Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[CH2:9][C:10]([F:13])([F:12])[F:11])(=O)=O.[Na].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CN(C=O)C>[N:27]1([CH2:6][CH2:7][N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OCCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCn2cncn2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Yield: 83 %

Procedure:
A mixture of 2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl methanesulfonate, Example 15C (0.050 g, 0.128 mmol) and 1,2,4-triazole sodium salt (0.023 g, 0.256 mmol) in DMF (2 mL) was heated at 60° C. under N2 for 45 min. Upon cooling, the mixture was partitioned between Et2O and water. The organic phase was washed with water and the combined aqueous phases were extracted twice with Et2O. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes gradient followed by 1-10% MeOH/EtOAc gradient) and the product was crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.038 mg, 83% yield): MS (ES) m/z 364 (M+1).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Br[CH2:40][C:41]([N:43]1[C:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][CH2:45][C:44]1([CH3:52])[CH3:51])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[C:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][CH2:45][C:44]2([CH3:52])[CH3:51])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 28.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.5 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].C(O)C.Cl>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)COc1cc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCC(=O)O
Temperature: 100 °C
Yield: 97.7 %

Procedure:
Compound 42 (50 mg, 0.12 mmol), NaOH (50 mg, 1.25 mmol), ethanol (5 mL) and water (500 uL) were combined in a sealed microwave vessel. The mixture was heated at 100° C. for 10 minutes in a Personal Chemistry Emrys Optimizer microwave. The reaction was then acidified with 1 N HCl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents removed in vacuuo to give 46 mg (98%) of 43 as a purple solid. 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.20-1.25 (m, 5H), 1.75 (s, 2H), 1.90 (s, 2H), 2.23 (s, 3H), 4.61 (s, 2H), 6.74 (d, J=8.3 Hz, 1H), 6.75-7.05 (m, 2H), 7.09-7.15 (m, 3H) 7.25-7.36 (m, 2H).
Reaction SMILES: O[C@@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C@@H:5]([CH2:16][CH2:17][C@@H:18]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:19]CC2C=CC=CC=2)[C@H:4]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:3]1.C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:74]1([CH3:81])[C:75](C)=[CH:76][CH:77]=[CH:78][CH:79]=1>>[C:74]1([CH2:81][CH2:19][C@H:18]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:17][CH2:16][C@@H:5]2[C@@H:6]3[C@@H:2]([O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]3)[CH2:3][C@H:4]2[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Reactant: Cc1ccccc1C
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Product: O=C1CCCC=CC[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (Z)-7-((1R,2R,3R,5S)-5-hydroxy-2-((3R)-5-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-5-enoic acid (52 g from Example 26) in xylene (250 mL) was treated with 2,2′-dipyridyl disulfide (28.9 g, 131.2 mmol) and triphenylphosphine (39.2 g, 149.5 mmol). This mixture was then stirred for 2 hr at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to 80° C. for 18 hr (TLC monitoring), followed by removal of xylene under reduced pressure. The residue was diluted with saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 80.0 g of crude product. The crude product was purified by column chromatography providing 17.1 g of the title compound (68.0% yield, 3 steps).
Reaction SMILES: [CH2:1]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:50]=[CH:49][C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:42])=[CH:39][CH2:38]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CO.[BH4-].[Na+].Cl>C(Cl)(Cl)Cl>[CH2:1]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:38]=[CH:39][C:40]([CH:41]([OH:42])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:49][CH2:50]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOC1(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)C=CC(C(=O)c2ccccc2)=CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOC1(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)C=CC(C(O)c2ccccc2)=CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
4,4-Di(12-docosoxydodecyloxy)benzophenone (1.04 g, 867 μmol) was dissolved in chloroform (20 ml), and methanol (2 ml) and sodium borohydride (98 mg, 2.60 mmol) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, 0.5N hydrochloric acid (20 ml) was added and the mixture was stirred for a while. The aqueous layer was removed, and the organic layer was washed with water (10 ml)×2. The organic layer was evaporated under reduced pressure, and the residue was crystallized from methanol to give 4,4-di(12-docosoxydodecyloxy)benzhydrol (1.03 g, 857 μmol, 98%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C@@H:14]1[CH2:19][C@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:17][CH2:16][C@@H:15]1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Si:21]([O:20][C@@H:18]1[CH2:17][CH2:16][C@H:15]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:14]([C:11]([CH3:12])=[CH2:1])[CH2:19]1)([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23]
Reactant: CC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (1.2 g) was suspended in toluene (16 mL) prior to the addition of 0.5M potassium bis(trimethylsilyl)amide (5.8 mL) in toluene. After 1 h, this solution was cooled to 0° C. prior to the addition of benzyl (1S,2R,4R)-2-acetyl-4-(tert-butyldimethylsilyloxy)cyclohexylcarbamate (660 mg) in toluene (5.4 mL). After 20 min at 0° C., the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-(prop-1-en-2-yl)cyclohexylcarbamate (380 mg). MS found: (M+H)+=404.2.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO.[I:18]I>CO>[I:18][C:14]1[CH:15]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=[CH:11][C:12]=1[NH2:13]
Reactant: II
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: OO
Solvent: CO
Product: CCCCCCCCc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.6 %

