Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([OH:14])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@H:22]1[O:27][C@@H:26]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@H:22]1[O:27][C@@H:26]([CH2:28][O:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:25][CH2:24][CH2:23]1
Reactant: OC(Cn1ccnc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@@H]2CCC[C@H](COC(Cn3ccnc3)c3ccccc3)O2)c(Cl)c1
Temperature: 85 °C
Yield: 35.5 %

Procedure:
1 ml of a dimethylformamide solution containing 23 mg of 1-phenyl-2-(1-imidazolyl)ethanol was heated at 50° C. for 30 minutes with 5 mg of 55% sodium hydride, and then 1 ml of a dimethylformamide solution containing 65 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, prepared as described in Example 2(a), were added thereto. The mixture was heated at 85° C. for 3 hours and then the mixture was treated and the product purified essentially as described in (a) above, to give 20 mg of the title compound as a liquid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:13](Br)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:20][N:21]([CH3:29])[CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.O>CCCCCC.O1CCCC1>[C:4]1([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:25]2([OH:28])[CH2:26][CH2:27][CH:22]([N:21]([CH3:29])[CH3:20])[CH2:23][CH2:24]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccccc1Cc1ccccc1
Reactant: CN(C)C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CN(C)C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 30.6 %

Procedure:
To 24.7 g of 2-bromodiphenylmethane and 100 ml of dry tetrahydrofuran (THF, hereinafter) is added 55 ml of 2.4 molar solution of n-butyllithium in hexane dropwise with stirring at -40° to 50° C. under a dry nitrogen atmosphere. The resultant solution is stirred one hour after addition of the n-butyllithium is completed. A solution of 15.5 g 4-dimethylaminocyclohexanone in 50 ml of dry THF is added dropwise with stirring while maintaining the temperature below -40° C. The resultant solution is stirred at -40°0 to -50° C. for two hours after addition of the ketone is completed and further stirred under N2 atmosphere overnight (16 hours) at room temperature. The solution is cooled to 0° C. and 350 ml of water and 400 ml of hexane are added thereto. The aqueous phase of the resultant mixture is removed and the product crystallized out of the organic phase. After filtration (washing the filter cake with hexane) the organic phase is washed three times with 100°ml portions of water and cooled overnight. A second crop is obtained, combined with the first crop and recrystallized from 50 ml of toluene to yield 9.46 g (30.6% yield) of 1-[2-(phenylmethyl)phenyl]-4-dimethylaminocyclohexanol, m.p. 140°-141° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:31])[CH:20]=[CH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CC(C)=O>[O:11]1[CH2:10][CH:9]1[CH2:7][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:31])[CH:20]=[CH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2
Reactant: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1OCC1CO1

