Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[C:6]([C:29]4[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=4)[CH:7]=[CH:2][CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (101 mg, 0.286 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (150 mg, 0.57 mmol) and K2CO3 (236 mg, 1.71 mmol) in DME-water (2:1) was added Pd(PPh3)4 (33 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide. 1H NMR (TFA salt, CD3OD) d (ppm): 8.97 (s, 1H), 8.23 (d, 1H), 8.12 (d, 1H), 7.85 (d, 1H), 7.78 (m, 2H), 7.5 (d, 1H), 7.37 (s, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.08-3.21 (m, 5H), 3.0 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Yield: 42.8 %

Procedure:
To a solution of 2-hydroxyacetophenone (10 g, 74.5 mmol) and imidazole (15 g, 220 mmol) in N,N-dimethylformamide (50 ml) was added tert-butyldimethylchlorosilane (22 g, 146 mmol) at room temperature for 6 hours. The mixture was poured into water (200 ml) and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to give 2-(tert-butyldimethylsilanyloxy)-1-phenylethanone (8.0 g, 31.9 mmol, 43%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.220 g, 0.57 mmol) and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 was added trimethylacetyl chloride (0.11 mL, 0.86 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]2=[O:38])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[O:42]1[CH:43]=[CH:44][C:40]([NH:39][S:23]([C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:13]([C:4]2[C:3]([O:2][CH3:1])=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=2)[C:14](=[O:38])[CH:15]=[CH:16]3)(=[O:24])=[O:25])=[N:41]1
Reactant: Nc1ccon1
Reactant: COc1cc2ccccc2cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2ccccc2cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of perfluorophenyl 1-(3-methoxynaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.250 g, 0.457 mmol), 3-aminoisoxazole (0.037 ml, 0.502 mmol) and THF (4.57 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.959 ml, 0.959 mmol) was added dropwise. After 60 min, the mixture was diluted with 1N aq. HCl and EtOAc. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was concentrated and then triturated with in Et2O. The resulting suspension was sonicated, then filtered. The collected solid was washed with Et2O (2×), dried under a stream of N2 (g), then dried under vacuum to give N-(isoxazol-3-yl)-1-(3-methoxynaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.175 g, 0.391 mmol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.49-11.79 (m, 1H), 8.68-8.78 (m, 1H), 8.38-8.42 (m, 1H), 8.24-8.29 (m, 1H), 7.96-8.01 (m, 2H), 7.86-7.91 (m, 1H), 7.78-7.84 (m, 1H), 7.66 (s, 1H), 7.56-7.64 (m, 1H), 7.42-7.50 (m, 1H), 6.75-6.86 (m, 2H), 6.42-6.47 (m, 1H), 3.72-3.81 (m, 3H). m/z (ESI) 447.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33]CCBr)[CH2:16][CH3:17].[C:37]1(C)C=CC=C[CH:38]=1>CC(C)=O>[CH3:1][C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:37][CH2:38][CH:32]([O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:30])([F:28])[F:29])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[CH3:33])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: Cc1ccccc1
Solvent: CC(C)=O
Product: CCCc1c(OC(C)CCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5-methyl-5-phenylimidazolidine-2,4-dione and the bromide from Example 8. After aqueous work-up and silica gel chromatography (toluene: 10% acetone), the title compound was obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)C.[Li]CCCC.[CH3:18][S:19]SC.Cl>C1COCC1>[CH3:18][S:19][C:7]1[O:6][C:5]([CH:4]=[O:3])=[CH:9][CH:8]=1
Reactant: CCOC(OCC)c1ccco1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C=O)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 2-(diethoxymethyl)furan (2.00 g, 11.75 mmol) in dry THF (8 mL) was added a solution of n-BuLi (1.6 M in Hexane) (8.80 mL, 14.1 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and treated with methyldisulfide (1.06 mL, 11.75 mmol). The reaction mixture was stirred at −78° C. for 30 min followed by warming to 0° C. for 1 hour. HCl (1N) (20 mL) was added and the organic material was extracted with ether (2×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford 1.58 g (94%) of crude title compound. LCMS (+ESI, M+H+) m/z 143.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.N1C=CC=C[CH:35]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:35])=[O:31])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 19 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-amino(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.32 mmol) in pyridine (3 mL) was added benzoyl chloride (45 μL, 0.38 mmol). The solution was stirred for 12 hours when water (80 mL) was added and the solid filtered. The solid was then taken up in methanol (3 mL) and 6N HCl (3 mL) and heated to 80° C. for 3 hours. Water (80 mL) was then added and the solid filtered and dried to give the title compound (20 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.3 (br s, 1H), 10.37 (s, 1H), 8.57 (s, 1H), 8.0-7.9 (m, 5H), 7.78 (d, 1H), 7.6-7.5 (m, 4H), 7.40 (t, 2H); ES-MS (m/z) 332 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([C:18]#[N:19])=[C:11]3[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[S:5][C:4](=[S:26])[NH:3]1.IC.[CH:29](N(C(C)C)CC)(C)C>C(#N)C>[CH3:29][S:26][C:4]1[S:5][C:6](=[CH:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([C:18]#[N:19])=[C:11]3[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:2](=[O:1])[N:3]=1
Reactant: N#Cc1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1cccnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(-c4cccnc4)c3c2)S1

