Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:11][C:3]1=2.[CH2:18]([C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([C@H:25]1[CH2:29][N:28]([C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:9]2[CH:10]=[CH:11][C:3]3[O:2][CH2:7][CH2:6][O:5][C:4]=3[CH:8]=2)[C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CCCc1ccc2c(c1)OCCO2
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CCCc1ccc2c(c1)OCCO2
Yield: 23.5 %

Procedure:
Proceeding as in Example 1, but substituting 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 33, (2S,4R)-4-benzyl-1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (8.4 mg, 23.5%). 1H-NMR (400 MHz, DMSO-D6): σ 9.93 (s, 1H), 7.54 (d, 2H), 7.26 (t, 2H), 7.18 (m, 5H), 6.98 (m, 4H), 6.71 (d, 1H), 6.45 (m, 2H), 4.45 (m, 1H), 4.17 (m, 4H), 3.57 (m, 1H), 3.14 (m, 1H), 2.64 (m, 3H), 2.64 (t, 2H), 2.19 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H). MS (EI) for C36H35FN2O5: 595.7 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCNC1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing the product from Example 160A (0.050 g, 0.195 mmol) in dichloromethane (1.0 mL) was added trifluoracetic acid (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was triturated with ether to give a white solid, which was collected by filtration and used without further purification.
Reaction SMILES: [CH:1]1[C:6]2[CH:7]=[C:8]3[C:22](=[O:23])[O:21][CH2:20][C:9]3=[C:10]([C:11]3[CH:12]=[CH:13][C:14]4[O:19][CH2:18][O:17][C:15]=4[CH:16]=3)[C:5]=2[C:4]2[O:24][CH2:25][O:26][C:3]=2[CH:2]=1.[CH3:27][NH2:28]>C1C=CC=CC=1>[CH3:27][NH:28][C:22]([C:8]1[CH:7]=[C:6]2[C:5](=[C:10]([C:11]3[CH:12]=[CH:13][C:14]4[O:19][CH2:18][O:17][C:15]=4[CH:16]=3)[C:9]=1[CH2:20][OH:21])[C:4]1[O:24][CH2:25][O:26][C:3]=1[CH:2]=[CH:1]2)=[O:23]
Reactant: CN
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Solvent: c1ccccc1
Product: CNC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Temperature: 120 °C
Reaction time: 96 h

