Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].CC(C)C(=O)CC(OC)=O.C(N)CN.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1CCCCC1.NCCC(O)=O>C1(C)C=CC=CC=1.O.CCCCCC.CCCCCCC.C(O)(=O)C>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: COC(=O)CC(=O)C(C)C
Agent: NCCC(=O)O
Solvent: C1CCNCC1
Solvent: NCCN
Solvent: CCCCCC
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
4-Methyl-3-oxo-N-phenylpentanamide (XIX) is obtained by heating a mixture of methyl 4-methyl-3oxopentanoate (XX), airline and ethylene diamine in toluene. 4-Methyl-3-oxo-N-phenylpentanamide (XIX) is subsequently reacted with benzaldehyde in the presence of a catalyst such as, for example, piperidine and glacial acetic acid, ethylene diamine and glacial acetic acid, β-alanine and glacial acetic acid, and the like in an inert solvent such as, for example, toluene, heptane, hexane, and the like for about 24 to about 36 hours at about 60° to about 120° C. with the removal of water to afford 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (XVIII). Preferably the reaction is carried out with β-alanine and glacial acetic acid at reflux for about 24 hours in hexane. The 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (XVIII) is reacted with 4-fluorobenzaldehyde in the presence of a catalyst such as, for example, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride, and the like, and a base such as, for example, N,N-diisopropylethyamine, pyridine, N,N-dimethylaniline, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), N,N,N',N'-tetramethylethylenediamine (TMEDA) and the like, either neat or in the presence of a solvent such as, for example, tetrahydrofuran, tertiary-butyl methyl ether, ethanol, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, methylisobutyl ketone, ethyl acetate, isopropanol, pyridine and the like for about 20 to about 30 hours under anhydrous conditions at about room temperature to about the reflux temperature of the solvent to afford the compound of Formula XVII. Preferably the reaction is carried out in the presence of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and triethylamine in ethanol at about 75°-80° C. for about 24 hours. The compound of Formula XVII is reacted with a compound of Formula ##STR45## wherein R10 and R11 are alkyl of one to eight carbon atoms or R10 and R11 together are ##STR46## --CH2CH2 -- or --CH2CH2CH2 -- in the presence of a catalyst of Formula
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Yield: 99 %

Procedure:
A solution of 2-methyl-5-nitrobenzoic acid (1.51 g, 8.34 mmol) and H2SO4 (catalytic) in MeOH (20 mL) was heated at reflux for 17 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (40 mL), washed with saturated NaHCO3(aq) (30 mL), then dried (MgSO4) and concentrated in vacuo to give yellow crystals (1.62 g, 99%). 1H NMR (CDCl3) δ2.72 (s, 3H), 3.96 (s, 3H), 7.44 (d, 1H, J=8.7 Hz), 8.24 (dd, 1H, J=8.7, 2.7 Hz), 8.78 (d, 1H, J=2.7 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[Cl:38].CCN(C(C)C)C(C)C.[CH2:48](Cl)[O:49][CH3:50].O>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH2:48][O:49][CH3:50])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[Cl:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Yield: 68.3 %

Procedure:
A solution of 50.0 g (80.0 mmol) of crude 6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide in 500 mL of THF was treated with 42.1 mL (241 mmol) of DIEA followed by 15.3 mL (201 mmol) of MOM-Cl and the resulting solution was heated to 50° C. with stirring. After 18 hours LCMS indicated complete reaction. The solution was cooled to RT and diluted with 600 mL of EtOAc followed by 600 mL of water. After stirring vigorously for 10 minutes the mixture was transferred to a separatory funnel and the phases separated. The aqueous phase was extracted with one additional 200 mL portion of EtOAc. The combined EtOAc solutions were washed with an aqueous solution of 5% citric acid and 5% NaCl (3×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated brine (1×300 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated to dryness at reduced pressure