Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]CC)=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2>C1COCC1>[N:8]12[CH2:9][CH2:10][C:11]([C:16]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:18])([CH2:12][CH2:13]1)[CH2:14][CH2:15]2
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A solution of phenyllithium (1.5-1.7 M in 70 cyclohexane/30 ether, 20.0 mL, 32 mmol) was chilled down to −30° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (1.51 g, 8.23 mmol) in THF (20 mL) was slowly added to the reaction mixture at −30° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with H2O and then evaporated to dryness under vacuum. H2O and EtOAc were added, causing a white solid to crash out. This solid was filtered off, to give the title compound (0.79 g). The aqueous phase was further extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was treated with EtOAc and hexane and filtered to yield more of the title compound (0.67 g). Total yield (1.46 g, 60.7%). EI-MS m/z 294 (M+H+) Rt (1.37 min).
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.P([CH:27]1[CH2:32][CH2:31]CCC1)(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[CH:31]1([C:2]2[C:3]([F:13])=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH2:32][CH2:27]1
Reactant: Cc1ccc2ccc(F)c(Br)c2n1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(F)c(C3CC3)c2n1
Temperature: 25 °C
Yield: 842.6 %

Procedure:
A solution of 8-bromo-7-fluoro-2-methylquinoline (1.00 g, 4.17 mmol), Pd(OAc)2 (0.047 g, 0.21 mmol), P(Cy)3 (0.13 g, 0.46 mmol), K3PO4 (3.09 g, 14.6 mmol) and cyclopropylboronic acid (0.72 g, 8.33 mmol) in toluene (20 mL) and water (2 mL) was stirred at 100° C. for 8 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3:1 hexane/DCM) to give 8-cyclopropyl-7-fluoro-2-methylquinoline (0.78 g, 92.7%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])=[CH:9][CH:8]=[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[CH3:28][O:29][CH2:30][CH2:31][C:32](Cl)=O>>[CH3:28][O:29][CH2:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCCC(=O)Cl
Reactant: Nc1cnc2cc(-c3ccccc3)ccc2c1NCCCN1CCCC1=O
Product: COCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCN1CCCC1=O

Procedure:
The methods described in Parts A of Example 204 were used to treat 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (1.19 g, 3.30 mmol) with 3-methoxypropionyl chloride (0.45 mL, 4.1 mmol) to afford 1-{3-[2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one, which was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized twice from acetonitrile and dried in a vacuum oven at 60° C. to provide 1-{3-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light brown solid, mp 187-191° C.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1cccc(F)c1F
Product: N#Cc1cccnc1-c1cccc(F)c1F
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloronicotinonitrile and 2,3-difluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 216.9 (M+H)+; 1H NMR (CDCl3) δ 7.21-7.29 (m, 1H), 7.30-7.39 (m, 2H), 7.49 (dd, J=8.0, 4.9 Hz, 1H), 8.12 (dd, J=7.8, 1.7 Hz, 1H), 8.92 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[NH:7]2.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>CN(C=O)C.O.[Cu]=O>[C:21]1([N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=3)[CH:5]=[C:6]2[C:16]([O:18][CH3:19])=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2[nH]1
Reactant: Brc1ccccc1
Agent: O=[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1-c1ccccc1
Reaction time: 6 h

Procedure:
Methyl 4,5,6-trimethoxyindole-2-carboxylate (533 mg), bromobenzene (0.22 mL), copper oxide (64 mg) and potassium hydroxide (336 mg) were suspended in dry DMF (10 mL), and the suspension was refluxed and stirred for 6 hours under an argon atmosphere. After cooling, the reaction mixture was dissolved in water (100 mL) and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and chloroform (20 mL), and water-soluble carbodiimide hydrochloride (192 mg) and N,N-dimethylaminopyridine (small amount) were added to the solution. The mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:3][CH2:2]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c6) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: CN(C=O)C.C[O:7][C:8](=O)[N:9]=[C:10](SC)[C:11]([C:25]1[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[NH:49][NH2:50])=[O:43])[CH3:40]>C(N(CC)CC)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[N:49]1[C:8](=[O:7])[NH:9][C:10]([CH:11]([C:25]2[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=2)[NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[N:50]1)=[O:43])[CH3:40]
Reactant: CCOC(=O)c1scnc1NN
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cnc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cnc(OC)c(OCC)c2)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To 4 ml of a DMF solution containing 117 mg of {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 160a), 52 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester and 0.038 ml of triethylamine were added. The mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 10 ml of methanol and 0.05 ml of acetic acid, and then 125 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:5][CH:4]=1.[CH3:24]I>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH3:24])=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CC(C)=O
Product: COc1ccc(N(C)CCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of (4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and methyl iodide (0.49 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4 methoxyphenyl)-N-methyl (3-(naphthalen-2-yloxy)propyl) amine, crystallized as yellow solid, m.p. 112° C., (yield 0.69 gm, 94%)
Reaction SMILES: C(Cl)Cl.[C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]2)([OH:6])=O.S(Cl)(Cl)=O.[OH:26][CH2:27][CH2:28][NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:26][CH2:27][CH2:28][N:29]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]2)=[O:6]
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: OCCNC1CCCCC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Reaction time: 1 h