Procedure:
Helioxanthin (1.0 g) was suspended in benzene (10 ml), followed by addition of methylamine (40% methanol solution: 2 ml). The mixture was heated at 120° C. under stirring for 4 days. The reaction mixture was concentrated under reduced pressure. The resulting residue was recrystalized from DMF to yield the title compound (144 mg).
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[ClH:18]>C(OCC)(=O)C>[ClH:18].[CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a mixture of tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (1.5 g) and ethyl acetate (10 mL) was added dropwise a 4N hydrochloric acid.ethyl acetate solution (2.5 mL) with stirring under ice-cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 4-(methylsulfonyl)piperidine hydrochloride as crystals (1.08 g, yield 95%). Recrystallization from ethanol gave colorless prism crystals. melting point: 271–272° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH:15]([C:17](=O)[CH3:18])[CH3:16]>C(O)(C)(C)C>[CH3:16][C:15]1[N:12]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[S:13][C:17]=1[CH3:18]
Reactant: CC(=O)C(C)Cl
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)(C)O
Product: Cc1nc(Cc2ccc([N+](=O)[O-])cc2)sc1C
Yield: 47.7 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (1.11 g), 2-chloro-3-butanone (0.75 g) and tert-butanol (50 ml) was heated under reflux for 4 days. The reaction mixture was concentrated, and water and saturated aqueous sodium hydrogen carbonate were added to the residue. 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 to give 4,5-dimethyl-2-(4-nitrobenzyl)-1,3-thiazole as pale-yellow crystals (0.67 g, yield 47%) from a fraction eluted with hexane-ethyl acetate (2:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 93-94° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)[nH]n1
Yield: 20.6 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.22 g, 0.55 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (0.17 g, 1.11 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 47 mg (21%) of the title compound. 1H-NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.51 (s, 3H), 4.31 (dd, 1H), 4.41 (dd, 1H), 4.52-4.61 (m, 1H), 6.79 (d, 1H), 7.23 (s, 1H), 7.67 (d, 1H), 7.70 (d, 1H), 7.83 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:14][C:15]1[C:23]2[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([NH:11]C=O)C(OCC)=O)C.[OH-].[Na+].C(O)(=O)C>C1COCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][CH:16]=[C:15]2[CH2:14][C@@H:5]([C:4]([OH:25])=[O:3])[NH2:11]
Reactant: CCOC(=O)C(Cc1c[nH]c2c(F)cccc12)(NC=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]c2c(F)cccc12)C(=O)O
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 2-(7-Fluoro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester in THF was treated with NaOH (300 mg in 10 mL water) at room temperature for 24 hr. The mixture was slowly acidified with acetic acid (5 mL) and then refluxed for 24 hr. The reaction mixture was concentrated under vacuum, and treated with dil. HCl (10 mL, 3M) and then again refluxed for ˜16 h. The reaction was allowed to cool to room temperature. The pH was adjusted to 6.0 with 2M KOH. The white solid that formed was filtered, washed with water, and dried under vacuum to give 7-fluoro-tryptophan (282 mg, 52%): mp 256-261° C., 1H NMR (500 MHz, DMSO-d6): 2.92-2.97 (dd, J=8.5 and 15 Hz, 1H), 3.25-3.29 (dd, J=4.0 and 15 Hz, 1H), 3.38-3.41 (dd, J=4.0 and 8.5 Hz, 1H), 6.87-6.96 (m, 2H), 7.25 (s, 1H), 7.37 (d, J=7.5 Hz, 1H), 11.36 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1([CH2:19][CH:20]=O)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH3:2].Cl.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.ClCCl>[CH2:1]([O:3][C:4]1([CH2:19][CH2:20][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH3:2]
Reactant: CCOC1(CC=O)c2ccccc2COc2ccccc21
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1(CCN2CCCC2)c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
Dissolved 2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanal (500 mg, 1.77 mmol) in 2 mL of dry THF and 6 mL of dry methanol. Added 3 A sieves, pyrrolidine hydrochloride (952 mg, 8.85 mmol), and then sodium cyanoborohydride (111 mg, 1.77 mmol). Stirred at room temperature under a drying tube for 24 hours. Added 30 mL of saturated K2CO3 and 15 mL of dichloromethane. Filtered through celite, and separated layers. Extracted aqueous solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% MeOH--CH2Cl2 then 10% MeOH--CH2Cl2. Combined appropriate fractions, and evaporated to give 0.21 g (35% yield) of 1-[2-(11-ethoxy-6,11-dihydrodibenz[b,e]oxepin-11-yl)ethyl]pyrrolidine as a colorless oil. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in ethanol. Evaporated, added ethyl acetate, and evaporated again. Added ether to precipitate maleate salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:26]=[C:25](C2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:24]3[CH:25]=[CH:26][C:19]([F:18])=[C:20]([CH:21]=[O:22])[CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)ccc21
Reactant: CC1(C)OC(c2ccc(C=O)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(C=O)c3)ccc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-indazole-1-carboxylic acid tert-butyl ester (3.37 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3] dioxolan-2-yl)-benzaldehyde (1.01 g, 4.04 mmol)) PdCl2(dppf).DCM (27 mg, 0.03 mmol) in 16 mL of dioxane was degassed (evacuate in vacuo and pressurize with argon, three times); cesium carbonate in water (2M, 6.73 mL, 13.46 mmol) was added and the mixture degassed three more times as described above. The resulting mixture was heated at 85° C. for 6 h, then it was allowed to cool to room temperature and left overnight. The mixture was diluted with dichloromethane and washed with brine. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to give crude product. Chromatography on silica gel (elution with diethyl ether/heptane) gave 820 mg of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]4[NH:45][C:44]([C@@H:46]5[CH2:50][CH2:49][CH2:48][N:47]5C(OC(C)(C)C)=O)=[N:43][C:42]=4[Cl:58])=[CH:37][CH:36]=2)[CH:29]=[CH:28]3)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[Cl:58][C:42]1[N:43]=[C:44]([C@@H:46]2[CH2:50][CH2:49][CH2:48][NH:47]2)[NH:45][C:41]=1[C:38]1[CH:37]=[CH:36][C:35]([C:30]2[CH:29]=[CH:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:22]4[NH:21][C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)=[N:24][CH:23]=4)[CH:26]=3)[CH:31]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5[nH]c([C@@H]6CCCN6C(=O)OC(C)(C)C)nc5Cl)cc4)ccc3c2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nc([C@@H]2CCCN2)[nH]c1-c1ccc(-c2ccc3cc(-c4cnc([C@@H]5CCCN5)[nH]4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
TFA (2 mL) was added to a solution of (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (75 mg) in DCM (10 mL) and the mixture was stirred for 2 h at room temperature. The solvents were removed in vacuo and the residue was taken up in a solvent mixture of 1:1 methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford 4-chloro-2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole (40 mg, 0.079 mmol) as yellow solid. LC-MS retention time 1.353 min; m/z 509.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD, partially soluble only) δ ppm 8.20 (s, 1H), 8.09 (s, 1H), 7.88-7.96 (m, 2H), 7.76-7.88 (m, 6H), 7.51 (s, 1H), 4.50 (t, J=7.28 Hz, 1H), 4.35 (t, J=7.15 Hz, 1H), 3.03-3.31 (partially masked by methanol, m, 4H), 2.24-2.42 (m, 2H), 1.88-2.21 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>CC(O)C>[Cl:8][C:7]1[C:2]([NH:11][CH3:10])=[N:3][CH:4]=[N:5][C:6]=1[Cl:9]
Reactant: Clc1ncnc(Cl)c1Cl
Reactant: CN
Solvent: CC(C)O
Product: CNc1ncnc(Cl)c1Cl

