Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=[CH:11]N=1)([C:3]1NC=CN=1)=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2.[OH2:24]>ClCCl.CN(C)C=O>[CH3:23][N:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][C:18]([NH:19][C:20]3[CH:16]=[CH:15][CH:3]=[C:1]4[C:21]=3[CH:11]=[CH:10][N:9]=[CH:8]4)=[O:24])=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: O
Reactant: Cn1ccc2cc(N)ccc21
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc2cc(NC(=O)Nc3cccc4cnccc34)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of carbonyl diimidazole (0.31 g, 2.15 mmol) in dichloromethane (20 ml) was added 5-aminosioquinoline (0.25 g, 1.7 mmol) in dichloromethane (20 ml). After stirring at room temperature for 0.5 h, the solution was evaporated to dryness. The residue was taken up in dimethylformamide (20 ml) and to this solution was added 5-amino-1-methyl-indole (D2) (0.25 g, 1.7 mmol) in dimethylformamide (20 ml). The reaction mixture was heated to 90° C. for 1 h, then cooled and added dropwise to water, with vigorous stirring. The resulting suspension was filtered off, washed with water and dried in vacuo to yield the title compound in 53% yield, m.p. 254°-259° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 2,2-dimethylpropanoyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2,2-dimethylpropanamide (27 mg, 0.064 mmol). 1H NMR (CDCl3-d) δ 1.35(s, 9H), 2.09 (m, 4H), 3.66(m, 2H), 3.96(s, 3H), 4.13(m, 2H), 4.97(m, 1H), 5.46(bs, 2H), 6.98(s, 1H), 7.04(s, 1H), 7.07(d, J=8.2 Hz, 1H), 8.15(s, 1H), 8.29(s, 1H), 8.49(d, J=8.2 Hz, 1H). LC/MS: MH30 =424.
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N)[CH2:23][NH2:24]>CN(C=O)C.O>[C:1]([O:5]/[N:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12]([C:23]#[N:24])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: CC(C)(C)O/N=C(\c1ccccn1)c1cc(Br)ccc1O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)O/N=C(\c1ccccn1)c1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Z)-2-(5-bromo-2-hydroxybenzoyl)pyridine O-t-butyloxime (12.7 g) was dissolved in DMF (100 ml). To the solution was added cuprous cyanide (4.64 g), and the mixture was heated, under argon atmosphere, for 3 hours under reflux. To the reaction mixture was added a solution of ethylenediamine (30 ml) in water (20 ml). The mixture was stirred for 30 minutes at room temperature, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography, eluting with ethyl acetate/hexane, to give (Z)-2-(5-cyano-2-hydroxybenzoyl)pyridine O-t-butyloxime (4.31 g) (Compound 76).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([CH2:19][O:20]C(=O)C)[CH:15]=2)[O:7][C@H:6]1[N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][C:27]([Cl:42])=[N:28][C:29]=2[NH:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[F:41])(=O)C.C(N)(C)(C)C>CO>[Cl:42][C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)[O:7]2)=[C:29]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[F:41])[N:28]=1
Reactant: CC(=O)OCc1cc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(Cl)cc5F)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Solvent: CC(C)(C)N
Solvent: CO
Product: OCc1cc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(Cl)cc5F)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To (2R,3R,4R,5S)-4-(acetyloxy)-5-{3-[(acetyloxy)methyl]isoxazol-5-yl}-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (4.02 mg) in methanol (2 ml) at 0° C. was added tert-butylamine (0.012 ml), and the mixture was allowed to stand at 0 ° C. for 3 h. The solvent was evaporated in vacuo to furnish the title compound as a yellow gum (2.48 mg).
