Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO>[CH3:25][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1
Reactant: ClCCl
Reactant: Oc1ccc(CCCCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCc1ccc(O)cc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of trans-4-[4-(4-phenylcyclohexylamino)-butyl]phenol (370 mg, 1.1 mmol) in a mixture of MeOH (5 mL) H2O (0.5 mL), and CH2Cl2 (5 mL) was added ρformaldehyde (170 mg, 5.7 mmol). After stirring for 10 minutes, NaBH(OAc)3 (300 mg, 1.4 mmol) was added, and the reaction mixture was stirred for 12 hours. Solid NaOH was added to give a clear solution, which was then concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) and formation of the HCl salt gave (b) trans-4-{4-[methyl-(4-phenylcyclohexyl)amino]butyl}-phenol (230 mg, 56%), as a white solid: mp 234-236° C.; IR (KBr): 2942, 1613, 1515 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br s, 1H), 9.13 (s, 1H), 7.31-7.18 (m, 5H), 7.00 (d, J=8.5 Hz, 2H), 6.68(d, J=8.5 Hz, 2H), 3.33-3.23 (m, 1H), 3.17-3.09 (m, 1H), 3.02-2.95 (m, 1H), 2.67(d, J=5 Hz, 3H), 2.55-2.49 (m, 3H), 2.16-2.06 (m, 2H), 1.95-1.89 (m, 2H), 1.72-1.50 (m, 8H); CI—MS (methane) (m/z): 338 [M+H]+; HPLC: method A, 6.38 minutes (>99%); method B, 11.28 minutes (>99%); Anal. Calcd for C23H31NO.HCl: C, 73.87; H, 8.62; N, 3.75. Found: C, 73.61; H, 8.55; N, 3.66.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C@@H:32]1[CH2:36][CH2:35][C@H:34]([C:37](O)=[O:38])[CH2:33]1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][O:29][C:30]([C@@H:32]1[CH2:36][CH2:35][C@H:34]([C:37]([N:13]2[CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:15]=3)[CH2:9][C@@H:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:38])[CH2:33]1)=[O:31]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](C(=O)N2CCN(c3ccc(OC)c(OC4CCCC4)c3)C[C@@H]2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (92 mg, 0.25 mmol) in CH2Cl2 (1 mL) at 0-5° C. was treated with a catalytic amount of DMAP and (1S,3R)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (47 mg, 0.28 mmol) followed by DCC (57 mg, 0.28 mmol). The reaction mixture was allowed to warm to room temperature and stir 1 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 30% then 50% EtOAc/hexanes as eluant to afford intermediate (1R,3S)-3-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid methyl ester as an oil (109 mg, 84%). LC/MS (Method B) 4.14 min, [M+1]+ 521. The intermediate (1R,3S)-3-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid methyl ester was then hydrolyzed with LiOH as described in Example 121, to afford the title compound as a colorless solid (85 mg, 80%) LC/MS (Method B) 3.68 min, [M+1]+ 507.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][NH:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:25][CH2:26]Cl)[CH3:24]>O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][N:5]([CH2:26][O:25][CH2:23][CH3:24])[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOCCl
Reactant: CCCNC(=O)NOc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCNC(=O)N(COCC)Oc1cc(Cl)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To 2.63 g of 3-(2,5-dichlorophenoxy)-1-n-propylurea, were added 4.14 g (20 mmoles) of anhydrous potassium carbonate and then 1.42 g (15 mmoles) of chloromethyl ethyl ether. The mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and 300 ml of water was added. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane) to give 0.44 g (yield 14 %) of the desired compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]2[N:12](COCC[Si](C)(C)C)[CH:13]=[N:14][C:4]=2[CH:3]=1.