Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][N:37]=1)[N:34]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:39]1)[CH:33]=[C:32]([C:51]([O:53]CC)=[O:52])[C:31]2=[O:56].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+].Cl>O1CCOCC1.O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:49]([N:46]([CH2:47][CH3:48])[CH2:45][CH2:44][N:40]1[CH2:41][CH2:42][CH2:43][C@@H:38]([N:34]2[C:35]3[C:30](=[CH:29][C:28]([C:9]4[CH:10]=[N:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:26])=[CH:7][C:8]=4[C:15]4[S:16][CH:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:19]=4)=[N:37][CH:36]=3)[C:31](=[O:56])[C:32]([C:51]([OH:53])=[O:52])=[CH:33]2)[CH2:39]1)[CH3:50]
Reactant: CCOC(=O)c1cn([C@@H]2CCCN(CCN(CC)CC)C2)c2cnc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(B(O)O)cn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@@H]4CCCN(CCN(CC)CC)C4)c3cn2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 6-(3-ethylureido)-4-(4-phenylthiazol-2-yl)pyridine-3-ylboronic acid (WO2009106885) (624 mg, 1.69, 1 equiv.) and (R)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate Intermediate 65 (765 mg, 1.69 mmol, 1 equiv.) in 1,4-dioxane (7 mL) was added tetrakis(triphenylphosphino)palladium(0) (196 mg, 0.17 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (828 mg, 2.54 mmol, 2.0 equiv.) in water (1.7 mL). This reaction mixture was stirred at 100° C. for 2 h. 2 M Lithium hydroxide (0.96 mL) was added. The reaction mixture was stirred at 100° C. for 9 h, cooled to room temperature, and diluted with water. 1 N HCl was added until pH 3-4 was reached, and the reaction was concentrated. The compound was purified (C18 silica gel chromatography) and concentrated to provide (R)-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-phenylthiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (422.1 mg, 36%). Calcd for C37H42N8O4S [M+H]+: 695.3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: OC1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)CC3)s2)noc1C(F)(F)F
Yield: 78 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxypiperidine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (141 mg, 78%). 1H NMR (CDCl3) 1.58-1.69 (m, 2 H), 1.93-2.00 (m, 2 H), 2.26 (br s, 1 H), 2.37 (s, 3 H), 3.44-3.52 (m, 2 H), 4.00-4.12 (m, 3 H), 7.33 (d, J=4.0, 1 H), 7.46 (d, J=3.5, 1 H). 13C NMR 7.9, 34.4, 42 (br), 66.9, 114.8, 118.7 (q, J=271), 128.0, 129.2, 131.2, 140.1, 155.2 (q, J=40), 158.1, 162.8. 19F NMR −63.1. LC/MS 5.71 min, [M+1]+ 361.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14]>C(O)C>[C:15]1([C:13](=[CH2:12])[CH2:14][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C(CBr)c1ccccc1
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(CSc1ccccc1N)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
The compound, 2-aminothiophenol, (12.5 g) was added to a solution of sodium hydroxide (4.5 g) in ethanol (100 ml) keeping the temperature less than 30° C. Then 1-bromo-2phenyl-2-propene (21 g) was added and the mixture was stirred at 60° C. for 3 h. The precipitated solid was filtered and washed with ethanol. The solvent was removed and the residue was chromatographed on silica gel with hexanes/ethyl acetate (7:1) to yield the title compound (14.5 g). As an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[C:10]([OH:24])([CH3:23])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([O:14][CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH3:23])[OH:24])=[CH:17][CH:18]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2ccc(Cl)cc2)CCNCC1(C)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(4-Chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.74 mmol) was dissolved in methylene chloride (5 mL) and the resulting solution was cooled to 0° C. Trifluoroacetic acid (1 mL) was added and the mixture was stirred 2 h. Solvents were then removed under reduced pressure and the residue dissolved in ethyl acetate. Water and 6 N aqueous sodium hydroxide were added until the pH=10. The organic phase was washed with brine and dried over magnesium sulfate, filtered and concentrated to afford 4-(4-chloro-phenyl)-4-methoxy-3-methyl-piperidin-3-ol.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CCOCC>C1C=CC=CC=1>[CH2:5]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCc1ccccc1CO
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCCCCc1ccccc1CBr
Temperature: 0 °C

