Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](Br)=[C:7]([CH:17]=[CH:18][CH:19]=1)[NH:8][C:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11](=[O:16])[CH:10]=1)([O:3][CH3:4])=[O:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:5]1[CH:19]=[CH:18][CH:17]=[C:7]2[C:6]=1[C:10]1[C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH2:14][C:9]=1[NH:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(NC2=CC(=O)CC(C)C2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Yield: 75.1 %

Procedure:
A suspension of 3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one (9.98 g, 29.5 mM), palladium acetate (0.66 g, 2.95 mM), tri-o-tolylphosphine (1.8 g, 5.9 mM), and triethylamine (5.10 ml, 36.6 mM) in 75 mL acetonitrile was heated at reflux for 3 hours. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with 1 N HCl, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 11 g of crude product. Purification by HPLC on silica gel (elution with gradient methylene chloride/ethyl acetate) afforded 5.7 g (75%) of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one. 1H NMR (CDCl3) δ 9.5 (bs, 1H), 7.4 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.2 (dd, J=8 and 8 Hz, 1H), 4.0 (s, 3H), 2.9 (dd, J=13 and 4 Hz, 1H), 2.55 (m, 2H), 2.4 (m, 1H), 2.25 (dd, J=15 and 9 Hz, 1H), 1.05 (d, J=7 Hz, 3H). MS (ES) m/e 226, 258.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:3]=1[F:18].O.NN>CO.[Ni]>[F:18][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(F)c2F)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2cccc(F)c2F)cc1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
Into a 500 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,2-difluoro-3-(4-nitrophenoxy)benzene (21.2 g, 84.40 mmol, 1.00 equiv) in methanol (200 mL), and Raney Nickel (2 g). A solution of hydrazine hydrate (12.67 g, 3.00 equiv) in methanol (50 mL) was added dropwise with stirring in 15 min. The resulting solution was stirred for 12 h at 25° C. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with 200 mL of ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 16.3 g (87%) of 4-(2,3-difluorophenoxy)aniline as black oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC2C=CC=CC=2)[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCCOc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCN(CC)CCCOc1cccc(O)c1
Yield: 80.2 %

Procedure:
A solution of N,N-diethyl-3-(3-benzyloxyphenoxy)propylamine (0.7 g) in ethanol was treated with ethereal hydrogen chloride solution and the mixture hydrogenated in the presence of Pd/C (0.25 g, 5% w/w) for 2 hours. The catalyst was removed by filtration and the filtrate evaporated. The residue was crystallised from a mixture of ethanol and ether to give N,N-diethyl-3-(3-hydroxyphenoxy)propylamine (0.4 g), m/z 223.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.N1CCOCC1.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: C1COCCN1
Solvent: O
Solvent: COCC(C)O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 112.5 °C
Reaction time: 1.75 h
Yield: 88.8 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 1-methoxy-2-propanol (13.0 g) and morpholine (1.3 g, 14.9 mmol, 1.16 equiv) and is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of morpholine (9.6 g, 110.2 mmol, 8.54 equiv) and 1-methoxy-2-propanol (0.8 g) and the solution added in portions to the Thebaine mixture over 1 h 10 min while maintaining the batch temperature in the range 110 to 115° C. The reaction mixture is held at 110 to 114° C. for 1.75 h then cooled to less than 20° C. and water (24 g) added. The resulting slurry (pH 9.7) is stirred and further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.59 g, 89.1% yield; 98.7 area % purity by HPLC).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])[C:3]([NH2:5])=[O:4].Cl.[CH2:15]([N:17]1[CH2:22][C:21]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:20][CH2:19][C:18]1=[O:28])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([N:25]2[CH2:26][CH2:27][C:21]3([O:20][CH2:19][C:18](=[O:28])[N:17]([CH2:15][CH3:16])[CH2:22]3)[CH2:23][CH2:24]2)[C:3]([NH2:5])=[O:4])=[C:7]([F:13])[CH:8]=1
Reactant: CCN1CC2(CCNCC2)OCC1=O
Reactant: NC(=O)C(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a mixture of 2-bromo-2-(4-bromo-2-fluorophenyl)acetamide (250 mg, 0.8 mmol) and 4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (189 mg, 0.8 mmol) in N,N-dimethylformamide (2 mL) at 23° C. was added potassium carbonate (333 mg, 2.4 mmol). The reaction mixture was stirred for 3 h and then was poured into brine (100 mL) and extracted with ether (3×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% ethyl acetate/hexanes) afforded the title product (214 mg, 62%). MS(ES)+ m/e 428 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.07 (t, J=7.07 Hz, 3 H) 1.65-1.77 (m, 2 H) 1.79-1.91 (m, 2 H) 2.10-2.16 (m, 1 H) 2.44 (br. s., 1 H) 2.54 (s, 1 H) 2.66 (br. s., 1 H) 3.17 (s, 2 H) 3.35 (q, J=7.16 Hz, 2 H) 3.93 (d, J=1.52 Hz, 2 H) 4.39 (s, 1 H) 6.00 (br. s., 1 H) 7.19 (br. s., 1 H) 7.27-7.35 (m, 1 H) 7.39 (t, J=2.27 Hz, 1 H) 7.41 (t, J=2.15 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6]Cl.C([O-])(=[O:13])C.[Na+].C[O-].[Na+].O>CN(C)C=O.CO>[Cl:1][CH:2]=[C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][O:13]1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCOC1=CCl
Temperature: 100 °C
Yield: 89 %