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[OH:22][CH2:23][C@H:24]([NH2:26])[CH3:25]>>[CH2:23]([CH2:24][NH2:26])[OH:22].[OH:22][CH2:23][C@H:24]([NH:26][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])[CH3:25]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Reactant: C[C@@H](N)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)N[C@H](C)CO)on1
Product: NCCO
Yield: 100.3 %

Procedure:
As described for example 24b, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (199 mg, 0.68 mmol), was converted using (R)-1-hydroxymethylethylamine (61 mg, 0.81 mmol), instead of ethanolamine, to the title compound (137 mg, 60%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=1:1 to 0:1). MS: m/e=338.5 [M+H]+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[C:16]([C:17]2(O)[CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[C:13]([CH3:22])[N:12]=1>ClCCl>[Cl:10][C:11]1[C:16]([C:17]2([F:7])[CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[C:13]([CH3:22])[N:12]=1
Reactant: Cc1ccc(C2(O)CCC2)c(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2(F)CCC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Diethylaminosulfur trifluoride (1.22 g, 1.00 mL, 7.57 mmol) was added to an ice cold solution of 1-(2-chloro-6-methylpyridin-3-yl)cyclobutanol (Example 130 a, 1 g, 5.06 mmol) in dichloromethane (10 mL) keeping the temperature below 5° C. The reaction mixture was stirred for 30 min. at 0° C., poured onto ice water/sat. aqueous Na2CO3 solution (35 mL) and extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with ice water/brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, heptane/EtOAc 0-10% in 75 min) to give the title compound (939 mg, 93%) as colorless oil, MS (ESI): m/e=200.3 [MH+].
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[CH:1]([O:4][CH:5]1[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC1CCC(=O)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 8-isopropoxy-1,4-dioxaspiro[4.5]decane (0.464 g, 2.317 mmol) in THF (2 mL) and water (2 mL), p-TsOH (0.080 g, 0.463 mmol) was added. The mixture was heated to 100° C. overnight. The resulting mixture was allowed to cool to room temperature and partitioned between EtOAc (30 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[O:16]=[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]=O)=[CH:19][NH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:11][CH2:12][N:13]([CH2:24][C:20]2[C:21](=[O:23])[NH:22][C:17](=[O:16])[NH:18][CH:19]=2)[CH2:14][CH2:15]1
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1[nH]cc(CN2CCC(/C=C/c3ccccc3F)CC2)c(=O)[nH]1
Reaction time: 20 h
Yield: 56.1 %

Procedure:
After dissolving 100 mg of (E)-4-[2-(2-fluorophenyl)vinyl]piperidine in 3 ml of tetrahydrofuran, 116 mg of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehyde, 0.05 ml of acetic acid and 198 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued for 20 hours at room temperature. An additional 200 mg of sodium triacetoxyborohydride was then added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: tetrahydrofuran/methanol). Ethyl acetate was added and the mixture was filtered to obtain the title compound (90 mg, 38% yield).
Reaction SMILES: C(NC(=NS([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=O)=O)C)(C)C.[OH-].[Na+].C[N:24]([CH:33]=[CH:34]C1C=CC([N+]([O-])=O)=CC=1)[C:25](=[NH:32])[C:26]1C=CC=CC=1.[CH3:44]C(C)=O>CS(C)=O>[CH:33]([N:24]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:25](=[NH:32])[CH3:26])([CH3:34])[CH3:44]
Reactant: CN(C=Cc1ccc([N+](=O)[O-])cc1)C(=N)c1ccccc1
Reactant: CC(C)=O
Reactant: CC(=NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1)NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=N)N(C=Cc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Treating N-isopropyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine with aqueous sodium hydroxide in acetone or dimethylsulfoxide according to the procedure of Example 32 (c) provides N-isopropyl-N-(3,4-dichlorostyryl)acetamidine.
Reaction SMILES: Cl.N[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C([N:16](CC)CC)C.[CH3:21][C:22]([O:25][C:26]([O:28]C(OC(C)(C)C)=O)=O)([CH3:24])[CH3:23].ClC(Cl)C.C>C1COCC1>[C:26]([C:4]1[C:5]([NH2:16])=[C:6]([OH:13])[C:7]2[C:12]([CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O:25][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:28]
Reactant: CCN(CC)CC
Reactant: Nc1ccc(O)c2ccccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2ccccc2c(O)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
4-Aminonaphthalen-1-ol hydrochloride (50.0 g, 0.256 mol) was suspended in 500 mL THF under N2. Triethylamine (39.2 mL, 0.281 mol) was added dropwise from an addition funnel. The reaction was stirred for 30 min. Boc anhydride (55.79 g, 0.256 mol), dissolved in 60 mL THF was added dropwise. The reaction was heated to reflux for 5 h and then cooled first to room temperature first and then in a dry ice-acetone bath. The triethylamine HCl salt was filtered off and the precipitate was washed with small portions of THF. The filtrate was concentrated in vacuo leaving a thick brown oil. About 500 mL dichloroethane was added tom the oil and the solution was treated with a small amount of activated charcoal and then filtered through diatomaceous earth, using cold dichloroethane to wash the cake. The filtate was concentrated in vacuo providing the desired Boc-aminonaphthol product as a purple-browish solid (50 g).
