Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:9]=2/[CH:10]=[C:11]2/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/2)[CH2:4]1.O=C[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].[Na].O>C(Cl)Cl>[O:16]=[C:14]1[NH:13][C:12](=[O:17])/[C:11](=[CH:10]/[C:9]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:8]=2[N:5]2[CH2:6][CH2:7][CH:3]([NH:2][CH2:26][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:4]2)/[S:15]1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(N(C)C)C2)cc1OC
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(NCCNC(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5Z)-5-{2-[3-(dimethylamino)pyrrolidin-1-yl]-4,5-dimethoxybenzylidene}-1,3-thiazolidine-2,4-dione (Example 52) (120 mg, 0.31 mmol) and tert-butyl 2-oxoethylcarbamate (198 mg, 1.24 mmol) in CH2Cl2 (20 mL) were heated to reflux for 15 min followed by the addition of sodium triacetoxyhydroborate (65.9 mg, 0.31 mmol). The reaction mixture was refluxed overnight before being allowed to cool to ambient temperature. Water (˜0.5 mL) was added and the mixture was allowed to stir for 15 min before being loaded onto a silica gel column which was eluted with ethyl acetate/hexane (10:1) to yield the title compound as an orange solid as (60.0 mg, 39.2%); m/z 493.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ccc(C(=O)O)cc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a solution of 2-methylquinoline-7-carboxylic acid (1.00 g, 5.34 mmol) and K2CO3 (2.36 g, 17.1 mmol) in DMA (10 mL) was added MeI (0.35 mL, 5.61 mmol) dropwise at ambient temperature. The reaction was stirred at ambient temperature for 18 hours. Water (30 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with water and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:5 hexane/ethyl acetate) to give methyl 2-methylquinoline-7-carboxylate (0.99 g, 92.1%) as a solid.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:18]>O1CCCC1>[Cl:18][C:1]1[NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Reactant: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution (60 mL) of ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g) in tetrahydrofuran was blown in hydrogen chloride (28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, nitrogen was blown in to remove excess hydrogen chloride. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1) to give the title compound as a pale-yellow solid (yield 4.24 g, 79%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:31]=1>O1CCCC1>[N:31]1[CH:30]=[CH:35][CH:34]=[CH:33][C:32]=1[C:36]1[N:37]=[C:38]([C:10]2[S:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: c1ccc(-c2cscc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2csc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
After placing 3.5 g of 3,4-diphenylthiophene and 60 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 11 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 4.1 g of a zinc chloride/tetramethylethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 3.8 g of 2-bromo-6-(2-pyridyl)pyridine and 0.52 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, the organic layer was extracted, and the concentrate obtained using an evaporator was purified by recrystallization to obtain 4.5 g of 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene. After placing 3.3 g of the 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene and 80 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 6.2 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 2.4 g of a zinc chloride/tetramethyl-ethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 2.2 g of 2-bromo-6-(2-pyridyl)pyridine and 0.30 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, and the organic layer was extracted. The organic layer was concentrated with an evaporator and purified by column chromatography and recrystallization to obtain 1.1 g of BPPDPT.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15]2[N:19]3[N:20]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH2:3]1.N(C1C=NC=CC=1N1CCC[C@H](N[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])C1)=C=S.FC1C(C2N=NC(NN)=CC=2)=NC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[F:30][C:29]1[C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([NH:14][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:8]=4[N:4]4[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:3]4)=[N:16][N:17]=3)[N:20]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=C=S)C1
Reactant: N[C@H]1CCCN(c2ccncc2Nc2nnc3ccc(-c4ncccc4F)nn23)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NNc1ccc(-c2ncccc2F)nn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2Nc2nnc3ccc(-c4ncccc4F)nn23)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
N-(4-((3S)-3-amino-1-piperidinyl)-3-pyridinyl)-6-(3-fluoro-2-pyridinyl)[1,2,4]triazolo[4,3-b]pyridazin-3-amine. A mixture of (S)-tert-butyl (1-(3-isothiocyanatopyridin-4-yl)piperidin-3-yl)carbamate (193 mg, 0.58 mmol, Preparation XI) and 3-(3-fluoropyridin-2-yl)-6-hydrazinylpyridazine (113 mg, 0.551 mmol) in ACN (2 mL) was heated at 85° C. for 30 min. After the reaction mixture was cooled to RT, it was treated with DCC (125 mg, 0.60 mmol) and heating was resumed at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-10% MeOH in EtOAc) to provide (S)-tert-butyl (1-(3-((6-(3-fluoropyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (250 mg, 90% yield) as a dark green crystalline solid. MS (ESI, pos. ion) m/z: 506.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH:29][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:24]=[CH:25][CH:26]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCc1cccc(F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 2-(3-fluoro-phenyl)ethylamine (0.051 mL, 0.389 mmol) and triethylamine (0.135 mL, 0.972 mmol) in acetonitrile (10 mL). The reaction mixture stirred for 1 hr at room temperature, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide. LCMS m/z=412.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)cc1OCc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2-ol ((5.8 g, 20.7 mmol) in DMF (75 mL) was added Cs2CO3 (8.8 g, 26.9 mmol). A solution of MeI (1.62 mL, 25.9 mmol) in DMF (10 mL) was added dropwise to this mixture. After stirring at room temperature for 3 h, the reaction mixture was concentrated. The residue was taken up in H2O and the aqueous solution was extracted with CH2Cl2 (3×). Combined organic solutions washed with brine (1×), dried over Na2SO4 and concentrated. Purification by flash chromatography (250 g silica gel, 50% EtOAc in hexanes) afforded 4.02 g (66%) of 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.32 (m, 5H), 7.05 (s, 1H), 6.91 (s, 1H), 5.11 (s, 2H).