Procedure:
A solution of 10 g of phosphorus tribromide in 50 ml of benzene is added dropwise over a period of 15 minutes to a stirred mixture of 6.6 g of 2-nonylbenzyl alcohol and 50 ml of benzene. The reaction mixture is heated under reflux for 30 minutes and, after cooling, ice-water and ether are added. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. Chromatographic purification of the residue on silica gel with petroleum ether yields 2-nonylbenzyl bromide in the form of a colourless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=1>C1COCC1>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To a suspension of LiAlH4 (1.5 g, 40 mmol) in THF (80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5□ under N2 atmosphere. The reaction mixture was stirred at rt for 3 h before it was quenched with 15% NaOH and water. The mixture was filtered through Celite® and the cake was washed with EtOAc (100 mL×3). The filtrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70%). [LCMS: RtA=0.88 min, m/z 144.2 [M+H]+].
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:15]([C:14]3[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-fluorobenzoic acid.
Reaction SMILES: [C:1]1([C:7](=[O:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:31]3[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:24]=[CH:23][C:22]=3[N:21]=[C:20]2[CH2:32][CH2:33][CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:44])C=1>>[O-:44][N+:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:35])[C:20]([CH2:32][CH2:33][CH3:34])=[N:21][C:22]=2[CH:23]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCCCCCCCC(=O)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-phenyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecan-1-one (6.0 g, 12.8 mmol) by reaction with m-CPBA (8.18 g) to provide 12-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenyldodecan-1-one followed by reaction with p-toluenesulfonyl chloride (3.65 g, 19.2 mmol) and ammonium hydroxide solution (40 mL). The product was dissolved a mixture of ethanol and diethyl ether, and a solution of hydrogen chloride (1 equivalent of a 1.0 M solution in diethyl ether) was added. A precipitate formed, and the solvents were removed under reduced pressure. The resulting solid was recrystallized from a mixture of isopropanol and hexane to provide 12-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenyldodecan-1-one hydrochloride as an off-white solid, mp 195-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])N.N([O-])=O.[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11]
Reactant: c1ccncc1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1OC
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccccn2)cc([N+](=O)[O-])c1OC
Reaction time: 0.25 h

Procedure:
10 g of finely powdered 3,4-dimethoxy-5-nitroaniline are suspended in 15 ml of 12N hydrochloric acid and 40 ml of water, whereupon the suspension is stirring at 30° for 1 hour. Thereupon, 3.8 g of sodium nitrite dissolved in 20 ml of water are added dropwise thereto at -5° within 15 minutes. The solution is stirred at -5° for 30 minutes and the cold diazonium salt solution is added dropwise within 45 minutes to 100 ml of pyridine of 40°. The mixture is subsequently stirred at 70° for 1 hour. The reaction mixture is evaporated and the residue is taken up in 300 ml of ethyl acetate. It is extracted three times with 200 ml of 2N hydrochloric acid each time. The acidic-aqueous phase is adjusted to pH 9 with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 250 g of silica gel with ethyl acetate. After crystallization from methylene chloride/hexane there is obtained 2-(3,4-dimethoxy-5-nitrophenyl)pyridine of m.p. 89°-90°.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][NH:14][C:15](=[O:27])[N:16]2[C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[C:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH:10]=1)([CH3:8])[CH3:7])=[O:4].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:11]1[CH:10]=[C:9]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)([CH3:8])[CH3:7])[CH:18]=[C:17]2[C:12]=1[CH2:13][NH:14][C:15](=[O:27])[N:16]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: C1COCCN1
Reactant: CC(C)(NC(=O)CBr)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)CN1CCOCC1)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 80 °C