to give an orange-brown foam. This material was dissolved in 250 mL of EtOAc and the solution heated to reflux with stirring. To the solution was added 375 mL of hexane over a 5 minute period maintaining reflux temperature. The solution was then allowed to cool to RT with stirring during which time a light tan solid crystallized. After 2 hours the solution was cooled in an ice water bath and stirred for an additional 2 hours. The solid was collected by filtration in a medium fritted funnel. The filter cake was washed with 250 mL of cold 3:2 hexane/EtOAc, dried by suction filtration for 30 minutes, and then dried in vacuo to give 36.4 g of 6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (q, J=4.30 Hz, 1H) 8.14 (s, 1H) 7.93-8.00 (m, 2H) 7.62 (d, J=2.74 Hz, 1H) 7.52 (d, J=2.74 Hz, 1H) 7.40 (t, J=8.94 Hz, 2H) 7.21 (s, 1H) 4.68 (s, 2H) 4.57 (s, 2H) 3.44 (s, 3H) 3.24 (s, 3H) 2.83 (d, J=4.59 Hz, 3H) 2.06-2.19 (m, 1H) 0.74-1.05 (m, 3H) 0.44 (br. s., 1H).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(NC2C=C(C(O)=O)C(NC3C=CC(C)=CC=3)=CC=2C(O)=O)=CC=1.ClC1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(Cl)=CC=3)=CC=2C(O)=O)=CC=1>>[NH:1]([C:8]1[CH:9]=[CH:13][C:14]2[NH:20][C:21]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17](=[O:18])[C:15]=2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Product: O=c1c2ccccc2[nH]c2ccc(Nc3ccccc3)cc12

Procedure:
Similar good results are obtainable when 2,5-dianilinoterephthalic acid is replaced by 2,5-di-p-toluidinoterephthalic acid or 2,5-di(4-chloroanilino)terephthalic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=1)=[O:17]>>[CH:25]([C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([N:10]3[CH2:11][C:6]4[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=4[CH2:9]3)[CH:14]=2)[CH:24]=[CH:23][CH:22]=1)([CH3:27])[CH3:26]
Reactant: CSc1ncc2c(n1)CNC2
Reactant: CC(C)c1cccc(NC(=O)c2cccc(Br)c2)c1
Product: CSc1ncc2c(n1)CN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 3-bromo-N-(3-isopropylphenyl)benzamide were converted to the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.250 g, 0.964 mmol) in CH2Cl2 (10 mL) were added aniline (0.088 mL, 0.964 mmol), HOAt (0.131 g, 0.964 mmol) and EDC (0.222 g, 1.157 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (2×), and the organics were dried over Na2SO4 and concentrated to afford the title compound (0.247 g) as a brown oil. LC-MS (ES) m/z=240 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCCCC)CCC.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[N:1]1([C:6]2([CH:11]([NH2:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: N#CC1(N2CC=CC2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: NC(c1ccccc1)C1(N2CC=CC2)CCCC1
Yield: 45 %

Procedure:
The title compound (1.35 g; 45%) was prepared from 1-(2,5-dihydro-1H-pyrrol-1-yl)cyclopentanecarbonitrile D37 (2.0 g; 12.3 mmol), and phenyllithium in di-n-butylether (7.5 ml of 1.8M solution; 13.5 mmol) in THF (20 ml), followed by reaction with sodium borohydride (1.402 g; 36.9 mmol) in methanol (20 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS): Found 243 (MH+). C16H22N2 requires 242. Ret. time 1.02 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([NH2:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].CO>ClCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([NH:10][C:19](=[O:21])[CH3:20])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(Cl)cc(C)c(C)c1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Cl)cc(C)c(C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloro-2-methoxy-5,6-dimethyl-phenylamine (4.9 g, 26 mmol) is dissolved in dichloromethane (20 mL) and pyridine (8 mL) and cooled to 0° C. Acetic anhydride (3.7 mL, 39 mmol) and DMAP (85 mg, 0.7 mmol) are added and the reaction is allowed to warm to room temperature. After stirring 2 h, the reaction is diluted with EtOAc (500 mL) and washed with water, 2N HCl (2×50 mL), water, brine and dried over MgSO4 and concentrated. The crude reaction mixture is dissolved in dichloromethane and a minimal amount of MeOH and then added to a dry pad of silica gel. The product is eluted with 50 to 80% EtOAc/hexanes to provide N-(3-chloro-2-methoxy-5,6-dimethyl-phenyl)-acetamide.