Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ncccn2)CCNC1
Yield: 87 %

Procedure:
500 mg of the compound of step 2 of Example 25 was dissolved in 10 ml of methylene chloride, 3.5 ml of trifluoroacetic acid (hereinafter referred to as TFA) was added, then the resultant mixture was agitated at room temperature for 30 minutes. This was concentrated, then an aqueous solution of 10% sodium hydroxide was added and extraction was performed with chloroform. The organic layer was washed by saturated saline and was dried with anhydrous magnesium sulfate. This chloroform was concentrated to obtain the above-referenced compound in an amount of 260 mg (yield of 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:17]([CH2:19][C:20]([N-:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=1)=[O:21])#[N:18]>>[OH:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][NH:22][C:20](/[C:19](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]([OH:13])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:17]#[N:18])=[O:21]
Reactant: COc1cc(C=CC=O)cc([N+](=O)[O-])c1O
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccc(O)c(O)c2)cc([N+](=O)[O-])c1O

Procedure:
The compound was prepared as described in Example 3 by adding 3-methoxy-4-hydroxy-5-nitrocinnamaldehyde (22 mg, 0.1 mmol) to N-(cyanoacetyl)3,4-dihydroxybenzylamide (21 mg, 0.1 mmol). After refluxing for 4 h and recrystallization from ethanol-water an orange solid was obtained (19 mg, 46%). The product gave the following analytical data:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([Cl:30])=[O:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(CCCCC(=O)O)C(=O)OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(CCCCC(=O)Cl)C(=O)OCc2ccccc2)cc1

Procedure:
5.6 g (15 mmol) of the 5-{[(benzyloxy)carbonyl](4-methoxybenzyl)amino}valeric acid obtained in this way are dissolved in 60 ml of dichloromethane, and 2.2 ml of thionyl chloride are added. The mixture is heated under reflux for 30 min. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 5.7 g (98% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(Br)cc12

Procedure:
In a manner similar to Example 17, 1-oxo-indan4-carboxylic acid and 4-bromophenylhydrazine hydrochloride were reacted to form 8-bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid which was converted to the ethyl ester in a manner similar to that described in Example 22 to afford the title compound as a tan solid: mp 198-200° C.; 1H NMR (DMSO-d6): δ 1.39 (t, 3H), 4.00 (s, 2H), 4.37 (q, 2H), 7.22 (d, 1H), 7.42 (d, 1H), 7.52 (t, 1H), 7.79-7.84 (m, 3H), 11.86 (s, 1H); MS [EI, m/z]: 355 [M]+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[C-:14]#[N:15].[Na+]>[Pd].[OH-].[Na+]>[C:14]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])#[N:15]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccccc1CC(=O)O

Procedure:
2-Nitrophenylacetic acid (ex Aldrich) (18.1 g) dissolved in 0.1M.aq.sodium hydroxide (100 ml) was subjected to catalytic hydrogenation (at 30-40 psi) over 10% palladium on charcoal (2 g) until uptake ceased. The resultant solution was subjected first to diazotisation and then reaction with sodium cyanide and cuprous cyanide according to Simchen and Hafner, Ann. Chem., 1974, 1802 to give crude 2-cyanophenylacetic acid (14.9 g). The latter was treated with phosphorous pentachloride (20.6 g) and anhydrous hydrogen chloride in di-n-butyl ether (250 ml) for 2 hours. After a further 18 hours the volatiles were removed, the residue washed with water and recrystallized from ethanol to give 1-chloro-3-hydroxy-isoquinoline (1.48 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].ICC.CCN(C(C)C)[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH:22]([CH3:24])[CH3:23])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccc(C23CNCC2C3)cc1Cl
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CC(C)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 146.2 %

