thus obtained as a yellow crystal powder having a melting point of 157-161° C. in the form of an isomeric mixture in a ratio of ca. 2:1.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([C:31]([OH:33])=O)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH:22]C(OC(C)(C)C)=O)[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[O:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH2:47])[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH:47][C:31]([C:8]2([CH2:7][C:4]3[CH:3]=[CH:2][C:1]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:6][CH:5]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH2:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[O:33])[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid (0.24 mmol; 0.13 g) in DMF (5 mL) was added C-(tetrahydro-pyran-4-yl)-methylamine (0.28 mmol; 0.027 g), N,N-diisopropyl-N-ethylamine (0.48 mmol; 0.084 mL) and HBTU (0.28 mmol; 0.108 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting solution was stirred for 7 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid(tetrahydro-pyran-4-ylmethyl)-amide as a hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Br[C:16]1[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:16]3[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)c1ccc(Br)s1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)s1

Procedure:
Using the same general procedure described in the preceding Example 11, but using instead 4,4-dimethyl-6-ethynylthiochroman and ethyl 5-bromothiophene-2-carboxylate, the title compound was synthesized.