Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.N1C=CN=C1.Cl[Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)C>C1COCC1>[Si:21]([O:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (3.0 g, 11.7 mmol) in dry THF (100 mL) was added imidazole (3.97 g, 58.4 mmol) and chloro-tert-butyl(diphenyl)silane (6.42 g, 23.4 mmol), and the mixture stirred under nitrogen at room temperature for 20 h. Diethyl ether was added and the mixture filtered through a pad of silica. The filtrate was evaporated in vacuo and the crude product purified by flash chromatography on silica, eluting with ethyl acetate/heptane (0:10 to 2:8), to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[I:10]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:9][C:7]1[N:6]=[C:4]([OH:5])[C:3]([I:10])=[C:2]([CH3:1])[N:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(=O)nc(N)[nH]1
Solvent: CC(=O)O
Product: Cc1nc(N)nc(O)c1I
Reaction time: 8 h

Procedure:
With protection from external moisture throughout, 250.3 mg. (2.0 millimoles) of finely powdered 6-methyl-isocytosine is dissolved in 4 ml. of hot glacial acetic acid. While still hot, 450 mg. (2.0 millimoles) of N-iodosuccinimide is added to the solution and the whole is heated on a steam bath for five minutes with occasional swirling. The reaction mixture is removed from the steam bath and allowed to stand at ambient temperature. After three and one-half hours, water is added, the crystalline cake is crushed, the solid collected, washed with water, then acetone and dried in air. The crude material [335 mg.] is crystallized from approximately 10 ml. of glacial acetic acid. After being kept at room temperature overnight, the pure compound is collected, washed with its mother liquor, then with anhydrous ether repeatedly and dried in vacuo at ca. 90°C. There is thus obtained 220 mg. of 2-amino-5-iodo-6-methyl-4-pyrimidinol which melts at 211.5° to 212.5°C. with previous darkening and sintering, has λ max0.1N NaOH 236 nm. (ε9,900); 284 nm. (ε10,900) and the infrared absorption below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C(OC([N:46]1[CH2:51][CH2:50][CH:49]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([NH:61][C:62]3[N:67]=[CH:66][C:65]([NH2:68])=[CH:64][N:63]=3)=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:48][CH2:47]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:68][C:65]1[CH:66]=[N:67][C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([S:52]([CH:49]3[CH2:50][CH2:51][NH:46][CH2:47][CH2:48]3)(=[O:53])=[O:54])=[CH:56][CH:57]=2)=[N:63][CH:64]=1)=[O:6]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
Intermediate 19 (Example 27) (0.136 g, 0.44 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were diluted with DCM (4 mL) and treated with TFA (0.2 mL). After 2 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.030 g, 11%).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[N+](=[CH2:20])=[N-].C(O)(=O)C>CCOCC>[CH3:20][N:7]1[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=[C:3]1[S:2][CH3:1]
Reactant: CCOC(=O)c1nc(SC)[nH]c1C(=O)OCC
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1nc(SC)n(C)c1C(=O)OCC
Reaction time: 8 h
Yield: 97 %

Procedure:
The diethyl 2-(methylthio)-4,5-imidazoledicarboxylate (10 g; 0.039 mol) was slowly added in small portions to a solution of diazomethane in ether (containing approximately 3 g of diazomethane). Nitrogen was evolved immediately and the solution was allowed to stand at room temperature overnight. Excess diazomethane was then decomposed by the addition of dilute acetic acid and the reaction mixture was worked up in the usual way. Diethyl 1-methyl-2-(methylthio)-4,5-imidazoledicarboxylate (10.2 g; 97%) was obtained as a thick yellow oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH3:30])[N:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:31][C:32]([S:35]([N:37]=[C:38]1[CH2:41][O:40][CH2:39]1)=[O:36])([CH3:34])[CH3:33]>O1CCCC1>[CH2:29]([N:15]1[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][C:13]([C:9]2[CH:8]=[C:7]([C:38]3([NH:37][S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])[CH2:41][O:40][CH2:39]3)[CH:12]=[CH:11][CH:10]=2)=[N:14]1)[CH3:30]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
A solution of n-butyllithium in hexanes (2.50 M, 1.3 mL, 3.2 mmol, 1.5 equiv) was added to a solution of -(3-bromophenyl)-1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazole (1.32 g, 3.21 mmol, 1.5 equiv) in tetrahydrofuran (18 mL) at −78° C. The reaction mixture was stirred at −78° C. for 20 minutes, and then a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (375 mg, 2.14 mmol, 1 equiv) in tetrahydrofuran (2 mL) was added via syringe. The reaction mixture was stirred at −78° C. for 5 minutes, then the cooling bath was removed. After stirring for an additional 15 minutes, saturated aqueous ammonium chloride solution was added, and the crude product was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (10% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to afford N-[3-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (894 mg, 82%). Calc'd (M+1)+: 508.2. Found: 507.9.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[Cl:23])C1C=CC=CC=1>CO.C(Cl)Cl.CC(O)=O.[Pd]>[Cl:23][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:19][CH:20]([CH3:22])[CH3:21])[C:9]=1[OH:8])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(OC(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(O)c(OC(C)C)c1
Yield: 92.6 %