Procedure:
To a stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (10.0 g, 43.8 mmol) in DMF (20 mL) was added 2-iodoethane (9.67 g, 56.9 mmol) and DIPEA (7.35 g, 56.9 mmol). The resulting solution was stirred at ambient temperature for 6 h. After this time, the solvent was removed under vacuum and the residue was dissolved in CH2Cl2 (50 mL). The organic layer was washed with water (2×50 mL), 2N sodium hydroxide (50 mL) and brine (50 mL). The organics were dried (Na2SO4) and concentrated under vacuum. Three reactions were run in parallel and then combined for purification via column chromatography (silica gel, EtOAc) to provide the title compound (17.3 g, 49% yield) as a yellow oil: LC (ELS)/MS: 91%, m/z 271.6 [C14H17Cl2N+H]+; 1H NMR (300 MHz, CDCl3): δ 0.75 (dd, 1H, J=4.2 Hz, J==8.1 Hz), 1.05 (dd, 6H, J=4.7 Hz, J=6.3 Hz), 1.44 (t, 1H, J=4.2 Hz), 1.67 (td, 1H, J=3.9 Hz, J=8.0 Hz), 2.50 (m, 3H), 3.11 (d, 1H, J=8.6 Hz), 3.31 (d, 1H, J=8.4 Hz), 6.96 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 7.22 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(Br)cc1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.25 g), 2,2-dimethyl-oxirane (0.26 mL), and potassium carbonate (0.40 g) in dimethylformamide (2.5 mL) was stirred under microwave irradiation at 120° C. for 30 min. After cooling to ambient temperature, the mixture was concentrated and purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound. Yield: 0.34 g (96% of theory); Mass spectrum (ESI+): m/z=246/248 (Br) [M+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[N:12]([CH3:16])[N:11]=2)=[CH:6][CH:5]=1.Cl[CH:18]([F:20])[F:19]>O.O1CCOCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH:18]([F:20])[F:19])[N:12]([CH3:16])[N:11]=2)=[CH:8][CH:9]=1
Reactant: FC(F)Cl
Reactant: CN1N=C(c2ccc(Cl)cc2)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F

Procedure:
A solution of 162 g (4.0 mol) of sodium hydroxide in l 1 of water was addedto a solution of 169.1 g (0,811 mol) of 3-(4-chlorophenyl)-1-methyl-2-pyrazolin-5-one in 2.5 1 of dioxane. Chlorodifluoromethane (about 175 g) was passed in over the course of 5 hours at 60°-65° C., after which the reaction solution was stirred into 1.5 1 of water. Extraction three times with methyl tertbutyl ether, followed by drying of the organic phase and removal of the solvent in vacuo, gave the crude product, which was purified further by chromatography on silica gel (hexane/ethyl acetate 7:3). Yield: 142.9 g; 1H-NMR (400 MHz, in CDCl3): δ [ppm]=7.60 (d,2H), 7.28 (d,2H), 6.54 (t,1H), 6.08 (s,1H), 3.69 (s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=O)=[C:5]2[OH:18].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:15])=[C:5]2[OH:18]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2nc(C)c(Br)cc2c1O
Solvent: CCOC(C)=O
Product: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1Br