Procedure:
806 g (4 moles) of 1,1,5-trichloro-3,3-dimethyl-1-pentene are heated under reflux with 360 g (4.4 moles) of anhydrous sodium acetate in 1 liter of dimethylformamide for 6 hours. After cooling to about 100° C., 1.6 liters (8 moles) of 30% strength sodium methylate solution in methanol are added dropwise and the mixture is heated under reflux for a further 4 hours. The cold solution is poured into water and extracted several times with methylene chloride. After the solution has been dried and the solvent has been distilled off, 654 g of product remain, and are fractionated over a column. 522 g (80% of theory) of 2-chloromethylene-3,3-dimethyl-tetrahydrofuran of boiling point 84°-87° C./20 mbar are obtained.
Reaction SMILES: [C:1]([C:5]1([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CSC2(C(=O)O)Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Dissolve 2-(carbomethoxy)-2-(4-methoxybenzylthio)indan (2.20 g, 3.55 mmol) in 95% ethanol (25 mL), water (12 mL) and tetrahydrofuran (15 mL). Treat with potassium hydroxide (1.3 g, 23 mmol) and stir at room temperature for 1 hour. Filter and evaporate the solvent in vacuo. Partition between water (125 mL) and ether (75 mL). Separate the aqueous phase and acidify with cold concentrated hydrochloric acid. Extract with methylene chloride (75 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (2:1 hexane/ethyl acetate) to give 2-carboxy-2-(4-methoxybenzylthio)indan as a yellow solid (0.48 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]2[O:16][CH3:17])=O.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[NH:27][C:28]2[S:29][CH2:30][C:31](=[O:33])[N:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:17][O:16][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3](/[CH:1]=[C:30]3/[C:31](=[O:33])[N:32]=[C:28]([NH:27][C@@H:25]4[CH2:26][C@H:24]4[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:29]/3)[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:13]([NH2:15])=[O:14]
Reactant: COc1c(C(N)=O)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Product: COc1c(C(N)=O)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid amide (example 2b) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f) to give 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid amide. LC-MS m/e 445 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: CON1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CON1CCC(O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (15.0 g, 116.1 mmol) in ethanol (430 ml) was added sodium borohydride 96% (2.29 g, 58.1 mmol) in portions. The reaction mixture was stirred at room temperature for 5 hours, evaporated to half of its volume, poured on cold saturated aqueous ammonium chloride and thoroughly extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate). Yield: 10.9 g of 1-methoxy-piperidin-4-ol as a liquid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:4]1[CH3:19])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:3]([CH2:1][CH3:2])[C:4]([CH3:19])=[C:5]2[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCn1c(C)c(-c2ccncc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2CC