Procedure:
Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2) (3.00 g, 8.96 mmol) was dissolved in a mixture of MeOH (100 mL), DCM (10 mL) and AcOH (0.1 mL) and the solution was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The solvents were removed in vacuo to afford methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (2.03 g, 89%): m/z 245 [M+H]+ (ES+), 243 [M−H](ES−).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH:19]=[CH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1cc(C(=O)OC)ccc1OCC1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(C(=O)OC)ccc1OCC1CCCCC1
Reaction time: 24 h

Procedure:
To 23-4 (560 mg, 2.0 mmol) in 15 mL of EtOAc was added 56 mg of 10% Pd on carbon and the whole was hydrogenated at atmospheric pressure for 24 h. Hydrogen was removed from the reaction mixture and the solution was filtered through Celite. Evaporation of the solvent afforded 23-5 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)=[S:12])=[O:9])[CH:5]=[C:4]([CH3:22])[N:3]=1.[H-].[Na+].[CH3:25]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11](=[N:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[S:12][CH3:25])=[O:9])[CH:5]=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1cc(C(=O)NC(=S)Nc2ccc(F)c(F)c2)cc(Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(=Nc1ccc(F)c(F)c1)NC(=O)c1cc(C)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of intermediate D1 (38 g; 111.4 mmol) in THF (400 ml) was cooled to 0° C. and NaH (60% pure) (6.7 g; 167 mmol) was carefully added. The reaction mixture was stirred for 15 minutes and then CH3I (14.2 g; 100 mmol) was added. The mixture was then warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water and then the mixture was extracted by CH2Cl2 (3×100 ml). The combined organic solvent was washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by silica column chromatography (gradient: Heptane/EtOAc from 80/20 to 50/50). Yield: 22.2 g of intermediate D2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CS(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([O:20][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)cc1
Yield: 45.1 %

Procedure:
A solution of 1-benzyl-4-hydroxy-4-phenylpiperidine (5.35 g, 20 mM) in dry DMSO (50 ml) was treated with a 50% sodium hydride dispersion (960 mg, 20 mM) followed by 4-fluoronitrobenzene (2.82 g, 20 mM). After 24 hours the reaction mixture was partitioned between water (200 ml) and ether (200 ml). The aqueous layer was extracted with ether (2×200 ml) and the combined organic layers washed with water (200 ml). The organic phase was dried and the solvent removed under reduced pressure. Recrystallisation of the residue from IPA gave the title compound (3.5 g) m.p. 135°-7° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[N:4][O:5][C:6]=1[C:7]1([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8]1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:15])=[N:4][O:5][C:6]=1[C:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: CCOC(=O)C1(c2onc(C)c2Br)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1noc(C2(C(=O)O)CC2)c1Br
Temperature: 45 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of ethyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropane-carboxylate (11.8 g, 43.0 mmol) in THF (60 mL) was added aqueous NaOH (86 mL, 86 mmol, 1 M). The dark brown bi-phasic reaction mixture was vigorously stirred and heated to 45° C. until consumption of SM (3-4 h) was detected by LC-MS and TLC analysis. After 4 h, the homogeneous mixture was cooled to room temperature and diluted with hexanes. The organic phase was separated and the aqueous phase (pH˜14) was acidified with aqueous 1 N HCl (pH 1) (˜100 mL). The product crystallizes upon acidification of the aqueous layer. After vigorously stirring for 30 min, the solids were filtered, washed with cold (0° C.) water (3×50 mL), and dried to give white crystals. The product 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylic acid (10.0 g, 40.6 mmol, 94% yield) was isolated as white crystals. LC/MS m/z 246 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:28]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3.0 g (12.1 mmol) of the compound from Example 11A were initially charged in 30 ml of dichloromethane and cooled to 0° C., and admixed with 3.4 ml (2.4 g, 12.1 mmol) of triethylamine and 2.4 g (12.1 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm up slowly to RT and stirred at RT for 16 h. The mixture was washed several times with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent dichloromethane→dichloromethane/methanol 100:2). Yield: 4.7 g (83% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:46])[C:29]([C:31]1[N:40]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:34]2[N:35]=[C:36](Cl)[N:37]=[CH:38][C:33]=2[CH:32]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:36]4[N:37]=[CH:38][C:33]5[CH:32]=[C:31]([C:29](=[O:30])[N:28]([CH3:27])[CH3:46])[N:40]([CH:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)[C:34]=5[N:35]=4)=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@]5(CCCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 35 %