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].C(O)(C)(C)C.F[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[C:39]([CH:54]3[CH2:56][CH2:55]3)=[N:40][N:41]4[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O>[CH:54]1([C:39]2[C:38]3[C:42](=[CH:43][CH:44]=[CH:45][C:37]=3[NH:36][C:34]([C:31]3[N:28]4[CH:29]=[CH:30][C:25]([O:18][CH2:17][CH2:16][N:13]5[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:15][CH2:14]5)=[CH:26][C:27]4=[N:33][CH:32]=3)=[O:35])[N:41]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)[N:40]=2)[CH2:56][CH2:55]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Reactant: CC(C)N1CCN(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(C)C)CC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A one dram vial was charged with solid potassium tert-butoxide (55 mg, 0.49 mmol), 2-(4-isopropylpiperazin-1-yl)ethanol (0.099 g, 0.57 mmol), and tert-butanol (0.3 mL, 3.4 mmol). The mixture was stirred at ambient temperature for 30 minutes. 7-Fluoro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.034 g, 0.077 mmol) was added in one portion. The mixture was heated at 90° C. with stirring for 16 hours. The mixture was cooled to ambient temperature and diluted with water until a precipitate formed. The precipitate was collected by filtration and dried under high vacuum to give the product (0.019 g). MS (APCI), positive scan, m/z=593.1 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=1>ClCCl>[Cl:3][CH2:13][C:12]1[C:7]([O:6][CH3:5])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Thionyl chloride (9.5 mL, 130 mmol) was added portionwise to a solution of (2-methoxy-pyridin-3-yl)-methanol (1.02 g, 7.3 mmol) in dichloromethane (36 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was carefully treated with saturated aqueous sodium hydrogen carbonate and the mixture was stirred for 5-10 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (sodium sulfate), filtered, and evaporated to give 3-chloromethyl-2-methoxy-pyridine (989 mg, 86%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[C:27]1([CH:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([NH:35][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(N)c1ccccc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Product: CC(Nc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc12)c1ccccc1
Temperature: 200 °C
Yield: 52.3 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.030 g, 0.072 mmol) was dissolved in l-phenylethylamine (1 ml, 7.83 mmol) and heated in a sealed vial at 200° C. for 2 h. The excess amine was removed under reduced pressure, and the solid residue was washed with diethyl ether, NH3 (28% in water) and CH3CN, giving the title product (0.018 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[NH:10][CH:9]2[C:30](O)=[O:31])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:39][C@@H:38]([CH2:40][CH2:41][NH2:42])[CH2:37][O:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:39][C@H:38]([CH2:37][OH:36])[CH2:40][CH2:41][NH:42][C:30]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:33])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:28])([CH3:29])[CH2:25][CH2:26][OH:27])[NH:10]1)=[O:31]
Reactant: CC(C)(CCO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCO)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 47.5 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid prepared in Example 116c (0.18 g, 0.36 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.16 g, 1 mmol), HATU (0.25 g, 0.65 mmol) and iPr2NEt (0.07 mL, 0.43 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:7]=1>C(O)C.C(N)CN>[CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1-c1ccccn1
Solvent: NCCN
Solvent: CCO