Procedure:
4,5,6-trichloropyrimidine 3a was reacted with aqueous methylamine in 2-propanol to afford 5,6-dichloro-N-methylpyrimidin-4-amine 3b.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].[N:23]1([C:27]([C:29]2[CH:30]=[C:31]([Cl:36])[C:32](Cl)=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:23]1([C:27]([C:29]2[CH:30]=[C:31]([Cl:36])[C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
A mixture of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.64 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (164 mg, 0.71 mmol) and potassium carbonate (178 mg, 1.28 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 120° C. for 4 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water (100 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (237 mg).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14]Br>C(O)(=O)C.O>[Br:14][C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Yield: 70 %

Procedure:
One mole of theophylline is dissolved in 2.5 liters of acetic acid containing one liter of water, and kept at 50° C., until the theophylline is dissolved and the medium becomes homogeneous. 1.1 mole of bromine is then added, drop by drop, and the bromine derivative, 8-bromotheophylline precipitates in the medium. The solution is then ccoled to room temperature , and the product filtered and washed with water, and then dried to give 70-85% yield of 8-bromo-theophylline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[CH:17][C:16]=2[N+:30]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:23])=[CH:17][C:16]=2[NH2:30])=[CH:10][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Oc1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1)c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1)c1ccccc1
Yield: 31.9 %

Procedure:
A solution of the product from Example 216C (1.78 g, 3.80 mmol), iron powder (0.85 g, 15.3 mmol) and ammonium chloride (0.25 g, 4.57 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.53 g, 32%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH3:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:18])=[CH:15][C:14]=1[CH3:32].Br[CH2:34][C:35]1[N:40]=[C:39]([NH:41][C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])[CH:38]=[CH:37][CH:36]=1.O>O1CCCC1.C(OCC)(=O)C>[F:46][C:43]([F:44])([F:45])[C:42]([NH:41][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:34][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28](=[O:29])[C:19]([C:17](=[O:18])[C:16]3[CH:30]=[CH:31][C:13]([O:12][CH3:11])=[C:14]([CH3:32])[CH:15]=3)=[CH:20]2)[N:40]=1)=[O:47]
Reactant: O=C(Nc1cccc(CBr)n1)C(F)(F)F
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(NC(=O)C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 173.9 %