Procedure:
A solution of ethyl 6-bromo-4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxylate (Prep 1 0.57 g) and 4-chlorobenzylamine (2.59 g) is heated to 180° C. for 1 h. The mixture is cooled and diluted with EtOAc. The resulting precipitate is collected and dried. Physical characteristics are as follows: m.p. 269-270° C.; 1H NMR (DMSO-d6) δ 13.21, 10.09, 8.67, 8.62, 7.38, 4.54, 2.71; IR (drift) 3028, 2974, 2907, 1653, 1598, 1555, 1526, 1493, 1410, 1354, 1326, 1242, 1096, 806, 639 cm−1; Anal. Calcd for C17H13BrClN3O2: C, 50.21; H, 3.22; N, 10.33; Found: C, 50.31; H, 3.23; N, 10.17.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Product: CNc1ccc(Cl)cc1C(=O)n1nc(O)c2ccccc21
Yield: 33.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-5-chloroisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 33.5% yield; m.p. 210°-213° C.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[C:7]([C:10](OCC)=[O:11])[N:6]=[CH:5][C:4]=2[C:3]2([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[O:2]1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:10]([C:7]1[N:6]=[CH:5][C:4]2[C:3]3([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)[O:2][CH2:1][C:9]=2[CH:8]=1)=[O:11]
Reactant: CCOC(=O)c1cc2c(cn1)C1(CN(C(=O)OC(C)(C)C)C1)OC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ncc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To the stirred solution of 1-tert-butyl 6′-ethyl 1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1,6′-dicarboxylate (0.2 g, 0.60 mmol, 1 eq) in DCM (10 mL) at −78° C. under nitrogen atmosphere was added 25% DIBAL in toluene (0.255 g, 2.56 mL, 1.80 mmol, 3 eq). Resulting reaction mixture was stirred at −78° C. for 1 hour under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by methanol (0.2 mL) followed by addition of saturated solution of sodium potassium tartarate salt (0.5 mL) at −78° C. and extracted with DCM (3×25 mL). Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the title compound as brown solid (0.15 g, crude). Crude compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.19 (d, J=10 Hz, 2H), 4.37 (d, J=10.04 Hz, 2H), 5.16 (s, 2H), 7.85 (s, 1H), 8.89 (s, 1H), 10.12 (s, 1H). LC-MS (m/z): 291.0 (M+H).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(Cl)cc3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
Lithium hydroxide (355 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (875 mg) and diethyl [(3S,8aR)-3-(4-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (2.5 g) in tetrahydrofuran (8 mL)-ethanol (30 mL), and the reaction solution was stirred under shading at room temperature for five hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.43 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=1>C1COCC1.CC(N(C)C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:35]3[N:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(OCCOc3ncc([N+](=O)[O-])cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 146.5 %

Procedure:
To a solution of 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-benzenesulphonamide (Example 2) (1838 mg) in anhydrous THF (18 ml) at 0° C. stirred under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 348 mg) A precipitate began to form which was stirred at 0° C. for 15 min. 2-Chloro-5-nitropyrimidine (Wempen, I.; Blank, H. U.; Fox, J. J. J. Heterocyclic Chem. 1969, 6, 593. Hurst, D. T.; Heterocycles 1984, 22, 79; Heterocycles, 1977, 6, 1999-2004.) (661 mg) in anhydrous DMA (3 ml) was added dropwise and the solution was allowed to warm to room temperature. The reaction was quenched after 130 min by cautiously pouring the mixture onto a vigorously stirred mixture of ethyl acetate (300 ml) and saturated ammonium chloride solution (300 ml). The ethyl acetate layer was separated off, dried (MgSO4) and evaporated to dryness. This afforded a yellow residue (3.44 g) which was purified by column chromatography on silica gel (256 g), eluting with a gradient of ethyl acetate:hexane (4:5 to 5:4).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:42][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][CH2:24][CH:25]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:26][NH:27][C:28]1([C:33]([OH:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:16]3.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C1COCC1>[O:35]=[C:33]1[C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[NH:27][CH2:26][CH:25]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:24][N:23]1[CH2:22][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][C:13]1[CH2:42][C@:3]3([CH2:11][C:12]=1[CH:21]=2)[C:4]1[C:5](=[N:6][CH:7]=[CH:8][CH:9]=1)[NH:10][C:2]3=[O:1]
Reactant: O=C(O)C1(NCC(CNCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1N(Cc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)CC(c2ccccc2)CNC12CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-{[3-({[(7,5)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)-2-phenylpropyl]-amino}cyclopentanecarboxylic acid from Step F (30 mg, 0.053 mmol) and HOBt (8.2 mg, 0.053 mmol) in THF (1 mL) were added EDCI (13.3 mg, 0.069 mmol) and triethylamine (19 μL, 0.14 mmol). This solution was stirred at ambient temperature for 18 h. The solution was then concentrated to yield a residue, which was applied to a silica gel column for purification, eluting with a gradient of 1-7% methanol in DCM. Concentration of the fractions containing the product provided the title compound. MS: m/z=544 (M+1). HRMS: m/z=544.2708, calculated m/z=544.2707 for C34H34N5O2.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:9]([O:11]C(=O)C=O)[CH3:10]>C(O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:10][C:9]1=[O:11]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccccc1N
Solvent: CCO
Product: O=c1cnc2ccccc2[nH]1

