Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:21].[Na+].CO>C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH:2]([OH:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)cc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(F)cc1

Procedure:
A mixture of ethyl 5-bromo-6-(4-fluorophenyl)-6-oxohexanoate (17.6 g), sodium formate (16.9 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml), and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, the residue was subjected to silica gel column chromatography, and ethyl 6-(4-fluorophenyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (13.8 g, 96%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[NH:20][C:19]4=[O:27])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[C:4]([O:28][CH3:29])[C:3]1=[O:30].Cl[C:32]1[C:41]2N=C(OC)C(=O)N(C3CC3)C=2N=CN=1.N1CCC(N2C3C=CC=CC=3NC2=O)CC1.C(N(CC)CC)C>C(O)CCC>[CH:1]1([N:2]2[C:11]3[N:10]=[CH:9][N:8]=[C:7]([N:12]4[CH2:13][CH2:14][CH:15]([N:18]5[C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=6[NH:20][C:19]5=[O:27])[CH2:16][CH2:17]4)[C:6]=3[N:5]=[C:4]([O:28][CH3:29])[C:3]2=[O:30])[CH2:41][CH2:32]1
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Reactant: COc1nc2c(Cl)ncnc2n(C2CC2)c1=O
Agent: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C2CC2)c1=O

Procedure:
8-Cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one was prepared in the same manner as 8-methyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one. The reaction of 4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one (0.59 g, 2.33 mmol), 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.507 g, 2.33 mmol, triethylamine (0.708 g, 7.99 mmol, 0.98 mL). anhydrous n-butanol (8 mL) at 80° C. for 16 hours gave rise to 0.856 g of 8-cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one as a light brown solid, which was used without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[C:26]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH2:17][CH3:18])[CH:11]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1cc(O)cc(C)c1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a mixture of 6.3 g of 4-benzyloxy-3-ethyl-5-methylphenol, 3.2 g of triethylamine and 50 ml of chloroform was added dropwise 4.0 g of benzoyl chloride with stirring at 0° C. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added 100 ml of 10% hydrochloric acid, which was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with 10% hydrochloric acid, aqueous sodium hydrogencarbonate solution and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, which afforded 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate (yield, 93%).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:25]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:34][CH:35]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-[3-({2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (51.0 mg, 0.247 mmol)(prepared as described in J. Med. Chem., 2006, 49, 4451-4454) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.021 g, 19%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42-8.39 (m, 1H), 7.85 (d, J=7.6 z, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.30-7.25 (m, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.64 (t, J=7.4 Hz, 1H), 6.52 (s, 1H), 6.29 (d, J=7.8 Hz, 1H), 5.27 (t, J=6.2, 1H), 4.77 (d, J=6.4 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 2.90 (t, J=6.0 Hz, 2H), 2.68-2.58 (m, 4H), 1.86-1.76 (m, 4H). MS=537 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CS(C)=O.Br[C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]>[F:27][C:25]1[CH:24]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:26]=1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: [Cu]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1-c1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 113.3 %

Procedure:
To 2-bromo-4-fluoro-1-nitrobenzene (185.16 mg, 0.842 mmol) was added Pd2dba3 (23.12 mg, 0.025 mmol) and copper powder (271 mg, 4.26 mmol). Dimethylsulfoxide (2.3 ml) and methyl 2-bromo-4-fluorobenzoate (0.122 ml, 0.842 mmol) were added and the mixture was stirred vigorously at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and dried (anhydrous Na2SO4) and concentrated to give a yellow oil (279.8 mg). This oil was utilized without purification for the preparation of Example 38b.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17](I)=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>>[Cl:1][C:2]1[C:3]2[C:17]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of N-[4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (see Example 1) with ethynyl-trimethylsilane according to the General Procedure A. tR=7.48 min. 1H NMR (CDCl3) δ 8.18 (s, 2H), 7.38 (s, 1H), 5.49 (s, 2H), 3.74 (s, 3H), 2.24 (s, 6H), 1.35 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][S:5][S:6][CH2:7][CH:8]([OH:11])[CH2:9]Cl.CO.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:11]1[CH2:9][CH:8]1[CH2:7][S:6][S:5][CH2:4][CH:3]1[O:12][CH2:2]1
Reactant: OC(CCl)CSSCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: C1OC1CSSCC1CO1
Temperature: 5 °C