Procedure:
Into 200 ml of methylene chloride was suspended 2.4 g of 6-(3-carboxypropoxy)carbostyril, and 2 ml of pyridine was added to the suspension. Then 1.4 g of thionyl chloride was added dropwise thereinto under stirring condition while the inside of the reaction vessel was kept at a temperature within the range from 0° to 20° C. After the addition operation, the reaction was continued at the same temperature for 1 hour under stirring condition. Then 2 ml of N-(2-hydroxyethyl)cyclohexylamine was added dropwise to the reaction mixture, then the reaction was continued at a room temperature for 4 hours under stirring. The reaction mixture was washed thoroughly with a K2CO3 aqueous solution, then further washed with water and a diluted hydrochloride acid, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue thus obtained was purified and isolated by a silica-gel column chromatography [the silica-gel used was "Wako C-200" and the solvent used was a mixture of chloroform:methanol=20:1 (V/V)] and was recrystallized from chloroform-petroleum ether. 1.2 Grams of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril was obtained as in the form of colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][CH2:26][C:27]2[NH:36][C:30]3=[N:31][CH:32]=[C:33](I)[CH:34]=[C:29]3[N:28]=2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][CH2:26][C:27]2[NH:36][C:30]3=[N:31][CH:32]=[C:33]([C:2]4[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=4)[CH:34]=[C:29]3[N:28]=2)[CH:20]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(N)(=O)=O)cc4)cnc3[nH]2)c1
Temperature: 125 °C
Yield: 20 %

Procedure:
A mixture of 0.354 g of 4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)ferrocene]-palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 125° C. in a sealed tube under N2 for 16 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphos-phine)palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 12:1+1% NH4OH). Concentration of the chromatographically pure fractions gives 0.08 g of the title compound as a brownish solid of m.p. 216-218° C. The mass spectrum shows the molecular peak MH+ at 410.2 Da.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:37])[CH2:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][C:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)=[O:37])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Product: O=C(CCC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(F)cc1

Procedure:
N-Cyclopropyl-N-{1-[4-(4-fluorophenyl)-4-oxobutanoyl]-piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide and 4-(4-fluorophenyl)-4-oxo-butanoic acid. LC: 100%. MS: m/z=527 (M+H+). 1H NMR (CDCl3): δ 8.14 (1H, s), 8.04 (3H, m), 7.87 (1H, d), 7.70 (1H, t), 7.12 (2H, t), 4.68 (1H, d), 4.09 (2H, m), 3.30 (2H, m), 3.09 (1H, t), 2.77 (2H, m), 2.53 (1H, t), 1.85 (5H, m), 0.92 (2H, m), 0.75 (2H, m);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O=S(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([Cl:19])=[O:9])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1

Procedure:
Heat 3-methoxycarbonyl-5-nitrobenzoic acid (2.0 g=8.9 mmol) with SOCl2 (2.1 g=18 mmol) in toluene at reflux 1 hr. Concentrate to obtain 3-methoxycarbonyl-5-nitrobenzoyl chloride, m.p. 66°-8° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[CH3:34])[CH3:6])=[O:4].[O:35]=[C:36]1[NH:49][C:39]2=[N:40][CH:41]=[C:42]([CH2:44][CH2:45][C:46](O)=[O:47])[CH:43]=[C:38]2[O:37]1.ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[CH3:26][O:25][C:22]1[N:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:14][C:9]3[C:8]([CH3:34])=[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:42]4[CH:43]=[C:38]5[O:37][C:36](=[O:35])[NH:49][C:39]5=[N:40][CH:41]=4)[CH:12]=[CH:11][C:10]=3[CH3:13])[C:24]=2[N:23]=1
Reactant: O=C(O)CCc1cnc2[nH]c(=O)oc2c1
Reactant: COc1nc2c(OCc3c(C)ccc(N(C)C(=O)CN)c3C)cccc2n1Cc1ccccn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COc1nc2c(OCc3c(C)ccc(N(C)C(=O)CNC(=O)CCc4cnc5[nH]c(=O)oc5c4)c3C)cccc2n1Cc1ccccn1