Reaction SMILES: [N:1]([C@@H:4]([CH3:16])[CH2:5][C:6]1[CH:7]=[C:8]([N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[CH3:12])=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][C@@H:4]([CH3:16])[CH2:5][C:6]1[CH:7]=[C:8]([N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(N(C)C)cc1C[C@H](C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)C)cc1C[C@H](C)N
Yield: 84.8 %

Procedure:
To a solution of N-{3-[(2S)-2-azidopropyl]-4-methylphenyl}-N,N-dimethylamine (71 mg, 0.325 mmol) in 10 mL of EtOAc was added Pd/C (30 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silica gel plug eluting first with EtOAc (10 mL), then MeOH/EtOAc/NH4OH 20:75:5 (20 mL). The fraction with product was evaporated to give N-{3-[(2S)-2-aminopropyl]-4-methylphenyl}-N,N-dimethylamine (53 mg, 85%) as pale yellow oil. ESI-MS: m/z (MH+) 193.1. 1H NMR (300 MHz, CDCl3): δ 7.02 (m, 1H), 6.57 (m, 2H), 3.16 (m, 1H), 2.90 (s, 6H), 2.44-2.74 (m, 2H), 2.22 (s, 3H), 1.48 (s, 2H), 1.14 (d, J=6.42 Hz, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5]1.[CH2:23]1[NH:28][CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH:24]12>>[CH2:23]1[N:28]([C:20]([C:15]2[CH:14]=[CH:13][C:12]3[CH2:11][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]4)[CH2:19][CH2:18][C:17]=3[CH:16]=2)=[O:22])[CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH:24]12
Reactant: C1CC2CNCCN2C1
Reactant: CN1CCN(C2CCc3cc(C(=O)O)ccc3C2)CC1
Agent: Cl
Product: CN1CCN(C2CCc3cc(C(=O)N4CCN5CCCC5C4)ccc3C2)CC1

Procedure:
(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-methanone is prepared from 6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid dihydrochloride and Octahydro-pyrrolo[1,2-a]pyrazine in a manner substantially analogous to Procedure B (See herein Example 8). Observed mass 383 (M++1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]#[N:12])=[CH:6][CH:5]=2.[Sn](Cl)(Cl)(Cl)Cl.[C:18](Cl)(=[O:20])[CH3:19].[OH-].[Na+]>ClCCl>[C:18]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3][C:2]=1[CH3:1])(=[O:20])[CH3:19]
Reactant: Cc1cc2cc(C#N)ccc2[nH]1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)c1c(C)[nH]c2ccc(C#N)cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 500 mg portion of 2-methyl-1H-indole-5-carbonitrile was dissolved in 5 ml of dichloromethane, and 27.0 ml of 1 M tin tetrachloride (a dichloromethane solution) was added dropwise thereto at 0° C., followed by stirring at 0° C. for 10 minutes. Then, 0.27 ml of acetyl chloride was added thereto at 0° C., followed by overnight stirring at room temperature. A 25 ml portion of a 2 M sodium hydroxide aqueous solution was added thereto at 0° C. to adjust the pH to 12, followed by stirring at 0° C. for 1 hour and extraction with a 20% methanol-chloroform mixed solvent. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 607 mg of 3-acetyl-2-methyl-1H-indole-5-carbonitrile as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]3)[CH:7]=1.[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36]([C:33]2[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=2)=[O:37])=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[N:9]2
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](CF)[C@H]2CS1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.5 %

Procedure:
To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (4.70 g) and 5-methoxypyrazine-2-carboxylic acid (2.65 g), in DCM (60 mL) was added N,N-diisopropylethylamine (8.0 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (9.0 g, portionwise over 10 min). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 50% EtOAc in DCM gradient) to afford the title compound (6.71 g, approx. purity 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (m, 9H), 2.71-2.83 (br. s., 1H), 3.03-3.34 (br. s., 1H), 3.81-4.01 (br. s., 1H), 4.09 (m, 3H), 4.48-4.75 (m, 4H), 7.05-7.20 (m, 1H), 7.36-7.58 (m, 1H), 7.93-8.02 (m, 1H), 8.20 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16].C(Br)C=C.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:9][O:10][C:11](=[O:25])[CH:12]([CH2:8][CH:6]=[CH2:7])[CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COC(=O)CC(CC(=O)O)c1cccc(F)c1