Procedure:
To a stirred solution of 2-bromo-N-{1-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methylethyl}acetamide (30 mg, 0.05 mmol, 1 eq) in DMF (0.5 mL) was added morpholine (0.01 mL) and diisopropylethylamine (0.02 mL). The mixture was warmed to and maintained at 80° C. for 1.5 h at which time HPLC analysis indicated complete reaction. The mixture was diluted with ethyl acetate and washed 3× with dilute NaOH. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated giving N-{1-[5-(2-chlorophenyl)-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methylethyl}-2-morpholin-4-ylacetamide. Mass spectrum 587.2 (M+1); 589.2 (M+3).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1
Reactant: ClCCCBr
Reactant: N#CC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC1CN(CCCCl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
In a 25 mL round-bottomed flask were mixed with stirring azetidine-3-carbonitrile hydrochloride (available from ASW MedChem. Inc., 250 mg, 2.11 mmol) and 1-bromo-3-chloropropane (664 mg, 415 μL, 4.22 mmol.0) in acetonitrile (5 mL) to the suspension was added Cs2CO3 (2.06 g, 6.33 mmol). The mixture was stirred at 25° C. for 18 h, then diluted with 15 mL of EtOAc and filtered to remove solids. Filtrate was evaporated and residue purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane (developing TLC in an iodine chamber) to give 1-(3-chloropropyl)azetidine-3-carbonitrile (230 mg, 1.45 mmol, 68.8%) as a clear dense liquid. 1H NMR (CDCl3) δ: 3.46-3.59 (m, 4H), 3.20-3.31 (m, 3H), 2.55 (t, J=6.8 Hz, 2H), 1.75 (quin, J=6.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH3:16].C(N(C(C)C)C(C)C)C.[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(OCC)(=O)C>C(Cl)Cl>[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39]([N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:16])=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1ccccc1-c1ccccc1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccccc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of 53 mg (0.25 mmol) (2′-methoxy-biphenyl-2-yl)-methyl-amine and 0.064 ml (0.375 mmol) N-ethyldiisopropylamine in 4 ml CH2Cl2 was cooled in an ice bath and a solution of 88 mg (0.275 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml CH2Cl2 was added dropwise. The reaction mixture was stirred overnight at room temperature. Ethyl acetate was added and the organic layer was washed with saturated Na2CO3 solution, 1 N HCl solution, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate 4:1) to give 107 mg (87%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2′-methoxy-biphenyl-2-yl)-N-methyl-isobutyramide as orange crystals, MS (ISP): 496.1 (M+H)+.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[CH:21]=1>CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[C:21]=1[I:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCC3)c(F)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 43.2 %

Procedure:
NIS (6.75 g, 30.0 mmol) was added to a solution of 2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (6.61 g, 30.0 mmol) in DMF (50 mL). The reaction mixture was stirred at ambient temperature for about 35 min and then partitioned between DCM and water. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and triturated with Et2O to give the title compound (4.49 g, 43%): LC/MS (Table 1, Method a) Rt=3.18 min; MS m/z: 347.2 (M+H)+.
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].Cl>CO>[NH:1]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
BOC-Leu-Pro-OBzl (82.76 g, 0.252 mM) was dissolved in methanol (600 ml). 1 N NaOH (327.6 ml, 1.3 molar excess) was added dropwise with ice cooling, and the mixture was stirred for one hour at room temperature. 1 N HCl (6 ml) was added to the reaction mixture with ice cooling, then the methanol was distilled off in vacuo. After washing the water layer with benzene and ethyl acetate, 1 N HCl (260 ml) was added with ice cooling to form an oily material which was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and water and dried with anhydrous sodium sulfate. The solution was dried in vacuo and the residue was dissolved in benzene and lyophilized to obtain the substance [11] (58.57 g, yield: 70.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-picoline (182 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL) and water (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 4/6 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (231 mg, 61%) as a white foam: [α]23589=−26.22° (c=0.45, chloroform); EI-HRMS m/e calcd for C22H25ClN2O4S (M+H)+ 449.1297, found 449.1302.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(CCO)cn1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)nc1
Yield: 64.5 %

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.110 g, 0.37 mmol) was reacted with 2-(6-aminopyridin-3-yl)ethanol (0.100 g, 0.74 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.096 g, 65%) as a light yellow solid. MW=402.32. 1H NMR (DMSO-d6, 500 MHz) δ 14.47 (s, 1H), 9.92 (s, 1H), 8.81-8.75 (m, 1H), 8.28 (s, 1H), 7.97 (m, 1H), 7.82-7.63 (m, 4H), 7.40 (d, J=8.5 Hz, 1H), 3.63 (t, J=6.5 Hz, 2H), 3.20 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.73 (t, J=6.5 Hz, 2H), 2.30-2.21 (m, 2H); APCI MS m/z 366 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[Cl:19][C:20]1[C:26]([OH:27])=[CH:25][C:23]([NH2:24])=[C:22]([F:28])[CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[C:26]([OH:27])=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[C:22]([F:28])[CH:21]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Temperature: 140 °C

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.1 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-2-fluoro-5-hydroxyaniline (432 mg, 0.82 mmol), (prepared as described in EP 061741 A2), in DMF (2.5 ml) was heated at 140° C. for 45 minutes. The work up procedure was as described in Example 6 and gave 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid, 157 mg, 49%).