Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:58])([F:57])[O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:48]([C:45]3[CH:46]=[CH:47][C:42]([O:41][C:40]([F:57])([F:58])[F:39])=[CH:43][CH:44]=3)(=[O:49])=[O:50])[CH2:56][CH2:55]2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1c(C(=O)O)ccc2cccnc12
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)ccc2cccnc12
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To the solution of 8-methyl-7-quinolinecarboxylic acid (may be prepared as described in Intermediate 2; 90 mg, 0.483 mmol) in N,N-Dimethylformamide (DMF) (2 ml), HATU (193 mg, 0.508 mmol) was added at room temperature. The reaction was stirred for 20 min and then 1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Intermediate 11; 150 mg, 0.483 mmol) was added followed by DIPEA (0.211 ml, 1.209 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into the separating funnel and partitioned between ethyl acetate (25 ml) and sodium hydroxide (15 ml). The organic phase was washed with sodium hydroxide (2×10 ml), water (2×10 ml) and brine (10 mL) before it was dried using phase separator and the solvent was removed under vacuum. The crude product was purified by MDAP to give the title compound as a white solid (115 mg).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:19])=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:24]O>ClCCl>[CH:1]1([C:6]2[C:7]([OH:19])=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([CH2:12][C:13]([O:15][CH3:24])=[O:14])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 2-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)acetic acid (270 mg, 1.02 mmol) in methanol was added thionyl chloride (149 μL, 2.04 mmol) dropwise at 25° C. The mixture was stirred at room temperature for 1 h. The reaction was diluted with dichloromethane and washed with 50% saturated NaHCO3 (2×50 mL), brine, dried over Na2SO4, and concentrated in vacuo to afford methyl 2-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)acetate as clear brown oil (180 g, 63% yield). LC/MS m/z 280.0 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]12([OH:17])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:17][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A total of 13 mmole of acrylyl chloride was added dropwise to a mixture of 10 mmole of 1,3-adamantanediol, 15 mmole of triethylamine and 100 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at 50° C. for 1.5 hours. After adding water, the reaction mixture was extracted with ethyl acetate, the organic layer was concentrated, and the resulting concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 63%.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH3:13])[CH2:11]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:31][C:32]1[CH:33]=[C:34]([CH2:39][C@H:40]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:41]([O-:43])=[O:42])[CH:35]=[CH:36][C:37]=1[OH:38].C(=O)(O)[O-].[Cs+]>CN(C)C(=O)C>[C:48]([O:47][C:45]([NH:44][C@@H:40]([CH2:39][C:34]1[CH:35]=[CH:36][C:37]([OH:38])=[C:32]([OH:31])[CH:33]=1)[C:41]([O:43][CH2:11][C@H:10]([O:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:13])=[O:42])=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)[O-]
Reactant: C[C@H](CBr)OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A suspension of (1R)-2-bromo-1-methylethyl benzoate 1b (4.98 g, 20.6 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid, tetrabutylammonium salt 1a (7.3 g, 25 mmol), and cesium bicarbonate (4.85 g, 25 mmol) in N,N-dimethylacetamide (100 mL) was stirred at 55° C. for 16 h. The solvent was evaporated under vacuum. Ethyl acetate was added to the residue and the resulting solution was washed with water, then 5% NaHCO3 and brine, and dried over Na2SO4. After removing the solvent under reduced pressure, chromatography (silica gel, 30% ethyl acetate in hexane) of the residue gave 6.3 g (68% yield) of the title compound 1c as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.25 (s, 9H), 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz, 1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=5.6, 7.4 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.53 (dd, J=2.2, 8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 360.15 (M+H)+ and 358.09 (M−H)−.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[CH3:8][N:7]([CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][S:12][C:11](=[NH:10])[NH2:13]
Reactant: NC(N)=S
Reactant: CN(C)CCCCCl