Procedure:
Heat benzene-1,2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethyl ester (20 mL) in ethanol (100 mL) at 120° C. for 18 h. Cool, filter the resulting precipitate, and wash with dry ether to give 1H-quinoxalin-2-one (6.7 g). Dissolve 1H-quinoxalin-2-one in acetic acid (300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h. Filter the resulting crystals and wash with ether to afford 7-bromo-1H-quinoxalin-2-one (7.2 g). Reflux 7-bromo-1H-quinoxalin-2-one in POCl3 (30 mL) for 18 h. Remove POCl3 in vacuo, dissolve the product in 3:1 chloroform/isopropyl alcohol, and wash the organic phase with saturated sodium bicarbonate. Dry over sodium sulfate and purify by silica gel flash chromatography eluting with dichloromethane to 10% methanol/90% dichloromethane to afford the title compound as a yellow solid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.O>CN(C)C(=O)C.C1C=CC([P]([Pd]([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)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][O:28][CH3:27])=[CH:31][CH:32]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: COCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 110 °C
Yield: 105.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.00 g, 3.26 mmol) in N,N-dimethylacetamide (15 mL). Add potassium carbonate (1.29 g, 9.36 mmol), 4-methoxymethylbenzeneboronic acid (649 mg, 3.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0225 g, 0.034 mmol), then water (5 mL) and degas with nitrogen for 30 min. Heat at 110° C. for 18 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Combine the DCM extracts and pass through an IST Phase Separator Frit® and concentrate. Purify (silica gel chromatography, eluting with 20:80 ethyl acetate:isohexane), to give 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as a yellow oil (1.32 g, 105%). MS (ES): m/z=385 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[NH:15][C:14](=[O:16])[NH:13][C:10]3=2)[CH2:5][CH2:4]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:16]=[C:14]1[NH:13][C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[C:9]2[NH:15]1)[CH2:5][CH2:4][CH:3]([CH2:2][O:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[O:12]3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]c2ccc3c(c2[nH]1)OC(CO)CC3
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Yield: 83 %

Procedure:
A solution of 8-hydroxymethyl-3,6,7,8-tetrahydro-1H-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-2-one (331 mg, 1.5 mmol) and p-toluenesulfonyl chloride (572 mg, 3 mmol) in anhydrous pyridine (50 mL) was stirred for 12 hours followed by removal of the solvent in vacuo to a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to a residue followed by chromatography (20% CH2Cl2-hexanes) to afford 466 mg (83%) of the title compound as a solid: mp 205° C.; 1H NMR (400 MHz, CDCl3): 1.87 (m, 1H), 2.02 (m, 1H), 2.48 (s, 3H), 2.81 (m, 2H), 4.22 (m, 2H), 4.31 (m, 1H), 6.56 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.58 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 8.18 (s, 1H); IR: 3280, 3000, 2950, 1700, 1510, 1350 cm−1; MS 375 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14](Cl)[CH3:15])[C:10](=[O:12])[CH3:11].[CH3:17][NH:18][CH3:19].C1C=CC=CC=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14]([N:18]([CH3:19])[CH3:17])[CH3:15])[C:10](=[O:12])[CH3:11]
Reactant: CNC
Reactant: CC(=O)N(CC(C)Cl)c1c(C)cccc1C
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A mixture of 3.0 g (12.5 mmoles) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2-chloro-propane and 9.4 ml of a 18 w/v % ethanolic dimethylamine solution is heated at 60° C. for 3 hours in a bomb. The mixture is cooled, admixed with 50 ml of benzene and 10 ml of water, and the organic phase is separated. The aqueous phase is extracted twice with 10 ml of benzene, each. The benzene solutions are combined, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 2.8 g (90.3%) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2dimethylamino-propane are obtained as a thick, light yellow oil; b.p.: 140°-141° C./120 Pa. The hydrochloride monohydrate of the base melts at 170°-172° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 71.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).