Reaction SMILES: C(O)(C)C.C(=O)=O.[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1.C([Li])(CC)C.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH:44]([C:48](Cl)=O)[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.CCOC(C)=O.CCCCCC>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:18][CH:19]=1)[C:14](=[O:15])[N:16]([CH3:17])[C:48]([CH:44]1[CH2:45][CH2:46][CH2:47][N:42]([C:40]([O:39][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:41])[CH2:43]1)=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(=O)OCc4ccccc4)C3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an isopropanol-dry ice cooled solution of 4-methoxy-N-methyl-2-(phenylmethyl)benzamide (500 mg, 1.96 mmol) in tetrahydrofuran (90 mL) was added dropwise a 1.3 M solution of sec-butyllithium (3.09 mL, 4.02 mmol). After 15 min. a solution of (±)-benzyl-3-(chlorocarbonyl)piperidine-1-carboxylate (550 mg, 1.96 mmol) in tetrahydrofuran (10 mL) was added. After 0.5 hours the contents of the reaction flask were first warmed to room temperature and then the solvent was removed in vacuo. The resulting mixture was treated with 1 M hydrochloric acid and extracted (3×) with ethyl acetate. The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated in vacuo. Trifluoroacetic acid (1 mL) was added and the resulting solution stirred 10 min. The reaction was quenched with water and made basic with saturated sodium bicarbonate. Extracted with ethyl acetate (3×), dried combined organic extracts with anhydrous sodium sulfate and removed solvent in vacuo to give a white foam. Flash column chromatography (50% EtOAc/hexane) afforded the title compound as a white foam. Proton NMR for the product was consistent with the titled compound. ESI+MS: 483.3 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2C2CCCC2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[N:47]([C:48]([N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)=[O:49])[C:46]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=3[O:65][CH2:66][CH3:67])=[N:45][CH:44]2[CH2:68][CH:69]2C[CH2:72][CH2:71][CH2:70]2)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[N:47]([C:48]([N:50]3[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]3)=[O:49])[C:46]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=3[O:65][CH2:66][CH3:67])=[N:45][CH:44]2[CH:68]2[CH2:72][CH2:71][CH2:70][CH2:69]2)=[CH:41][CH:42]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
[5-(4-Chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 19) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 525.2634, calculated for C29H38N4O3Cl [(M+H)+]525.2627.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)cn1
Temperature: 80 °C
Yield: 87.1 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 6-methoxypyridin-3-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.87 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 15 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a white solid (105 mg, 86.6%). ESI-MS m/z calc. 415.5. found 416.5 (M+1)+. Retention time 1.66 minutes.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][CH:8]([C:29](=[O:45])[NH:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH2:9][CH2:10][P:11]([O:21]CC1C=CC=CC=1)([O:13]CC1C=CC=CC=1)=[O:12])(C)(C)C.C1(C2C=CC=CC=2)C=CC(CCNC(C(CC(=O)NO)CC(O)=O)=O)=CC=1>>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][NH:30][C:29]([CH:8]([CH2:9][CH2:10][P:11]([OH:21])([OH:13])=[O:12])[CH2:7][C:6]([OH:46])=[O:5])=[O:45])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1
Agent: O=C(O)CC(CC(=O)NO)C(=O)NCCc1ccc(-c2ccccc2)cc1
Product: O=C(O)CC(CCP(=O)(O)O)C(=O)NCCc1ccc(-c2ccccc2)cc1

Procedure:
This compound was prepared by deprotection of the compound of Example 157 using a procedure similar to that of the synthesis of the compound of Example 156.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.C(C(C)=[O:31])C(C)C.N(C(C)(CC)C([O-])=O)=NC(C)(CC)C([O-])=O>CCCCCCC>[CH3:16][O:17][CH2:18][CH2:25][O:31][CH2:15][CH2:10][O:9][CH2:7][CH3:8].[C:1]([O:6][CH:7]([O:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1
Reactant: CC(=O)CC(C)C
Agent: C=C(C)C(=O)OC(C)OC1CCCCC1
Agent: C=Cc1ccc(OC)cc1
Agent: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Solvent: CCCCCCC
Product: CCOCCOCCOC
Reaction time: 6 h

Procedure:
A 500 ml three-necked flask was charged with 63.7 g (0.30 mol) of 1-cyclohexyloxyethyl methacrylate, 40.3 g (0.30 mol) of p-methoxystyrene and 300 ml of methyl isobutyl ketone. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) as a radical polymerization initiator was added to the mixture, and polymerization was performed in a nitrogen stream at 80° C. for six hours. The obtained reaction liquid was cooled, and poured in a large volume of heptane, thereby precipitating a polymer. The polymer crystal was collected by filtration, and dissolved in diethylene glycol ethyl methyl ether. The heptane and methyl isobutyl ketone contained in the solution were distilled off in vacuum, thereby obtaining a diethylene glycol ethyl methyl ether solution of polymer A1-6 (1-cyclohexyloxyethyl methacrylate/p-methoxystyrene).