Product: Cc1ccc(N)nc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-methyl-2,2′-bipyridin-6-yl)isoindoline-1,3-dione (129 mg, 0.41 mmol) in ethanol (2 ml) is added a couple of drops of ethylenediamine at room temperature. The solution is stirred at room temperature for 30 minutes. The solvents are removed by rotary evaporation and the crude product is purified by silica gel flash chromatography, eluted with 3% methanol in dichloromethane to afford 3-methyl-2,2′-bipyridin-6-amine as an off-white solid. LC-MS m/z: 186.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C(c1cccc(F)c1)c1cccc(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC(c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of ethyl 3,3-bis(3-fluorophenyl)acrylate (38.81 g, 134.8 mmol) in absolute ethanol (300 mL) was hydrogenated in the presence of palladium hydroxide on carbon (5 g wet, Degussa type) at 60 p.s.i. H2 for 30 min at ambient temperature. After this time the reaction was filtered and concentrated to afford 39.08 g (100%) of the title compound as a clear, colorless oil. GC/EI-MS analysis gave a single component: Rt=6.21 min, m/z (rel.int.) 290 (M+,6), 262 (1), 244 (5), 216 (100), 203 (67), 201 (48), 183 (63), 101 (41), 96 (17), and 75 (25).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([N:12]([CH3:14])[CH3:13])=O.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH3:14][N:12]([CH2:10][C:9]1[CH:15]=[CH:16][CH:17]=[C:18]([NH2:19])[C:8]=1[NH2:7])[CH3:13]
Reactant: CN(C)C(=O)c1cccc([N+](=O)[O-])c1N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cccc(N)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1M Lithium aluminium hydride in THF (18.1 ml, 18.1 mmol) was added dropwise over 5 min. to a stirred, ice cooled solution of 2-Amino-N,N-dimethyl-3-nitro-benzamide, D14 (1.26 g, 6.03 mmol) in anhydrous THF (40 ml) under argon. The reaction mixture was stirred at 0° C. for 0.5 h then at room temperature for a further 2 h before being recooled in ice, as water (3.2 ml), 2N sodium hydroxide (3.6 ml) and water (3.2 ml) were added dropwise sequentially. The mixture was stirred for 10 min, solid Na2SO4 added and stirring continued for 10 min. Solids were filtered, washed with ethyl acetate and the combined organics evaporated in vacuo to give the title compound as an orange solid (0.9 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[CH2:23]([Mg]Br)[CH3:24]>>[Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]([OH:18])[CH2:23][CH3:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC[Mg]Br
Reactant: CC(C)Oc1c(C=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Product: CCC(O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
As described in General Procedure P, 8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene-6-carbaldehyde, (Compound 135, 0.98 g, 3.05 mmol) was treated with ethylmagnesium bromide (3 M in ether, 1.6 mL, 4.9 mmol) to give rise to the title compound as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:11]1[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)NN
Reactant: COc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccccc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 55.7 %

Procedure:
A mixture of 7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.40 g), aminoguanidine hydrochloride (0.17 g), concentrated hydrochloric acid (0.22 ml), water (0.22 ml) and ethanol (40 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 5-guanidinoimino-7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 67) (0.3 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:38]=[CH:39][C:40]([CH3:43])=[N:41][CH:42]=1)[CH3:36]>CN(C=O)C.[Cu]I>[F:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8](/[CH:34]=[C:35](/[C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][CH:38]=3)\[CH3:36])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(F)c(F)cc3c2C1
Reactant: CC(=CBr)c1ccc(C)nc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(F)c(F)cc31)CN(C)CC2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7,8-Difluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (177 mg, 0.8 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0.20 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (212 mg, 1 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.10 (s, 1H), 8.22 (d, 1H), 7.60 (d, 1H), 7.15 (t, 1H), 7.02 (s, 1H), 6.95 (t, 1H), 4.70 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.30 (m, 2H), 3.05 (s, 3H), 2.90 (m, 1H), 2.80 (s, 3H), 2.0 (s, 3H).