Procedure:
The above compound was prepared from 1-ethyl-2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:20]12[C:27]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:26]3[C:25](=[O:32])[O:24][C:22](=[O:23])[C:21]1=[CH:33][CH:34]=[CH:35][CH:36]=2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([C:21]1[CH:33]=[CH:34][CH:35]=[CH:36][C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:32])([OH:24])=[O:23]
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (252 mg), diphenic anhydride (224 mg), triethylamine (202 mg) and catalytic amount of 4-dimethylaminopyridine in dichloromethane (15 ml) was stirred for 8 hours at ambient temperature. The mixture was evaporated in vacuo and diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate aqueous solution, brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and triturated from ethyl acetate to give 1-{4-[2-(2-carboxyphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (400 mg).
Reaction SMILES: Br[C:2]1[C:15]2[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[C:7](=[O:16])[C:6]=2[C:5]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1>[Pd].CO>[O:16]=[C:7]1[C:6]2[C:5]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=[CH:2][C:15]=2[NH:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=2
Reactant: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCCC3
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCCC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 152.7 %

Procedure:
A mixture of methyl 4-bromo-9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate (0.19 g, 0.56 mmol), MeOH (20 mL), and Pd/C (5% Pd on carbon, 50% water, 0.05 g) were stirred at room temperature under an atmosphere of hydrogen for 6 hours. The mixture was filtered through celite and the filtrate was concentrated to give crude methyl 9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate (0.22 g), which was used to next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[O:21][CH2:20]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:21])[CH2:20][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:13]2)=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: Fc1ccc(C(CCCN2CCN(CC3CO3)CC2)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNc1ccccc1)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 10.4 %

Procedure:
3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 0.93 g (0.01 mol) of aniline were refluxed with heating with 200 ml of DMF for 21 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride --methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:35].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.O.CO.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:35])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1N1CCOCC1
Reaction time: 0.5 h

Procedure:
A solution of 2-ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline (1.61 g, 5.51 mmol) in 40 mL of CH2Cl2 was treated with MCPBA (1.78 g, 6.70 mmol, 77% max). After 30 min, the reaction mixture was treated with 20 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (1.03 g, 5.41 mmol). After 15 min, the reaction mixture was diluted with CH2Cl2 and water and the phases were separated. The organic portion was washed with 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan foam. Chromatography (SiO2, 97:3 CHCl3:MeOH) gave a light yellow foam. The foam was triturated with diethyl ether and filtered to give 2-ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.794 g) as a light cream colored solid. mp 223–224° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)Cl.[CH3:18][C:19]([CH3:22])([O-])[CH3:20].[K+]>CN(C=O)C.ClCCCl.C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:19]([CH3:22])([CH3:20])[CH3:18])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
A solution of 4-chloro-3-nitrobenzoic acid (10.03 g, 50 mmol), SOCl2 (4.4 mL, 60 mmol) and DMF (4 drops) in 1,2-dichloroethane (150 mL) was stirred under reflux for 14 h, cooled and evaporated. The resulting crude acid chloride was dissolved in THF (100 mL), cooled to 0° C., and a solution of potassium t-butoxide (5.57 g, 50 mmol) in THF (150 mL) was added dropwise over 30 min under nitrogen. The mixture was stirred a further 15 min at 0° C., diluted with aqueous NaHCO3 and extracted with EtOAc (×2), and the extracts were dried (Na2SO4) and evaporated. Flash chromatography of the residue on silica gel (petroleum ether/EtOAc; 30:1) gave t-butyl 4-chloro-3-nitrobenzoate as a white crystalline solid (11.45 g, 89%), mp (petroleum ether) 70-71° C. 1H NMR (CDCl3) δ8.42 (d, J=2.0 Hz, 1H, H-2), 8.11 (dd, J=8.4, 2.0 Hz, 1H, H-6), 7.61 (d, J=8.4 Hz, 1H, H-5), 1.61 (s, 9H, t-Bu). Anal. Calculated for C11H12ClNO4 : 51.3; H, 4.7; N, 5.4; Cl, 13.8. Found: C, 51.6; H, 4.8; N, 5.4; Cl, 14.0%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[C:5](=[O:13])[O:4][C:3]1=O.[NH2:15]C(N)=O>>[CH3:1][N:2]1[C:7]2[C:6](=[C:11]([CH3:12])[CH:10]=[CH:9][CH:8]=2)[C:5](=[O:13])[NH:15][C:3]1=[O:4]
Reactant: Cc1cccc2c1c(=O)oc(=O)n2C
Reactant: NC(N)=O
Product: Cc1cccc2c1c(=O)[nH]c(=O)n2C