Agent: Cl
Solvent: CCO
Product: CN(C)CCCCSC(=N)N
Reaction time: 24 h
Yield: 84.4 %

Procedure:
A stirred mixture of 1-chloro-4-(dimethylamino)-butane hydrochloride (115 g), thiourea (51.9 g) and ethanol (500 ml) was heated under reflux for 24 hours then allowed to stand at 4° C. for 24 hours. The resulting solid was collected by filtration, washed with ether, and dried in vacuo at ambient temperature for 24 hours to give S-[4-(dimethylamino)butyl]isothiourea dihydrochloride as an off-white solid (140 g), m.p. 179°-182° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:29])[O:22][CH2:21][CH2:20]1>>[CH3:17][N:15]([CH3:16])[C:13]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[O:22][CH2:21][CH2:20]2)[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=1)=[O:14]
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: Cc1cccc2c1C(Cl)CCO2
Product: Cc1cccc2c1C(Oc1cc(C(=O)N(C)C)cc3c1nc(C)n3C)CCO2
Yield: 50 %

Procedure:
The title compound was prepared as a white solid in 50% yield (116 mg) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (100 mg, 0.61 mmol, WO 2004054984) and 4-chloro-5-methylchromane (191 mg, 1.0 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28]I>CN(C=O)C.[H-].[Na+]>[CH3:28][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCOCC2)c2nc(-c3cnn4ccc(C#N)cc34)ncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.5 %

Procedure:
To a solution of example 1 (48 mg, 0.13 mmol) in DMF (6 mL), 55-65% NaH dispersion in mineral oil (7.3 mg, 0.18 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then MeI (0.015 mL, 0.25 mmol) was added and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was quenched with saturated NaCl aqueous solution (10 mL) and extracted with EtOAc (3×10 mL) and CH2Cl2 (2×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH2Cl2 mixtures of increasing polarity as eluent, to afford 50 mg of the desired compound (quantitative yield).
Reaction SMILES: [OH-].[Zr+4:2].[OH-].[OH-].[OH-].[C:6]([OH:11])(=[O:10])[C:7]([OH:9])=[O:8].O.O.[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[O-2].[Zr+4].[O-2]>O>[C:6]([O-:11])(=[O:10])[C:7]([O-:9])=[O:8].[Zr+4:2].[C:14]([O-:19])(=[O:18])[C:15]([O-:17])=[O:16]
Reactant: O=C(O)C(=O)O
Agent: [Zr+4]
Agent: [O-2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 90 °C

Procedure:
A dispersion liquid was prepared by adding 100 g (31 g in terms of ZrO2) of zirconium hydroxide to 100 g of water, followed by well stirring. Next, as a first addition of oxalic acid, 31.7 g (a mol ratio of oxalic acid to Zr=1.0) of oxalic acid dihydrate was added to the dispersion liquid, followed by heating at 90° C. for 15 minutes. Next, as a second addition of oxalic acid, 15.8 g (a mol ratio of oxalic acid to Zr=0.5) of oxalic acid dihydrate was added to the dispersion liquid, followed by heating at 90° C. for 15 minutes to obtain a sol. When diluted to 0.5% by weight in terms of ZrO2, the zeta potential of the sol was −61 mV and the particle diameter D50 was 65 nm.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:18]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:19][N:20]4[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[CH:23]=[CH:22][C:21]=34)[CH:14]=[CH:13][N:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl>[CH:5]1([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:18]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:19][N:20]4[C:25]([CH3:26])=[C:24]([C:27]([NH:40][CH:37]5[CH2:39][CH2:38]5)=[O:28])[CH:23]=[CH:22][C:21]=34)[CH:14]=[CH:13][N:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CC1
Reactant: Cc1c(C(=O)O)ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)NC2CC2)ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Thionyl chloride (200 μL, 2.7 mmol) was added to 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylic acid (31 mg, 0.072 mmol) which had been pre-cooled to 0° C. The reaction mixture was stirred at room temperature for 1 hour. The excess thionyl chloride was removed in vacuo. To a solution of the residue in dichloromethane (300 μL) was added cyclopropylamine (50 uL 0.72 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was quenched with water and diluted with ethyl acetate. Saturated aqueous sodium bicarbonate solution was added to the biphasic mixture. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:2 hexanes:ethyl acetate to 2:3 hexanes:ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxamide (15 mg, 44%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (d. 1H), 8.05 (d, 1H), 7.62 (m, 2H), 7.30 (d, 1H), 7.13 (t, 2H), 6.29 (d, 1H), 5.10 (d1 1H), 4.30 (m, 1H), 2.96 (s, 3H), 2.94 (m, 1H), 2.05 (m, 2H), 1.76–1.50 (m, 6H), 0.92 (m, 2H), 0.66 (m, 2H); MS m/z 471 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([Br:18])=[CH:11]2)[S:5][CH3:6].[OH-].[Na+].Cl>C(O)C.O>[Br:18][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH:4]([S:5][CH3:6])[C:3]([OH:19])=[O:2])=[CH:17][CH:16]=2