Procedure:
2-amino-N-(2,4-dimethyl-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)propanoic acid were used to prepare 3 as described above for compound 1. LCMS (+APCI) 650 (M+). 1H-NMR (CDCl3, δ ppm): 8.59 (m, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.60 (dt, J=2.0, 7.6 Hz, 1H), 7.22 (m, 2H), 7.05 (t, J=8.0 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.82 (m, 3H), 6.73 (bt, 1H), 5.30 (m, 4H), 4.21 (s, 3H), 3.72 (dd, 4.0, 18.0 Hz, 1H), 3.44 (dd, J=4.4, 18.0 Hz, 1H), 3.25 (s, 3H), 2.95 (m, 2H), 2.56 (m, 2H), 2.33 (s, 3H), 2.27 (s, 3H). Calcd. for C35H35N7O6+0.3H2O: C, 64.17; H, 5.48; N, 14.97. Found: C, 64.06; H, 5.46; N, 14.96.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.NC(C1C=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=1)CNC(=O)OC(C)(C)C>>[NH2:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:11]1[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccc(C(F)(F)F)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using tert-butyl [2-amino-2-(4-trifluoromethylphenyl)ethyl]carbamate instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 446 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (1H, br. s.) 10.92 (1H, s) 9.40 (1H, d, J=8.00 Hz) 8.28 (3H, br. s.) 8.01 (1H, d, J=6.83 Hz) 7.95 (1H, d, J=5.27 Hz) 7.53-7.58 (2H, m) 7.47-7.52 (2H, m) 7.43 (1H, d, J=2.54 Hz) 7.31 (1H, d, J=5.27 Hz) 7.00 (1H, br. s.) 6.55 (1H, d, J=7.03 Hz) 5.39 (1H, td, J=8.79, 4.30 Hz) 3.19 (1H, t, J=10.93 Hz)
Reaction SMILES: O[C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:20]=2[CH:21]=1)=[N:9][C:10]1[CH:11]=[C:12]2[O:19][CH2:18][O:17][C:13]2=[CH:14][C:15]=1[CH:16]=3.C(Cl)Cl.[CH3:27][N:28]=[C:29]=[O:30]>CN(C)C1C=CN=CC=1>[CH3:27][NH:28][C:29]([C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:20]=2[CH:21]=1)=[N:9][C:10]1[CH:11]=[C:12]2[O:19][CH2:18][O:17][C:13]2=[CH:14][C:15]=1[CH:16]=3)=[O:30]
Reactant: COc1cc2c(cc1O)-c1nc3cc4c(cc3cc1C2)OCO4
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1cc2c(cc1OC)Cc1cc3cc4c(cc3nc1-2)OCO4
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Compound 8, prepared in Example 8, (308 mg, 1 mmol), anhydrous methylene chloride (5 mL), 4-dimethylamino pyridine (489 mg, 4 mmol) and methyl isocyanate (171 mg, 0.18 mmol) are stirred at about 0° C. under a dry nitrogen atmosphere for about an hour. The reaction is allowed to cool to ambient temperature. Stirring is continued for about 16 hrs. while maintaining the nitrogen atmosphere. The solvent is then removed by reduced pressure evaporation to give a solid residue. This residue is chromatographed (silica gel eluded with ethyl acetate) to yield 7-n-Methylcarbamoyl-8-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[CH3:38][O:39][C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH2:49].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:38][O:39][C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH:49][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:18]
Reactant: COc1cc(Br)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4OC)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.90 g; 5.04 mmol), 1-hydroxybenzotriazole hydrate (0.85 g; 5.55 mmol) and 2-(2-methoxy-4-bromophenyl)ethanamine (Preparation 6; 1.28 g; 5.55 mmol) in dry dimethylformamide (15 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.16 g; 6.05 mmol) at ambient temperature. After stirring at ambient temperature for 4 hours, the solution was diluted with 150 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). Aqueous HCl (1M, 50 mL) was added to enable layer separation. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-methoxy-4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a light yellow solid (1.81 g). MS (apci, pos) m/z=590.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[CH:41][C:40]=1[C:53]([F:56])([F:55])[F:54])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[CH:41][C:40]=1[C:53]([F:54])([F:55])[F:56])[CH3:35]
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (5-trifluoromethanesulfonyloxy-2-trifluoromethyl-phenyl)-acetic acid ethyl ester.