Procedure:
First 3.46 g of potassium carbonate and then 10.5 ml of epichlorohydrin were added to a solution of 4 g of 1-[2-hydroxyphenyl]-3-(1H-indol-4-yl)-2-propen-1-one in 80 ml of acetone and the mixture was refluxed for 50 hours under an inert atmosphere and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica. Elution with a 95-5 dichloromethane-ethyl acetate mixture yielded 2.26 g of 1-[2-[(2-oxiranyl)-methoxy]-phenyl]-3-(1H-indol-4-yl)-2-propen-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.C([O-])=O.[NH4+].[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25]1.C(O)(=O)C>CN(C)C=O.O.[Zn]>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:17]=3)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Reactant: O=Cc1ccnc(C2CC2)n1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 45 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
(R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid, prepared during the previous step, was dissolved in a mixture of N,N-dimethylformamide (45.5 mL) and water (4.9 mL). Ammonium formate (1.925 g, 30.625 mmol) was added followed by zinc dust (1.05 g, 15.3 mmol). The reaction mixture was stirred at 45° C. for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added N,N-dimethylformamide (24.5 mL) followed by a solution of 2-cyclopropylpyrimidine-4-carbaldehyde in N,N-dimethylformamide (24.5 mL, 6.125 mmol, 0.25M) and acetic acid (3.675 mL, 61.25 mmol). The reaction mixture was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via preparative HPLC to afford the title compound (0.637 g, 28.6%).
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:13][I:14]>C1(C)C=CC=CC=1>[I-:14].[CH3:13][N+:4]1([CH2:3][C:2]([CH3:1])([N+:10]([O-:12])=[O:11])[CH3:9])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CI
Reactant: CC(C)(CN1CCCC1)[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C[N+]1(C)CCCC1)[N+](=O)[O-]
Product: [I-]
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Here, N-methyl-N-(2-methyl-2-nitro-propyl)-pyrrolidinium iodide was prepared by dissolving N-(2-methyl-2-nitro-propyl)-pyrrolidine (70 g, 0.4 mol) in toluene (100 mls), and thereafter under ice bath conditions adding drop wise methyl iodide (58 g, 26 mls, 0.41 mol) in toluene (70 mls) over a period of time of 30 minutes. After the addition was complete, the ice bath was removed and the solution was heated to a temperature of 80° C. A white solid was observed to precipitate. Stirring and heating were continued for an additional period of time of 6 hours. The white precipitate was recovered by filtration, and thereafter washed first with acetone (100 mls) and then with diethyl ether (50 mls) to yield after air drying 83 grams (65%), FTIR: (KBr, cm−1) 3026, 2978, 2874, 1544, 1492, 1475, 1459, 1439, 1377, 1344, 1307, 1229, 1195, 1152, 1052, 1012, 997, 926, 852, 833. 1H NMR (60 MHz, CDCl3/DMSO-d6, ref TMS, ppm) 1.85 (s, 6H) 2.1-2.3 (m, br, 4H) 2.96 (s, 2H) 3.9-3.7 (m, br, 4H) 4.45 (s, 3H). Elemental
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:17])=[O:7]
Reactant: COc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Product: COc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
To 3-methoxy-2,4,5-trifluorobenzoic acid (9.4 g) was added thionyl chloride (50 ml), the mixture was refluxed for 3 hours and then concentrated. The residue was purified by distillation under reduced pressure to give 3-methoxy-2,4,5-trifluorobenzoyl chloride (8.86 g) as yellow oil, bp 108-112° C./20 mmHg.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]>O1CCOCC1.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]
Reactant: O=C1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 6.5 h
Yield: 69 %

Procedure:
A mixture of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline {alternatively named as N-(2,6-dioxopiperidin-3-yl)-4-nitrophthalimide} (1 g, 3.3 mmol) and 10% Pd/C (0.13 g) in 1,4-dioxane (200 mL) was hydrogenated at 50 psi for 6.5 hours. The catalyst was filtered through Celite and the filtrate concentrated in vacuo. The residue was crystallized from ethyl acetate (20 mL) to give 0.62 g (69%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline {alternatively named as N-(2,6-dioxopiperidin -3-yl)-4-aminophthalimide} as an orange solid. Recrystallization from dioxane/ethyl acetate gave 0.32 g of yellow solid: mp 318.5-320.5° C.; HPLC (nova Pak C18.15/85 acetonitrile/0.1%H3PO4) 3.97 min (98.22%). 1H NMR (DMSO-d6) δ 11.08(s, 1H), 7.53-7.50 (d, J=8.3 Hz, 1H), 6.94(s, 1H), 6.84-6.81(d, J=8.3 Hz, 1H), 6.55(s,2H), 5.05-4.98(m, 1H), 2.87-1.99(m 4H); 13C NMR (DMSO-d6) δ 172.79,170.16, 167.65, 167.14, 155.13, 134.21, 125.22, 116.92, 116.17, 107.05, 48.58, 30.97, 22.22; Anal. Calcd for C13H11N3O4: C, 57.14; H, 4.06; N, 15.38. Found: C, 56.52-H, 4.17; N, 14.60.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4C(C=C)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.S([O-])([O-])=[O:29].[Na+].[Na+].[C:34]([OH:38])([CH3:37])([CH3:36])C>O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:36]([C@@H:34]([OH:38])[CH2:37][OH:29])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: C=Cc1nc2ccc(-c3c(C)noc3C)c3c2n1[C@@H](c1ccccn1)CO3
Reactant: O=S([O-])[O-]
Reactant: CC(C)(C)O
Agent: [Na+]
Solvent: O
Product: Cc1noc(C)c1-c1ccc2nc([C@@H](O)CO)n3c2c1OC[C@@H]3c1ccccn1
Reaction time: 8 h
Yield: 50 %