Procedure:
Similar procedure as described in example 41b was used, starting from 6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63d), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 6-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile. LC-MS m/e 389 (MH+).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:26]=[C:27](C(F)(F)F)[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O.[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH3:35])[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)[C:5]1[CH:26]=[CH:27][CH:28]=[CH:3][CH:4]=1
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccccc2)C2(CCN(Cc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
(rac)-8-Benzyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (3.0 g, 9.0 mmol, synthesis described in example 156) was dissolved in dry tetrahydrofuran (50 mL) and triphenylphosphin (3.1 g, 11.7 mmol), methanol (0.374 g, 11.7 mmol) and diethylazodicarboxylate (5.35 mL, 40% in toluene, 11.7 mmol) were added sequentially and stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/methanol/triethyl amine 98:1:1) to yield the intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (2.57 g, 82%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].[CH2:28]([O:36][CH2:37][CH:38]([CH2:40][O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C1(S(Cl)(=O)=O)C=CC=CC=1.S(=O)(=O)(O)O>N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[CH:16]([C:20]([O:22][CH:38]([CH2:37][O:36][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:40][O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:21])[CH:17]=[CH:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: CCCCCCCCOCC(O)COCCCCCCCC
Agent: O=S(=O)(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Yield: 30 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.0 g) and molecular sieves (20 g) in dry pyridine (60 ml) was stirred at 0° to 5° C. for an hour, and 2-n-octyloxy-1-n-octyloxymethylethanol [4.6 g] was added thereto. Benzenesulfonyl chloride (2.6 g) was dropwise added to the stirred solution at -5° to -3° C. over 30 minutes, and then stirred at 0° C. for an hour. The resultant mixture was poured into the crushed ice (300 g), adjusted to pH 1 to 2 with 20% sulfuric acid, and then extracted with ethyl acetate (300 ml). The extract was washed with a saturated aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over anhydrous magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel (200 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [3.1 g] of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:28][C:29]([NH2:32])([CH3:31])[CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([NH:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 3 h

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-indole-2-carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropan-2-amine (8.8 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) containing triethylamine (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-tert-butyl-1H-indole-2-carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)+; retention time 3.12 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([OH:21])=O)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[C:8]2=[O:31])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH:42]1[C:46]([C@@H:47]2[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]2)=[N:45][N:44]=[N:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@@H:18]([CH3:22])[C:19](=[O:21])[N:49]4[CH2:50][CH2:51][CH2:52][C@@H:47]([C:46]5[NH:45][N:44]=[N:43][N:42]=5)[CH2:48]4)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)[C:8]2=[O:31])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: C1CNC[C@H](c2nnn[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2nnn[nH]2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
To a cold (0° C.) solution of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (0.050 g, 0.088 mmol) in DMF (1 mL) was added (R)-3-(1H-tetrazol-5-yl)-piperidine trifluoro-acetic acid salt (0.047 g, 0.18 mmol), HATU (0.040 g, 0.11 mmol) and Et3N (0.026 mL, 0.18 mmol). The reaction was allowed to stir for 10 minutes and HOAt (0.024 g, 0.18 mmol) was added and the mixture allowed to warm to room temperature overnight. The crude reaction mixture was purified by reverse-phase HPLC to give 10 mg of the title compound as a white solid, m/z 701.4 [M]+.
Reaction SMILES: [C:1]([C:3]1[C:12]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][C:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5]=2[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:40])C.O>ClCCl>[CH:1]([C:3]1[C:12]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][C:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5]=2[CH:4]=1)=[O:40]
Reactant: CC(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C#N)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 4.6 g (11.9 mmol) of 2-cyano-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.in 40 mL of dichloromethane at −78° C. was added 17.9 mL (17.9 mmol) of diisobutylaluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to slowly warm to room temperature. After 16 hours, acetic acid was added dropwise, followed by addition of water and dichloromethane. The organic fraction was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 4-25% ethyl acetate/hexane) to afford 2.48 g (53%) of 2-formyl -3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. M+=389).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:32]=[O:33].C(N(CC)CC)C.O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[N:28]5[CH2:32][OH:33])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: C=O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Temperature: 80 °C

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1 g) synthesized in the same manner as in WO2006/112464 (Example 11) in DMF (10 ml) were added 37% aqueous formalin solution (3.7 ml) and triethylamine (0.05 ml), and the mixture was heated at 80° C. for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give a mixture (1 g, 3:2) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one and 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].BrC[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.O>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][CH2:2]2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CCOC(=O)c1cccc2c1NCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1N(Cc1ccc(Cl)cc1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a mixture of ethyl 1,2,3,4-tetrahydroquinoline-8-carboxylate (1.1 g) and DMF (9.0 mL) was added sodium hydride (55% dispersion in paraffin liquid, 280 mg) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a solution of 1-(bromoethyl)-4-chlorobenzene (1.2 g) in DMF (2.0 mL) under ice-cooling, followed by stirring at room temperature for 3 days. To the reaction mixture was added sodium hydride (55% dispersion in paraffin liquid, 280 mg), followed by stirring for 1 day. To the reaction mixture were added water and ethyl acetate, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate (510 mg).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:30][C@H:31]1[CH2:35][NH:34][C@H:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:32]1.ClC1C=C2C(=CC=1)N(S(C1C=CC(OC)=CC=1OC(F)(F)F)(=O)=O)C(=O)C2(N1C[C@H](OCC(O)CO)C[C@H]1C(N(C)C)=O)C1C=C(C)C=CC=1OC>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:34]1[CH2:35][C@H:31]([OH:30])[CH2:32][C@H:33]1[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[C:13]1[CH:14]=[C:15]([CH:16]=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCC(O)CO)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C=O)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 26.3 g of the compound obtained in Step 198-1 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (35.1 mmol) as starting materials, 12.5 g of a diastereoisomer mixture of the title compound (colorless amorphous) was obtained by a similar method to Step 4-2.