Reaction SMILES: [C:1]([C@@H:4]([O:34][CH3:35])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)(=[O:3])[NH2:2].[ClH:36]>ClCCl>[ClH:36].[CH3:35][O:34][C@@H:4]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([NH:25][CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:1]([NH2:2])=[O:3]
Reactant: CO[C@@H](C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)C(N)=O
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](OC)C(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
For the preparation of the starting material compound 94.5, please see Example 94. A 25-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-carbamoyl-2-methoxyethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (100 mg, 0.20 mmol, 1.00 equiv) in dichloromethane (10 mL). Hydrochloric acid (2 M, 0.8 mL) was added at 0° C. and the resulting mixture was stirred at room temperature for 5 h. After completion, the resulting mixture was concentrated under vacuum to afford (2S)-2-methoxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide hydrochloride (90 mg) as a light yellow solid. The residue hydrochloride (90 mg) dissolved in 5 mL of methanol was added HCHO (37%, 0.5 mL) and stirred for 30 min at room temperature. Then NaBH3CN (50 mg) was added and the resulting solution was allowed to react, with stirring, for an additional 2 hr at ambient temperature. After completion, the resulting solution was diluted with 20 mL of water, extracted with 3×50 mL of DCM and concentrated under vacuum. The crude product (90 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.1% HCOOH and CH3CN (6.0% CH3CN up to 75% in 20 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired (2S)-3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2-methoxypropanamide (31.3 mg, 40%) as an off-white semi-solid. MS (ES): m/z 419 [M-1.2HCOOH+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (m, 2H), 5.30-5.27 (s, 1H), 3.67-3.63 (m, 1H), 3.46-3.27 (m, 5H), 3.08-2.84 (m, 8H), 2.72-2.66 (m, 1H), 2.48-2.17 (m, 6H), 1.83-1.28 (m, 5H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCOC(C)=O>C(Cl)Cl.CCCCCC>[CH:12]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -74 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
To a solution of oxalyl chloride (28 mL, 56.2 mmol) in 14 mL dry CH2Cl2 cooled at -78° C. (a dry ice acetone bath) was added 12 mL dry DMSO over 40 minutes. The reaction was stirred at -74° C. for additional 40 minutes and (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, (5.40 g, 26.86 mmol) in 14 mL CH2Cl2 was added dropwise at -65° C. over 30 minutes. The reaction stirred additional 20 minutes at room temperature and partitioned between Et2O and H2O. The Et2O layer was washed with more H2O (50 mL×4) and the H2O layers was extracted with Et2O (40 mL×3). All the Et2O layers was combined, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was isolated by a silica-gel column using EtOAc and hexane (1:5 ratio) as an eluting solvent to give title compound (84% yield).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>O1CCCC1>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)=[CH:24][CH:25]=1)#[N:30]
Reactant: CCC[Mg]Cl
Reactant: N#Cc1ccc(CCCC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(C#N)cc3)CC2)CC1

Procedure:
50 ml (0.18 moles) of a tetrahydrofuran (hereinafter referred to simply as THF) solution of 2.5M of propylmagnesium chloride was dropped in a mixed solution of 37.4 g (0.1 mol) of 1-chloro-4-(trans-4-(4-(4-cyanophenyl)butyl)cyclohexyl)-1-silacyclohexane and 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of the solvent and salts, followed by isolation through chromatography to obtain 30.2 g (yield: 79%) of the intended trans isomer product.