Procedure:
Next, a mixed solution of bis(3-chloro-2-hydroxypropyl)disulfide described above and 250 g of methanol was dripped into a reaction vessel containing a mixed solvent consisting of 500 g of toluene and 240 g of 47% aqueous solution of sodium hydroxide with the temperature of the solution in the reaction vessel being maintained at 0 to 10° C. At the point of the completion, no scum-like insoluble matter was generated. 100 g of toluene was added to carry out extraction, the aqueous layer was removed, and the organic layer was washed with 180 g of water three times. After that, no scum-like insoluble matter was generated. After that, the solvent was distilled away, thereby obtaining 171 g of bis(β-epoxypropyl)disulfide.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].CC1C=CC(C(C)C)=CC=1.C[O-].[Na+]>>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C
Yield: 33.1 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (21.0 g, 0.067 mol), 2-hydroxy-4-n-octyloxybenzophenone (22.0 g, 0.067 mol), and p-cymene (80 g) are charged to a reaction flask. The mixture is heated to dissolve, and sodium methoxide (1.0 g, 25% in methanol) is added as catalyst. The solution is heated with agitation under a nitrogen flow at reflux (176°-178° C.) for 24 hours. After cooling to room temperature, the solution is filtered, and the black filtered solid (~1 g) is discarded. The product is then precipitated with methanol. The yellow solid (12.5 g) obtained is vacuum filtered, and identified using thin layer chromatography, with toluene:acetone (1:1) as the mobile phase. To remove the yellow color, the solid product is dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 8.2 g of the title compound as an off-white solid, m.p. 124°-126° C. H NMR shows proton resonances at 0.73 ppm, triplet, 3 protons, (terminal --CH3 in --OC8H17); 1.06-1.24 ppm, complex, 8 protons, (inner 4X-CH2 in --OC8H17); 1.32 ppm, quintet, 2 protons, (--CH2 beta to Ar--O); 1.71 ppm, quintet, 2 protons, (--CH2 gamma to Ar--O); 2.32 ppm, singlet, 3 protons (--CCH3); 4.03 ppm, triplet, 2 protons, (--CH2 alpha to Ar-0); 4.24 ppm, singlet, 2 protons, (Ar--CH2 --Ar); 6.48 ppm, doublet, 1 proton, (C8H17OCCH--); 6.82 ppm, 1 proton, (CH3CCHC--CH2 --Ar); 7.40-7.64 ppm, complex, 6 protons, (Ar--COCCHCH3 --, C8H17OCCHCH--,--NCCHC2H2 --); 7.68 ppm, doublet, 2 protons, (AR--COCCHC3H3CH), 7.95 ppm, complex, 2 protons, (--NCCHC2H2CH); 8.05 ppm, 1 proton, (CH3CCHCNCOH); 11.46 and 12.80 ppm, two singlets, two protons, (exchangeable --OH protons).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:26]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:14][C:13]1[C:8]([CH2:7][C:6]([NH2:26])=[O:5])=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:11][CH:12]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1cnc(N2CCN(C)CC2)cc1CC(=O)OC(C)(C)C
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N2CCN(C)CC2)cc1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-Methyl-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester (320 mg, 1.05 mmol) is dissolved in a mixture of TFA and CH2Cl2 (10 ml/10 ml) and stirred at RT. After 1 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (1.5 ml). Under an atmosphere of argon, carbonyl diimidazole (187 mg, 1.16 mmol) is added. After 30 minutes at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 16 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 95:5 to 40:60) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.07 (s, 3H), 2.38 (s, 3H), 2.64 (s, broad, 4H), 3.34 (s, 2H), 3.46 (s, broad, 4H), 6.72 (s, 1H), 6.95 (s, broad, 1H), 7.44 (s, broad, 1H), 7.87 (s, 1H). ES+−MS: 249.3 [M+H]+, ES−−MS: 247.3 [M−H]−.
Reaction SMILES: [O:1]=[C:2]([C@H:23]([CH3:70])[C@@H:24]([O:61][C:62]([O:64][CH2:65][C:66]([Cl:69])([Cl:68])[Cl:67])=[O:63])[C@@H:25]([CH3:60])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:59])=[CH:30]\[CH2:31][C@H:32]([O:51][Si](CC)(CC)CC)/[C:33](/[CH3:50])=[CH:34]/[C:35]1[N:36]=[C:37]([CH2:40][O:41][C:42]([O:44][CH2:45][C:46]([Cl:49])([Cl:48])[Cl:47])=[O:43])[S:38][CH:39]=1)[C:3]([CH3:22])([CH3:21])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.Cl.P([O-])([O-])([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[O:1]=[C:2]([C@H:23]([CH3:70])[C@@H:24]([O:61][C:62]([O:64][CH2:65][C:66]([Cl:67])([Cl:68])[Cl:69])=[O:63])[C@@H:25]([CH3:60])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:59])=[CH:30]\[CH2:31][C@H:32]([OH:51])/[C:33](/[CH3:50])=[CH:34]/[C:35]1[N:36]=[C:37]([CH2:40][O:41][C:42]([O:44][CH2:45][C:46]([Cl:47])([Cl:48])[Cl:49])=[O:43])[S:38][CH:39]=1)[C:3]([CH3:22])([CH3:21])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:15][CH3:16])[CH2:17][CH3:18])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC[Si](CC)(CC)O[C@@H](C/C=C(C)\C=C\C[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H](CC(=O)O)C(C)(C)C(=O)[C@H](C)[C@@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C/C=C/C(C)=C\C[C@H](O)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 10 h