[Cl:23][C:24]1[N:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[C:27]2[N:34]=[CH:35][N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]=2[CH:25]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[N:14]1[C:4]2[CH:3]=[CH:2][N:7]=[CH:6][C:5]=2[NH:12][CH:13]=1.[Cl:23][C:24]1[N:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[C:27]2[N:34]=[CH:35][N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]=2[CH:25]=1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Agent: C[Si](C)(C)CCOCn1cnc2c(S(C)(=O)=O)nc(Cl)cc21
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1cc2nc[nH]c2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of 6-chloro-4-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine 2.07 and 6-chloro-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 2.08 (536 mg, 1.62 mmol) in dichloromethane (10 mL) at 0° C., was added mCPBA (<77%, 841 mg) and mixture was warmed to room temperature. After 2 h, a 20% solution of Na2S2O3 (aq) (20 mL) was added and reaction mixture stirred at room temperature for 15 minutes. The mixture was taken up in ethyl acetate (150 mL) and washed with saturated NaHCO3 (aq) and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure, This residue was purified by silica gel column chromatography (eluted with 30% to 100% of ethyl acetate in hexane) to yield 6-chloro-4-(methylsulfonyl)-34(2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine 2.09 and 6-chloro-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 2.10.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:5]1[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]1[CH2:12][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 168.3 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (400 mg, 1.05 mmol), 6-mercaptopurine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17]Br>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: BrCCCBr
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
A suspension of sodium hydride (6.8 g, 60% in mineral oil) and dimethyl formamide (200 mL) was kept at 20-25° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (25.0 g) in dimethyl formamide (180 mL). The resulting mixture was stirred at room temperature for 10 min followed by the addition of a solution of 1,3-dibromopropane (172 g) in dimethyl formamide (150 mL) at a temperature of 20-35° C. The resulting mixture was stirred at 30° C. for 20 min and concentrated in vacuo. The residue was poured onto ice, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a yellow oil (27 g).
Reaction SMILES: C(N(CC)C1C=C2C(=CC=1)N(C(=O)C1C=CC(F)=CC=1)[C@@H](C)C[C@H]2N(C1C=CC(N(CC)CC)=CC=1)C(=O)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]([C@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([N:64]4[CH2:69][CH2:68]O[CH2:66][CH2:65]4)[CH:62]=3)[N:57]([C:70](=[O:78])[C:71]3[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=3)[C@@H:56]([CH3:79])[CH2:55]2)[C:50](=[O:53])[CH2:51][CH3:52])=[CH:45][CH:44]=1.C(NCC)C.N1CCOCC1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N:49]([C@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([N:64]([CH2:65][CH3:66])[CH2:69][CH3:68])[CH:62]=3)[N:57]([C:70](=[O:78])[C:71]3[CH:72]=[CH:73][C:74]([F:77])=[CH:75][CH:76]=3)[C@@H:56]([CH3:79])[CH2:55]2)[C:50](=[O:53])[CH2:51][CH3:52])=[CH:47][CH:48]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N3CCOCC3)cc21
Agent: CCC(=O)N(c1ccc(N(CC)CC)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N(CC)CC)cc21
Solvent: CCNCC
Solvent: C1COCCN1
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N(CC)CC)cc21