Procedure:
Following general N—C coupling procedure 1, (S)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a white solid (0.075 g, 0.115 mmol) in 35% yield. MS m/z 619.5 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:10]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: N[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)c2cccc(Cl)c2)cc1
Yield: 28.2 %

Procedure:
Under nitrogen, a solution of (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N′-phenylurea hydrochloride (150 mg), (R)-3-chlorostyrene oxide (56 mg) and N,N-diisopropylethylamine (0.17 ml) in ethanol (5 ml) was refluxed for 28 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give N-[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (45 mg) as a colorless form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(5-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](O)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1>[Pd].C(O)(=O)C>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(C(O)c2cccnc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc(Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.5 %

Procedure:
Under an atmosphere of hydrogen, a mixture of 1.9 g of the hydroxymethyl compound (prepared as described in Example 8), 1.0 g of 5% palladium on carbon and 12 ml of acetic acid was stirred at room temperature for 24 hours, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in water, neutralized with sodium bicarbonate, extracted with diethyl ether, and the extract was concentrated under reduced pressure. After addition of 6 N hydrochloric acid to the residue, the solution was concentrated under reduced pressure. The residue was purified by recrystallization from ethanol-diethyl ether to give 0.204 g of the title compound having the following physical characteristics:
Reaction SMILES: [OH-].[Na+:2].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[C:11](=[S:13])=[S:12]>O.CCO>[C:3]([C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([S-:13])[S-:12])#[N:4].[Na+:2].[Na+:2]
Reactant: CCOC(=O)CC#N
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C#N)=C([S-])[S-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
A solution of NaOH (40 g, 999 mmol) in H2O (40 mL) was slowly added via an addition funnel such that the internal temperature did not exceed 10° C. to a cold (0° C.) solution of ethyl 2-cyanoacetate (53.3 mL, 499.5 mmol) and carbon disulfide (30.2 mL, 499.5 mmol) in absolute EtOH (600 mL) Once the addition was complete, the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was then cooled to 5° C. The resulting solids were isolated by filtration and washed with EtOH (100 mL), ether (500 mL) and dried in vacuo to give sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate) (110.0 g, 97%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=1)C(OCC)=O)C.C([O-])([O-])=O.[K+].[K+]>O>[Br:17][C:13]1[CH:12]=[C:11]([CH2:5][C:4]([OH:18])=[O:3])[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccnc(Br)c1
Temperature: 100 °C

Procedure:
A suspension of 2-(2-bromo-pyridin-4-yl)-malonic acid diethyl ester (115 g, 316 mmol) and K2CO3 (125.23 g, 907.5 mmol) in water (500 ml) was heated at 100° C. for 8 h under constant stirring. Reaction mixture was cooled to rt and concentrated under reduced pressure to remove solvent completely. The solid residue was dissolved in minimum quantity of water (25 ml) and washed with 20% ethyl acetate in hexane to remove non polar impurities. The aqueous layer was separated and cooled to 0° C. followed by adjusting pH to 7 using aq. 6 N HCl. The precipitated solid was filtered using Buchner funnel, washed with ice cold water and dried under vacuum to furnish title compound as an off white solid. with sufficient purity. Yield: 60.0 g (76.3%). TLC (70% ethyl acetate in hexane) Rf=0.05; LCMS: RtH8=0.193; [M+1]+=215.9 and 217.9; HPLC RtH9=3.025 min (98%); 1H NMR (400 MHz, CDCl3): b 12.71 (s, 1H), 8.33 (d, 1H), 7.61 (s, 1H), 7.37 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15].Cl[O-].[Na+]>ClCCl>[OH:16][CH:12]([C:11]1[O:9][N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: C#CC(O)CCC
Reactant: ON=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(O)c1cc(-c2ccccc2)no1

Procedure:
In 25 ml of dichloromethane, were dissolved 5.0 g (41.3 mmol) of benzaldoxime and 4.5 g (45.9 mmol) of 1-hexyne-3-ol. Under ice cooling, 29.0 g of a 12.0% aqueous solution of sodium hypochlorite were added dropwise to the solution over 30 minutes. After completion of the dropwise addition, they were reacted at 20° C. for 2 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby the target compound, namely, 5-(1-hydroxybutyl)-3-phenylisooxazole was obtained as an oil.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C12CCCCC2
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCCC1
Reaction time: 1.25 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 75 minutes while stirring through a solution, cooled to -70°, of 18.4 g of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.55 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 200 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 17.0 g (97%) of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one were obtained as a yellow oil.