Procedure:
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (40 mg, 0.1 mmol) was dissolved in tert-butyl alcohol (4 mL) and water (4 mL). To the resulting solution, the mixture of A-D mixβ (300 mg, 0.7 mmol) [Aldrich, cat. #392766] was added at room temperature. The resulting mixture was stirred overnight. Saturated aqueous sodium sulfite (2 mL) was added and the suspension was stirred for 15 min at room temperature. The mixture was then extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the desired product (0.021 g, 50%). LCMS for C21H21O4N4 (M+H)+: calculated m/z=393.2. found 393.2.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=[C:8]1[CH2:20][CH2:21][CH3:22])[C:3]([NH2:5])=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:36][C:11]1[C:10]2[N:9]=[C:8]([CH2:20][CH2:21][CH3:22])[N:7]([CH2:6][C:2]([CH3:23])([CH3:1])[C:3]([NH2:5])=[O:4])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(N)=O
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
2,2-Dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide was treated with mCPBA (3.24 g, 14.4 mmol) followed by ammonium hydroxide (75 mL) and p-toluenesulfonyl chloride (2.5 g, 13 mmol) according to a modification of the method described in Part F of Example 1. The reaction was cooled to 0° C. before the addition of mCPBA. After the addition, the reaction was stirred for 15 minutes at 0° C. and 1.75 hours at ambient temperature. The reaction was not washed prior to the addition of ammonium hydroxide. The amination reaction was stirred for one hour. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol), recrystallized from toluene:methanol, dried overnight in a vacuum oven at 80° C., recrystallized from acetonitrile:water, and dried overnight in a vacuum oven at 80° C. to provide 0.553 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as a yellow solid, mp 219-221° C.
Reaction SMILES: OCCCCCC[CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH:45]1CCN[CH2:47][CH2:46]1>>[CH3:44][O:43][C:39]1[CH:38]=[C:37]([NH:36][C:25]2[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=[C:22]([S:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([N:10]5[CH2:47][CH2:46][NH:45][CH2:8][CH2:9]5)=[O:12])[CH:14]=4)(=[O:21])=[O:20])[CH:23]=3)[N:28]=[CH:27][C:26]=2[C:33]([NH2:35])=[O:34])[CH:42]=[CH:41][CH:40]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: C1CNCCN1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCNCC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using piperazine in place of 8-aminooctanol. ES/MS calcd. for C29H30N5O5S+ 560.2. Found m/z=560.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1C
Yield: 98.6 %

Procedure:
A mixture of 5,6-dimethyl-1H-benzo[d]imidazole (500 mg, 3.42 mmol), trityl chloride (1.05 g, 3.76 mmol) and TEA (524 μL, 3.76 mmol) in 5 mL DMF was stirreds at rt for 3 h. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 1.31 g of Intermediate 415.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:9][CH:8]=1>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:23])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:11][CH:12]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCO)cc5)c4)cc23)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCCO)cc5)c4)cc23)c1
Reaction time: 5 h
Yield: 104.8 %

Procedure:
Pd(OH)2 (20% on activated carbon, 250 mg) was added to a solution of Intermediate 72 (250 mg, 0.38 mmol) in MeOH/THF (1:1) (10 mL). The solution was hydrogenated via balloon for 5 h. The Pd was filtered through a plug of celite. The filtrate was then concentrated in vacuo to afford the title compound as a yellow solid (260 mg). ES/MS calcd. for C36H37N4O6S+ 653.2. Found m/z=653.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4cc(C(F)(F)F)ccn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
5-Chloro-3-(4-(4-(trifluoromethyl)pyridin-2-yloxy)phenyl)pyridin-2-amine (470 mg) was added to a mixture of NaH (60%, 257 mg) and 2-chloroethanesulfonyl chloride (628 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with IPE to give the title compound (502 mg) as a yellow solid. The solid was crystallized from CH3CN—IPE to give a pale yellow solid (1st crop impure, 2nd crop (254 mg)). The 1st crop was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (263 mg) as a white solid.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][CH2:10][C@H:11]([NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[N:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[OH:7][C:6]([CH2:8][O:9][CH2:10][C@H:11]([NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[N:13]=1)=[O:5]
Reactant: Cc1cc(C(=O)N[C@@H](COCC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](COCC(=O)O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 90 %