Procedure:
(±)-Cis-N-[6-diethylamino-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N(4-diethylamino-phenyl)-propionamide was made in the same way as (±)-cis-N-(4-chloro-phenyl)-N-[1 -(4-fluoro-benzoyl)-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide except diethylamine was substituted for morpholine. The reaction was non-selective and yielded (±)-cis-N-(4-chloro-phenyl)-N-[6-diethylamino-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide in addition to the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:24].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl>[Br:24][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([CH3:21])[CH:12]=1
Reactant: [Br-]
Reactant: Cc1ccc2ccc3cc(C(C)(C)C)cc4ccc1c2c34
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc(Br)c2ccc3cc(C(C)(C)C)cc4ccc1c2c43
Temperature: 25 °C
Reaction time: 4 h
Yield: 155.4 %

Procedure:
Next, a mixed solution of 3 g of 7-t-butyl-1-methylpyrene, 130 ml of dichloromethane and 43 ml of methanol was cooled to 0° C. under a nitrogen gas stream and then 4.3 g of benzyltrimethylammonium tribromide dissolved in 5 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 4 hours and 50 ml of water was poured into the solution, followed by extraction with 50 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 3.4 g of 1-bromo-7-t-butyl-3-methylpyrene.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([OH:15])[CH:13]=[CH2:14])=[C:3]1[CH3:17].C(N(CC)CC)C.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([O:15][Si:26]([CH3:29])([CH3:28])[CH3:25])[CH:13]=[CH2:14])=[C:3]1[CH3:17]
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(C=CC1=C(C)C(=O)CCC1(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-1,4-pentadiene-3-ol (2.34 g, 10 mmoles)(prepared as described in J. Org. Chem. 47, 2130-2134 (1982)) in methylenechloride is added triethylamine (2.08 ml, 15 mmoles), trimethylchlorosilane (1.9 ml, 15 mmoles), and N,N-dimethyl-4-aminopyridine (5 mg, catalytic amount). The mixture is stirred at room temperature for four hours, followed by concentration in vacuo and trituration with dry diethylether. The suspension is filtered and the filtrate is concentrated in vacuo yielding the title compound as a slightly yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[Cl-:11].[NH4+]>CCO.[Fe]>[Cl:11][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=1[NH2:8]
Reactant: [Cl-]
Reactant: CCn1cc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Product: CCn1ncc(N)c1Cl
Temperature: 80 °C
Yield: 30 %

Procedure:
To a suspension of 1-ethyl-4-nitro-1H pyrazole (1 equiv) and iron dust (5 equiv) in EtOH (0.285 M) was added ammonium chloride (10 equiv). The mixture was heated to 80° C. for 20 h then cooled to room temperature. The solvent was removed under reduced pressure to give crude material that was purified by silica gel chromatography (1.5% MeOH in DCM) to provide the desired product (30% yield) as a yellow oil. MS (ESI) m/z 146.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:20]([C:23]1[C:24]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[CH:25][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:27]([CH:31]=1)[C:28](O)=[O:29])([CH3:22])[CH3:21].C(N=C=NCCCN(C)C)C>ClCCl>[CH:20]([C:23]1[C:24]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)=[CH:25][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:27]([CH:31]=1)[C:28]([N:11]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:29])([CH3:22])[CH3:21]
Reactant: Cn1ccc2cc(NCC(=O)OC(C)(C)C)ccc21
Reactant: COc1ccc(COc2cc(OCc3ccc(OC)cc3)c(C(C)C)cc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(COc2cc(OCc3ccc(OC)cc3)c(C(C)C)cc2C(=O)N(CC(=O)OC(C)(C)C)c2ccc3c(ccn3C)c2)cc1
Reaction time: 2 h

Procedure:
tert-butyl 2-(1-methyl-1H-indol-5-ylamino)acetate (1) and 5-isopropyl-2,4-bis(4-methoxybenzyloxy)benzoic acid were dissolved in dichloromethane at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) was added to the reaction solution and stirred for 2 hours. Work-up with water and extracted with dichloromethane followed by drying and concentration produced tert-butyl 2-(5-isopropyl-2,4-bis(4-methoxybenzyloxy)-N-(1-methyl-1H-indol-5-yl)benzamido)acetate (2). Without further purification, compound 2 was treated with Lawesson's reagent in toluene at 100° C. produced tert-butyl 2-(5-isopropyl-2,4-bis(4-methoxybenzyloxy)-N-(1-methyl-1H-indol-5-yl)phenylthioamido)acetate (3) in 82% over 2 steps.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[C:13]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]2=[C:16]([CH:31]=1)[C:17](=[O:30])[N:18]([O:25]C(C)(C)C)[C:19]3=[O:24])(=[O:10])[CH3:9]>>[C:8]([NH:11][C:12]1[C:13]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]2=[C:16]([CH:31]=1)[C:17](=[O:30])[N:18]([OH:25])[C:19]3=[O:24])(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OC(C)(C)C)C2=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
Following the procedure from Example 62, TFA (1.0 mL) and 5-acetamido-2-tert-butyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.2 g, 0.5 mol, from Example Q2) was stirred at room temperature overnight. It was concentrated, and the solid recrystallized from ethanol/ether to give 0.02 g of the title compound, mp 280-284° C.
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]1)=[CH:11][C:10]2=[O:22])[CH3:4].[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[C:34]([F:36])[CH:35]=1)[NH2:32]>CC(N(C)C)=O>[F:28][C:29]1[CH:30]=[C:31]([NH:32][CH:3]([C:5]2[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][C:10]3=[O:22])[CH3:4])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Reactant: Nc1cc(F)cc(F)c1
Agent: Br
Solvent: CC(=O)N(C)C
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Yield: 58.9 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (1 g, 1.98 mmol) and 3,5-difluoroaniline (1.024 g, 7.93 mmol) in DMA (5 mL) were reacted as described in Example 9.0 to give 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (0.550 g, 57%). Mass Spectrum: M+H+ 472. NMR Spectrum (DMSOd6): 1.16 (d, 3H), 1.52 (d, 3H), 2.74 (bs, 3H), 2.75-2.84 (m, 1H), 2.95 (bs, 3H), 3.08-3.16 (m, 1H), 3.56-3.68 (m, 2H), 3.86-4.04 (m, 3H), 4.97-5.08 (m, 1H), 5.62 (s, 1H), 6.12-6.19 (m, 2H), 6.22 (t, 1H), 6.93 (d, 0.5H), 6.94 (d, 0.5H), 6.54 (d, 0.5H), 6.55 (d, 0.5H), 7.81 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14](=[N+]=[N-])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([O:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Reactant: COc1ccc(O)cc1
Product: CCOC(=O)c1cc2ccccc2n1Oc1ccc(OC)cc1
Yield: 51 %