Procedure:
To a stirred mixture of 4-octyl aniline (0.33 g, 1.6 mmol) and H2O2 (30%, 0.5 ml) in CH3OH (1.5 nil) was added I2 (0.2 g, 0.8 mmol) and the mixture was stirred overnight at room temperature. The solvent was distilled off and the residue was diluted to 10 ml with CH2Cl2, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.46 g, 86%) as yellow paste. 1H NMR (CDCl3) 7.44 (d, 1H, J=1.83 Hz); 6.93 (dd, 1H, J=8.07, 1.86 Hz); 6.65 (d, 1H, J=8.1 Hz); 4.1 (b, 2H); 2.43 (t, 2H, J=7.5 Hz); 1.54-1.49 (m, 2H); 1.26 (b, 10H); 0.87 (t, 3H, J=6.39 Hz).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:52]=1)([CH3:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:45]([C:48]1[S:49][CH:50]=[C:51](/[CH:53]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[N:52]=1)([CH3:47])[CH3:46]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Reactant: CC(C)c1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(C(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 11.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.60 g), [(2-isopropyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.7 g), potassium carbonate (0.57 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 17 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:4, v/v) to give ethyl {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as colorless crystals (0.22 g, yield 11%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [N+:1](=C)=[N-].[CH2:4]([N:11]1[C:23]2[C:22]([S:24][CH3:25])=[C:21]([CH2:26][C:27]([OH:29])=O)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>C(OCC)C>[CH2:4]([N:11]1[C:23]2[C:22]([S:24][CH3:25])=[C:21]([CH2:26][C:27]([NH2:1])=[O:29])[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: CSc1c(CC(=O)O)ccc2c3ccccc3n(Cc3ccccc3)c12
Solvent: CC(=O)O
Solvent: CCOCC
Product: CSc1c(CC(N)=O)ccc2c3ccccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An excess of a solution of diazomethane in diethyl ether was added to a solution of 150 mg of 9-benzyl-1-methylthiocarbazol-2-acetic acid, as obtained in Example 5, in 3 ml of diethyl ether. The resulting reaction mixture was stirred for 10 minutes at room temperature and then glacial acetic acid was added. The reaction mixture was next concentrated by evaporation under reduced pressure. 10 ml of saturated methanolic ammonia was added to a solution of the resulting residue in 5 ml of methanol, and the reaction mixture was stirred for 7 days at room temperature. After this time, the reaction mixture was concentrated by evaporation under reduced pressure and the resulting residue was subjected to column chromatography using 400 mg of silica gel using, as eluent, a 4:1 by volume mixture of hexane and ethyl acetate to yield 131 mg of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12].ClC1C=CN=CN=1.CO[CH2:24][N:25]([CH2:30][Si](C)(C)C)[C:26]([CH3:29])([CH3:28])[CH3:27].FC(F)(F)C(O)=O>ClCCl>[C:26]([N:25]1[CH2:30][C@@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)/C=C/c1ccc(F)cc1F
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Agent: Clc1ccncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl (2E)-3-(2,4-difluorophenyl)acrylate from preparation 3 (10 g, 50.5 mmol) and N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (preparation 4) (10.3 g, 50.5 mmol) in dichloromethane (200 mL) at room temperature under dry nitrogen was added trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 17 hours. To the reaction mixture was then added a further portion of N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (from preparation 4) (3.9 g, 19.2 mmol) and trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 18 hours, then quenched by the addition of saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 40 g column) eluting with 5% ethyl acetate in pentane increasing polarity with a linear gradient up to 100% ethyl acetate over the course of 1 hour. The residue was then subjected to chiral HPLC (eluting with 95:5 hexane:isopropyl alcohol at 80 mL/min at ambient temperature on a Chirapak AD500*80 mm column) to afford the desired enantiomer of the title compound, which we designate here Enantiomer 1, and which was obtained as the faster running enantiomer (retention time 8 minutes) as a clear oil (6.1 g, 80%) with enantiomeric excess of >99% as determined by chiral HPLC with reference to a racemic standard. The undesired enantiomer was obtained as the slower eluting component (Enantiomer 2, retention time 8.7 min) 1H NMR (400 MHz, CDCl3) δH 1.10 (9H, s), 2.80 (1H, m), 3.00 (1H, m), 3.15 (3H, m), 3.60 (3H, s), 3.80 (1H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCI) 298 (100%) [MH+].
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH:14]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[CH:20][C:19]=1[O:29][CH3:30])[CH3:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:26]([NH:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:17]([NH:16][CH:14]([CH3:15])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:32])=[O:31])=[C:19]([O:29][CH3:30])[CH:20]=1)(=[O:28])[CH3:27]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)O