Reactant: COC(=O)C(Oc1ccc2ncc(Br)cc2c1)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of (3-bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid methyl ester (20 g) from Step 1, Stage 1 above in ethanol (150 ml) at R.T. a 2 M solution of sodium hydroxide in water (35.06 ml) was added. The reaction mixture was stirred at R.T. for 2 hours. The reaction mixture was poured into ice-could water (200 ml) and acidified with a 2 M solution of hydrochloric acid in water (35.06 ml). The precipitate was filtered off and washed with water to give (3-Bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid as yellowish solid (18.79 g). 1H NMR (CDCl3) δ ppm: 13.50 (1H, s br); 8.83 (1H, d); 8.59 (1H, d); 7.99 (1H, d); 7.57 (1H, dd); 7.50 (1H, d); 6.09 (1H, s); 2.17 (3H, s).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1>CCOC(C)=O.CCCCCC>[O:31]=[C:4]1[C:3](=[CH:2][NH:49][C:46]2[CH:45]=[CH:44][C:43]([CH2:42][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:48][CH:47]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN4CCCC4)cc3)c2)nn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A small screw cap test tube was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 345, 70 mg, 0.1681 mmol) and THF (2.0 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (30.1 mg, 0.171 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. iPrOH (˜10 mL) affording the title compound in 18% yield (0.018 g, 0.031 mmol).
Reaction SMILES: [O:1]([CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:12]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]([CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][C:12]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2oc(COc3ccccc3)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc2oc(COc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
A tetrahydrofuran (1 mL) solution of 2-phenoxymethyl-benzofuran-5-carbonitrile (25 mg, 0.1 mmol) described in Production Example 75-1-2 was dropped into a tetrahydrofuran (5 mL) suspension of lithium aluminum hydride (19 mg, 0.5 mmol). This mixture was stirred at room temperature for 3 hours and 45 minutes. After adding ice water to the reaction mixture and stirring, insoluble matter was filtered out through Celite followed by rinsing with ethyl acetate. The organic layer was separated followed by washing with sat. NaCl, drying over anhydrous magnesium sulfate and concentrating under a reduced pressure to obtain the title compound (12 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-])=O>CO.[Pt]=O>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7]
Reactant: Nc1ccc(C(=O)Nc2nccc3ccccc23)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc(C(=O)Nc2nccc3ccccc23)cc1N
Reaction time: 18 h

Procedure:
A suspension of give 4-amino-N-isoquinolin-1-yl-3-nitrobenzamide and platinum oxide (330 mg) in MeOH (100 mL) was hydrogenated at 40 psi for 18 h. The catalyst was filtered from the solution through Celite and the filtrate evaporated to give 3,4-diamino-N-isoquinolin-1-yl-benzamide as a thick oil. MS (ESI) m/z 279.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:25][CH2:24]2)[CH3:22])[C:9]([N+:37]([O-:39])=[O:38])=[C:8]([CH3:40])[NH:7][C:6]=1[NH2:41])=[O:4].ClC1C=CC=C(C(OO)=[O:50])C=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:18][CH2:19][CH2:20][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:25][CH2:24]2)[CH3:22])=[O:50])[C:9]([N+:37]([O-:39])=[O:38])=[C:8]([CH3:40])[NH:7][C:6]=1[NH2:41])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCC(C)N1CCN(c2ccccc2OC)CC1
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)CCCC(C)N1CCN(c2ccccc2OC)CC1

Procedure:
This compound was prepared from 2-amino-1 4-dihydro-4-(2-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-pentylthio}phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester and m-chloroperbenzoic acid in the same manner as described for Example 2. 1H-NMR (CDCl3) δ 1.65(br s,4H); 2.02(m,2H); 2.42(s,3H); 2.49(m,2H); 2.71(s,4H); 2.98(m,2H); 3.12(s,4H); 3.61(s,3H); 3.86(s,3H); 5.76(s,1H); 6.68(s,2H); 6.84-7.01(m,4H); 7.27(m,4H); 7.81-7.86(m,1H). Mass spectrum: 598 (M+H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[S:10][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[N:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ncc(CO)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ncc(CCl)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-yl]-methanol (560 mg, 2.78 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.50 mL, 3.60 mmol) followed by DMAP (34 mg, 0.28 mmol) and Ms-Cl (0.28 mL, 3.51 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil. TLC:rf (1:2 hept-EA)=0.50. LC-MS-conditions 01: tR=0.81 min; [M+H]+=219.89.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1([CH3:20])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])=[N:8]1>O1CCCC1>[CH3:6][C:7]1([CH3:20])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH2:19][CH2:1][C:2]2[CH:14]=[CH:13][CH:12]=[C:17]([CH3:16])[C:3]=2[CH3:4])=[N:8]1
Reactant: [Li]CCCC
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(C2=NC(C)(C)CO2)c(CCc2cccc(C)c2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (6.9 ml of a 2.5M soln in hexanes) was added dropwise to the product of example 21 step (i) (3.51 g) in tetrahydrofuran (60 ml) at -78° C. After 2 hours the product from step (i) (3.45 g) was added. After 1 hour the solution was left to warm to room temperature. The solution was quenched with water and extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. Yield 1.83 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15](C=O)[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: O=CN1CCN(c2ccc3cc(F)ccc3n2)CC1
Agent: O=S(=O)(O)O
Product: Fc1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
The title compound may be prepared by treatment of 4-(6-fluoroquinolin-2-yl)piperazine-1-carbaldehyde of Step E with 4M sulfuric acid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].F[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C1(B(O)O)C=CC=CC=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccccc1
Product: CCc1c(-c2ccccc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with phenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 9.39 (broad s, 1H); 7.36-7.50 (m, 5H); 5.40 (s, 2H); 2.85 (q, J=7.3 Hz, 2H); 1.22 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C21H20NO3 (M+H): 334.1938. Found 334.1430
Reaction SMILES: N1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)CCCCC1.C(Cl)(=O)C.[C:18]([C:21]1[CH:22]=[C:23]2[N:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]=13)[C:25]([CH2:40][CH3:41])=[C:24]2[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)(=[O:20])[CH3:19]>C(COC)OC>[CH2:33]([O:32][C:29]1[C:30]2[N:31]3[C:26](=[CH:27][CH:28]=1)[C:25]([CH2:40][CH3:41])=[C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[CH:44][CH:43]=1)[C:23]3=[CH:22][C:21]=2[C:18](=[O:20])[CH2:19][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C1CCN(CN2CCCCC2)CC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3c(OCc4ccccc4)ccc1n23
Solvent: COCCOC
Solvent: CC(=O)Cl
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)CCN3CCCCC3)c3c(OCc4ccccc4)ccc1n23
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
Dipiperidinomethane (0.3 ml, 1.5 mmol) was dissolved in 20 ml of dimethoxyethane and acetyl chloride (0.11 ml, 1.5 mmol) was added. The mixture was stirred for 30 minutes, while 4-acetyl-5-benzyloxy-2-(4benzyloxyphenyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (0.5 g, 1.0 mmol) was added and HCl-gas was bubbled through the mixture for 15 minutes. The reaction mixture was refluxed for 5 hours and stirred at room temperature for 16 hours. The solvent was evaporated, and the crude HCl-salt was purified by column chromatography over silica gel 60, using 5% of methanol in dichloromethane as the eluent. Fractions containing the HCl-salt were combined and the solvent was evaporated. The salt was dissolved in 20 ml of dry dichloromethane and 2.13 g sodium sulfate and 2.76 g potassium carbonate was added. The mixture was stirred at room temperature for 24 hours. Remaining salts were filtered off, and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 5% methanol in dichloromethane as the eluent to afford 170 mg (28%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-4-(1-oxo-3-piperidinopropyl)pyrrolo[2,1,5-cd]indolizine as an oil. 1H--NMR (CDCl3, 200 MHz) δ: 1.35-1.75 (m, 9 H); 2.34-3.75 (m, 10 H); 5.17 (s, 4 H); 7.10-7.78 (m, 17 H).