Procedure:
A solution of tert-butyl (3S,6R,7S,8S,10E,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-10,12,16-trienoate (2.8 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brine, dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][C:36]1[C:37]([CH2:42]Br)=[CH:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O>[CH2:42]1[C:37]2[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][N:1]1[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Reactant: BrCc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2-n2cnc(-c3nc(CN4Cc5ccccc5C4)no3)c2[C@@H]2CCN12
Yield: 60.8 %

Procedure:
1.5 g (4.65 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 20 ml of N,N-dimethylformamide, 4 ml (13.9 mmol) of N-ethyldiisopropylamine and 1.3 g (4.9 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 1 hour. The reaction solution was evaporated, the residue was dissolved in methylene chloride and chromatographed on 50 g of silica gel while eluting with methylene chloride/ethyl acetate 1/1. There were obtained 1.2 g (61%) of (S)-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 210°-213°.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:41]([Si:45]([CH3:48])([CH3:47])Cl)([CH3:44])([CH3:43])[CH3:42].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:45]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:48])[CH3:47])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (4.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxy-phenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 42 ml of DMF are silylated, under a protective gas, with 3.15 g (20.9 mmol) of tert-butyldimethylchlorosilane and 2.53 g (37.3 mmol) of imidazole at RT for 20 h. The reaction mixture is diluted with ethyl acetate, and this mixture is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are exitacted 2× with ethyl acetate, and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 50 ml of methanol and 13 ml of THF, and this solution is treated with 3.8 g of potassium carbonate and 13 ml of water, and stirred at RT for 1 h. Subsequently, the reaction mixture is partially evaporated and the residue is diluted with ice-cold 10% citric acid solution; this mixture is then extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2:1) results in the pure title compound: TLC Rf (C)=0,13; tRet (II)=21.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH2:18]([SH:21])[CH2:19][SH:20].C(=O)([O-])[O-].[Na+].[Na+]>CS(O)(=O)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[S:21][CH2:18][CH2:19][S:20]2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: SCCS
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cl
Product: Clc1ccc(CCC2(Cn3ccnc3)SCCS2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole (2.49 g) in 98% methanesulfonic acid (10 ml) was treated with ethane-1,2-dithiol (6 ml) and the mixture stirred overnight at room temperature. The resulting mixture was poured into excess aqueous sodium carbonate, extracted with ether (3×20 ml), the extracts washed, dried (MgSO4) and the ether evaporated. The residue was taken up in a small volume of ether and treated with ethereal hydrogen chloride until precipitation was complete. The resulting precipitate was filtered off and recrystallized from methanol/ethyl acetate, to give 1-[[2-(2-(4-chlorophenyl)ethyl)-1,3-dithiolan-2-yl]methyl]imidazole hydrochloride, m.p. 206.5°-208° C. Similarly proceeding as above, but substituting the appropriate ethan-1,2-dithiol and the appropriate ketone as exemplified in Preparations 1, 2, 3 or 4 in place of 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole there may be prepared, for example, the following compounds:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CN1CCC(N)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NC2CCN(C)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 31.2 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methyl-piperidin-4-ylamine (0.134 mg, 0.95 mmol), N-methylmorpholine (99 mg, 0.95 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 75 mg, 31.2%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH-].[K+].[Br:13]Br>O>[CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[C:7]([Br:13])=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: BrBr
Reactant: Oc1ccnc(C2CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(C2CC2)ncc1Br
Temperature: 25 °C
Yield: 69.8 %

Procedure:
13.6 g (0.1 mol) of 2-cyclopropyl-4-hydroxy-pyrimidine were added to a solution of 5.6 g (0.1 mol) of potassium hydroxide in 100 ml of water. 16 g (0.1 mol) of bromine were then added dropwise at 15°-20° C., with slight cooling, and the mixture was stirred for a further hour at room temperature. The product which had precipitated was filtered off and rinsed with water. 15 g (70% of theory) of 2-cyclopropyl-4-hydroxy-5-bromo-pyrimidine were thus obtained in the form of colorless crystals of melting point 200° C.