Procedure:
Prepared from 96c by treatment with TFA/CH2Cl2. After complete reaction, the solvent is removed in vacuo and the residue repeatedly concentrated from toluene. The resulting residue was dried under vacuum to a constant weight.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12](Cl)[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)cccc3n2)C1
Yield: 54.9 %

Procedure:
A suspension of 2-[(5)-3-amino-1-pyrrolidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 44) (0.10 g) and triethylamine (0.04 mL) in ethanol (20 mL) was treated with 5% palladium on charcoal (0.05 g) and stirred under 2 atmospheres of hydrogen at ambient temperature for 16 hours. The reaction mixture was filtered through Celite and the liquors concentrated to dryness. Recrystallisation from methanol/ethyl acetate afforded to title compound (0.05 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:13]3)[CH2:4][CH2:3]1.CCN(CC)CC.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:12]2[N:11]=[C:10]3[N:14]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH:9]3[O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)=[CH:28][CH:27]=1)=[O:42]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(N)cc4)nc32)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(NC(=O)C(C)(C)C)cc4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 16A) (100 mg, 0.258 mmole) in CH2Cl2 (2 mL) is added NEt3 (72 μL, 0.515 mmole) and pivaloylchloride (48 μL, 0.387 mmole). The reaction mixture is stirred at room temperature overnight. Solvent is removed under reduced pressure. AcOEt is added to the residue and the organic phase is washed with water and dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (100:0) to (90:10) to afford 2,2-dimethyl-N-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-propionamide melting at 120° C.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([O:14]CC)=O)=[N:10][CH:9]=[C:8]2[N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:19][C:7]=12)[CH3:2].[NH2:28][OH:29].[OH-].[Na+].Cl>CO>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([NH:28][OH:29])=[O:14])=[N:10][CH:9]=[C:8]2[N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:18]=[CH:19][C:7]=12)[CH3:2]
Reactant: CCO/C=C/c1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO/C=C/c1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
To ethyl 4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.2 g, 0.54 mmol) in methanol (5 mL) were added hydroxylamine (1 mL, 50% in water, 15.2 mmol) and sodium hydroxide (0.0763 g, 1.9 mmol). The mixture was stirred at room temperature for 5 h, neutralized with 4N aq. HCl solution (0.48 mL, 1.9 mmol), and extracted with ethyl acetate. The organic extract was concentrated and recrystallized from ethyl acetate/ethyl ether/hexane to give the title compound (0.12 g, 62% yield). 1H NMR (DMSO-d6) δ; 11.76 (d, 1H, J=1.9 Hz), 8.88 (d, 1 H, J=1.9 Hz), 8.60 (s, 1 H), 7.83 (d, 1 H, J=3.0 Hz), 7.31 (t, 2H, J=8.9 Hz), 7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz), 6.82 (d, 1H, J=3.0 Hz), 6.66 (d, 1H), J=13.2 Hz), 5.54 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 1.28 (t, 3H, J=7.0 Hz). LCMS (APCl, M+H+): 356.1. Anal. (C19H18FN3O3) C, H, N. HPLC: 95% purity.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)[CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(CCN2CCNCC2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
4-(Methylsulfonylamino) benzoic acid (2.16 g, 10.05 mmol) was added to a stirring solution of 1-hydroxybenzotriazole hydrate (1.36 g, 10.05 mmol) and dicyclohexylcarbodiimide (2.08 g 10.05 mmol) in DMF (30 mL) at 25° C. under nitrogen. After 45 minutes, 1-[2-(6-methyl-2-pyridyl)ethyl]piperazine (2.27 g, 11.05 mmol) was added as a suspension in DMF (15 mL). The resulting mixture was stirred at room temperature overnight. The work-up was performed as disclosed in Example 5 to give 2.94 g (73%) of the title compound which was treated with ethanolic HCl to afford 2.15 g of product as a dihydrochloride: mp 165°-167° C.; 1H NMR (DMSO-d6): δ 10.14 (s, 1H), 8.19 (m, 1H), 7.63 (m, 2H), 7.45 (d, J=8.72 Hz, 2H), 7.25 (d, J=8.71 Hz, 2H), 3.85-3.20 (m, 12H), 3.06 (s, 3H), 2.67 (s, 3H); IR (KBr): 3420, 3000, 2560, 1640 cm-1 ; MS (m/z) 403 (MH+, 25%) 217 (30), 91 (100).