Procedure:
Prepared analogously to Example 17 from N-[(1R)-2-(tert-butoxycarbonylmethyloxy)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and trifluoroacetic acid. Yield: 90%; Rf value: 0.50 (silica gel; dichloromethane/methanol=4:1); C24H25ClN4O5 (484.94); mass spectrum: (M+H)+=485/487 (chlorine isotope) and (M−H)-=483/485 (chlorine isotope).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][N:14]1[C:18]2=[N:19][C:20]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[CH:21][CH:22]=[C:17]2[C:16]2[CH2:40][NH:41][CH2:42][CH2:43][C:15]1=2>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:42][CH2:43][C:15]2[N:14]([CH3:13])[C:18]3[C:17]([C:16]=2[CH2:40]1)=[CH:22][CH:21]=[C:20]([N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)=[CH:25][C:24]1=[O:39])[N:19]=3)(=[O:10])[CH3:9]
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc3n2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Triethylamine (40 μL, 0.28 mmol), DMAP (3.5 mg, 0.028 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added to a solution of 1-(9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride (80 mg, 0.14 mmol) in CH2Cl2 (8 mL) and the resulting solution was stirred at ambient temperature for 3 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 14 column volumes) gave the title compound (51 mg, 77%) as a yellow solid and a mixture of rotomers: mp 238-242° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.11-8.04 (m, 3H), 7.44-7.37 (m, 1H), 7.03 (d, J=1.5 Hz, 1H), 6.86-6.83 (m, 1H), 4.73-4.68 (m, 2H), 3.90-3.83 (m, 2H), 3.71-3.69 (m, 3H), 3.01-2.86 (m, 2H), 2.16-2.12 (m, 3H); ESI MS m/z 468 [M+H]+; HPLC (Method A)>99% (AUC), tR=17.8 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][C:20]=2[O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:26])=[CH:21][C:20]=2[O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:17][CH:18]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: COCCOc1cc(C(=O)O)ccc1-c1ccc(F)cc1
Product: COCCOc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccc(F)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (21 mg, 0.14 mmol) and 4′-fluoro-2-(2-methoxyethoxy)-1,1′-biphenyl-4-carboxylic acid (D77) (50 mg, 0.17 mmol) as an orange solid. MS(ES): MH+ 417, M-H+ 415
Reaction SMILES: [CH3:1][C:2]([CH3:10])([O:4][C:5]([N:7]=[N+]=[N-])=[O:6])[CH3:3].[C:11]1([CH2:17][N:18]2[CH2:23][CH2:22]N[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.O.CCOCC>[CH3:1][C:2]([CH3:10])([O:4][C:5]([N:7]1[CH2:20][CH2:19][N:18]([CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:23][CH2:22]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 3.4 g (0.024 mole) of 1,1-dimethylethoxy carbonylazide in 5 ml of pyridine was rapidly added to a stirred solution of 1-phenylmethylpiperazine (4.2 g, 0.024 mole) in 5 ml of pyridine. An initial exothermic reaction was noted. The mixture was allowed to stir overnight, diluted with water and the product was extracted with two 50 ml portions of ether. The ether extracts were dried (MgSO4), filtered, and evaporated to yield a yellow oil. Column chromatography (2" diameter column, 500 g of silica gel, ether eluent) followed by sublimation at 110°/0.5 mm returned 5.7 g (86%) of white solid, m.p. 64°-73°. The solid was dissolved in 50 ml of ether and cooled to -70°. The resultant white solid was filtered off to yield 4.5 g (68%) of product, m.p. 71-3°. Calc. for C16H24N2O2 (276.38): C, 69.53; H, 8.75; N, 10.14. Found: C, 69.44; H, 8.82; N, 10.15.