Procedure:
Starting from 1,5-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione (prepared according to WO 98/42688) and urea and using Procedure R, the title compound was obtained as an off-white solid (681 mg, 57% yield).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@H:17]([CH2:20][O:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[N:16]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>C(Cl)Cl>[CH3:65][O:64][C:62]([NH:1][C@@H:2]([C@@H:38]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[C:39]1[CH:40]=[C:41]([F:46])[CH:42]=[C:43]([F:45])[CH:44]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@H:17]([CH2:20][O:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[O:23])[N:16]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:15]1)=[O:4])=[O:63]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S,3S)-2-amino-3-(4-fluorophenyl)-3-(3,5-difluorophenyl)-N-(5-fluoro-4-(2-((2R,5R)-4-(tert-butyloxycarbonyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-2-yl)ethyl)pyridin-3-yl)propanamide (Example 90, step 5) (64 mg, 0.084 mmol) in 1 mL of CH2Cl2 was added triethylamine (0.047 mL, 0.34 mmol) and methyl chloroformate (0.013 mL, 0.17 mmol). The mixture was stirred at ambient temperature for 1 h, then diluted with CH2Cl2 and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.38 min, M+H=816 (2 min gradient)
Reaction SMILES: ICI.[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]=O)[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH2:30](OCC)C>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]=[CH2:30])[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ICI
Product: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Under cooling with ice, titanium tetrachloride (3.30 mL, 1.0M toluene solution) was added to a suspension of zinc powder (1.86 g, 28.5 mmol) in tetrahydrofuran (15 mL) over 2 minutes, followed by stirring for 5 minutes at the same temperature. A solution of diiodomethane (1.15 mL, 14.3 mL) in tetrahydrofuran (5 mL) was added thereto over 8 minutes, and the resultant mixture was stirred for 15 minutes while the temperature thereof was elevated to room temperature. A solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine (900 mg, 2.58 mmol) in tetrahydrofuran (5.0 mL) was added thereto over 7 minutes, followed by stirring for 1.5 hours. Subsequently, under cooling with ice, the resultant mixture was poured to 0.5 mol/L hydrochloric acid (10 mL), followed by dilution with diethyl ether (60 mL). The obtained aqueous layer was extracted with diethyl ether (100 mL×2). The combined organic layer was washed by saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby yield the title compound as a colorless oily substance (3.09 g, 31%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:17][C:18]1[N:22]=[C:21]([C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])[O:20][N:19]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:25]([C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[C:21]1[O:20][N:19]=[C:18]([CH3:17])[N:22]=1)=[O:26]
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Product: Cc1noc(-c2ccccc2C(=O)N2CCCCC2Cc2nc3ccccc3s2)n1

Procedure:
The title compound (0.170 g) was prepared from 2-piperidin-2-ylmethyl-benzothiazole, D30 (0.135 g), and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)benzoic acid (0.126 g) using the procedure described in Example 60.