Procedure:
Potassium hexamethyldisilazane (2.44 mL, 1.22 mmol, 0.5 M in THF) was added to a solution of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one (0.30 g, 1.02) in 10 mL of tetrahydrofuran. After the reaction was stirred at rt for 20 minutes, N-(6-Bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide (0.35 g, 0.246 mmol) was added and stirred overnight at room temperature. Water and ethyl acetate were added and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude brown solid was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 212 mg of 2,2,2-Trifluoro-N-{6-[3-(4-methoxy-3-methyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridin-2-yl}-acetamide
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C3CCCCO3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][OH:28]>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:23][C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([CH2:27][OH:28])[CH:25]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cccc(OC3CCCCO3)c2)n1
Reactant: Nc1cccc(CO)c1
Product: OCc1cccc(Nc2ncc(Cl)c(Nc3cccc(O)c3)n2)c1
Yield: 53 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 3-aminobenzyl alcohol as the starting materials in 53% yield. LCMS for C17H16ClN4O2 (M+H)+: m/z=343.0.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH:4]=[CH:3]1.[N:14](OCCC(C)C)=[O:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[OH:15][N:14]=[C:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH:4]=[CH:3][N:2]([CH3:1])[C:8]1=[O:9]
Reactant: CC(C)CCON=O
Reactant: CN1C=Cc2ccccc2CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2ccccc2c(=NO)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A THF (0.5 L) solution of 3-methyl-2,3-dihydro-1H-3-benzazepin-2-one (113.8 g, 0.657 mol) was cooled to 0° C. and isoamyl nitrite (100.75 g, 0.86 mol) was added dropwise. To the resulting mixture was added LiHMDS (1 N THF solution, 854 mL, 0.854 mol) at a rate such that the temperature remained below 10° C. After addition, the reaction was allowed to stir at room temperature for 2-3 h while monitoring for the reaction progress by HPLC. Upon completion of the reaction, the mixture was cooled to 0° C., and the pH adjusted from 12 to 2-3 using aqueous HCl (2N). The resulting precipitate was stirred for 12-16 h before isolation by filtration and drying to provide 86.3 g (64.9%) of 1-hydroxyimino-3-methyl-2,3-dihydro-1H-3-benzazepin-2-one; mp=225-226° C.; (M+H)+=203.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1=[O:28])[CH3:2].[Cl:30]N1C(=O)CCC1=O>ClCCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[C:11]([Cl:30])=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:7]1=[O:28])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1ccnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Solvent: ClCCCl
Product: CCOC(=O)Cn1c(Cl)cnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Yield: 90.3 %

Procedure:
A solution of {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (250 mg, 0.61 mmol, preparation described in example 21, step D) and N-chlorosuccinimide (73 mg, 0.55 mmol) in 1,2-dichloroethane (4.2 ml) was heated to 80° C. for 1.5 h. Additional N-chlorosuccinimide (8 mg) was added and the reaction mixture was heated for 1 h. Concentration and flash chromatography (silica gel, hexane-ethyl acetate, 80:20) gave {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-6-chloro-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (0.22 g, 81%); 1H NMR (CDCl3, 400 MHz) δ 6.94 (s, 1H), 4.90 (s, 2H), 4.26 (q, 2H, J=7.1 Hz), 3.40 (m, 4H), 3.10 (m, 2H), 1.87 (m, 2H), 1.48 (s, 9H), 1.31 (t, 3H, J=7.1 Hz), 0.97 (m, 1H), 0.49 (m, 2H), 0.21 (m, 2H).