Procedure:
React 3-diazo-3H-indole-2-carboxylic acid ethyl ester, 5, (231 mg, 1.10 mmol) with 4-methoxyphenol (1.4 equiv., 186 mg, 1.5 mmol) as described in General Synthetic Procedure VIII to afford 3-(4-methoxyphenoxy-1H-indole-2-carboxylic acid ethyl ester 6 (R1=4-methoxyphenyl, 169 mg, 51%) as an ivory-colored solid. Hydrolyze the ester to the carboxylic acid 7 (R1=4-methoxyphenyl) using General Synthetic Procedure IX and then transform the carboxylic acid to the corresponding primary amide as described in General Synthetic Procedure V to afford the title compound Im as a colorless oil, tlc (silica gel) Rf=0.10.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>CN(C=O)C>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.4 %

Procedure:
A solution of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (380 mg, 2 mmol) in anhydrous DMF (10 ml) was treated with potassium carbonate (552 mg, 4 mmol) followed by 4-nitrobenzyl chloride (343 mg, 2 mmol) and the whole mix stirred under argon for 16 h at room temperature. The reaction mixture was separated between water (20 ml) and ethyl acetate (20 ml). The organic layer was washed again with a water/brine mix (1:1) (10 ml) then dried over sodium sulphate and the solvent removed under reduced pressure to give a yellow oil (751 mg) which was chromatographed on a 5 g pre-packed silica column eluting from 0-20% ethyl acetate in petroleum ether to give the title compound as a yellow oil (416 mg, 64%).
Reaction SMILES: [Si](O[C@@H]([C@H:11]1[C:44](=O)[N:13]2[C:14]([C:33](OCOC(=O)C(C)(C)C)=O)=[C:15](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:16](C)[C@@H:12]12)C)(C(C)(C)C)(C)C.S[C@@H:47]1CNC(=S)C1>C(#N)C>[CH:44]([N:13]([CH2:12][CH3:16])[CH:14]([CH3:15])[CH3:33])([CH3:11])[CH3:47]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: S=C1C[C@H](S)CN1
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Yield: 104 %

Procedure:
In 1 ml of acetonitrile was dissolved 20 mg of pivaloyloxymethyl (1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate, 4.3 mg of (4S)-4-mercaptopyrrolidin-2-thione obtained in the above (3) and 4.1 mg of N,N-diisopropylethylamine were added thereto under nitrogen gas at -20° C., and the mixture was stirred for 2 hours while gradually elevating a temperature thereof to 0° C. The reaction mixture was poured into a 0.1M phosphate buffer (pH 7) and extracted with ethyl acetate. After the extract was washed and dried, the solvent was removed under reduced pressure. The residue was purified by thin layer chromatography (solvent; ethyl acetate:n-hexane=5:5) to obtain 7 mg of pivaloyloxymethyl (1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[(4R)-pyrrolidin-2-thion-4-ylthio[-1methylcarbepen-2-em-3-carboxylate as colorless crystal.