Reactant: CC(C)[N-]C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C(=O)OC)C(CC(=O)O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a cooled (-78° C.) solution of LDA (7.1 mL, 2.0 M, 14.2 mmol) in 50 mL THF was added a solution of 3-(3-fluoro-phenyl)-pentanedioic acid monomethyl ester (2-4) (1.58 g, 6.58 mmol) in 10 mL THF gradually. The mixture was stirred for 40 min, treated with allyl bromide (1.71 mL, 19.7 mmol) at -78° C. and stirred overnight while it was warmed to room temperature. It was then concentrated and diluted with 20 mL CH2Cl2 and 15 mL EtOH. To the resulting solution was added EDAC (1.88 g, 9.87 mmol) and DMAP (25 mg, 0.02 mmol). After stirring for 5 hr, the reaction was quenched with 20 mL 10% NaHCO3 and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide 2-5 as an oil, which was further purified using flash silica chromatography (Hexane/EtOAc, 4:1).
Reaction SMILES: C(C1C=CC(C([O:9][CH3:10])=O)=C(C)C=1)#N.Br[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17](C)[CH:16]=1.[C:26]([Cu])#[N:27]>CN(C=O)C.CCOC(C)=O>[O:9]=[C:10]1[C:15]2[C:16](=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)[CH2:26][NH:27]1
Reactant: COC(=O)c1ccc(C#N)cc1C
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 175 °C
Reaction time: 6 h

Procedure:
methyl 4-cyano-2-methylbenzoate. To a stirred solution of methyl 4-bromo-2-methylbenzoate (2 g, 8.7 mmol) in DMF (20 mL), was added CuCN (1.9 g, 12.2 mmol). The reaction was then stirred at 175° C. for 6 h. The progress of the reaction was monitored by TLC (10% EtOAc in hexanes). The reaction was diluted with EtOAc (10 mL) and filtered through Celite® brand filtering agent. The filtrate was concentrated in vacuo and the material was purified by column chromatography (SiO2, 0-50% EtOAc in hexanes) to give the title compound. MS (ESI pos. ion) m/z: 177.1 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]=[C:16]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][N:17]1[CH2:33][C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:7]([NH:8][C:34](=[O:35])[CH2:33][N:17]1[CH2:18][CH2:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]1=[O:15])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenylmethanamine (0.18 g, 1.00 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.96 (d, J=8.5 Hz, 1H), 7.21-7.37 (m, 20H), 6.13 (d, J=8.4 Hz, 1H), 4.08 (s, 2H), 3.37 (t, J=6.5 Hz, 2H), 2.71 (t, J=6.4 Hz, 2H); MS (DCI+) m/z 461 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:5]=2[C:4](=[O:16])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCl>[CH3:17][C:2]1([CH3:1])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[O:15])[C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: CCNCC
Reactant: CC1(C)CC(=O)c2c(CCC(=O)O)c[nH]c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCN(CC)C(=O)CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a suspension of 1.18 g of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5 mmol) in dichloromethane (25 mL) was added 0.97 g (6 mmol) of carbonyldiimidazole. After stirring at room temperature for 2 hours, 2.1 mL (20 mmol) of diethylamine was added. The mixture was stirred at room temperature overnight. The reaction was concentrated and the residue dissolved in dichloromethane, washed with brine, dried and concentrated to give 1.2 g (83% yield) of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-N,N-diethyl-propionamide as a white solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.91 (br s, 1H, NH), 6.46 (s, 1H), 3.20–3.29 (m, 4H, 2×CH2), 2.72–2.76 (m, 2H, CH2), 2.57 (s, 2H, CH2), 2.45 (m, 2H, CH2), 2.17 (s, 2H, CH2), 0.96–1.06 (m, 12H, 4×CH3). MS m/z 290 [M+].