Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8]CC.Cl>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1)[CH2:6][P:7](=[O:8])([OH:11])[OH:14]
Reactant: CCOP(=O)(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 49.3 %

Procedure:
Diethyl 3,5-bis(trifluoromethyl)benzylphosphonate (1.0 g, 2.7 mmol)in 15 mL of cone hydrochloric acid and 0.5 mL of ethanol was heated at reflux for 72 hours. The mixture was evaporated to an oily residue which crystallized upon standing to give 0.41 g of the product (49% yield) the as a white solid: mp. 206°-208° C.; D.C.I.M.S. [MH+, 309].
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:41])C(=O)C1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([Br:41])[C:22]([OH:25])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(O)c1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(OCc2ccccc2)nc(Br)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A mixture of benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate (0.29 g, 0.66 mmol) and NBS (0.13 g, 0.72 mmol) in DMF (1.2 mL) was stirred at room temperature for 5 min then treated with water. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate (0.23 g, 68%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[C:25]([O:24][C:22](=[O:23])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCN1CCNCC1
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 4-(4-tert-butoxycarbonylaminobutyl)piperazine-1-carboxylic acid benzyl ester (16) (3.26 g, 8.33 mmol), acetic acid (0.5 mL), and palladium hydroxide on carbon (60% wet, 0.98 g) in methanol (15 mL) was stirred under atmospheric hydrogen for 16 h. The catalyst was removed by suction filtration over Celite. The filtrate was concentrated in vacuo and the resulting residue was purified by Biotage silica gel column chromatography using concentrated ammonium hydroxide/methanol/dichloromethane to give 17 as a yellow oil (1.94 g, 91% yield): 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.53 (m, 4H), 2.35 (m, 6H), 2.45 (br, 1H), 2.94 (t, 4H), 3.12 (m, 2H), 5.32 (br, 1H); ESI MS m/z 258 [C13H27N3O2+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([C:8]1[CH:17]=[C:16]2[C:12](=[CH:13][CH:14]=[C:15]2[CH3:18])[C:11]([CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:1]([O:22][CH2:21][CH2:20][CH:19]([C:11]1[C:12]2[C:16](=[CH:17][C:8]([CH:5]([CH3:7])[CH3:6])=[CH:9][CH:10]=1)[C:15]([CH3:18])=[CH:14][CH:13]=2)[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(C(C)CCO)ccc(C(C)C)cc1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCC(C)c1ccc(C(C)C)cc2c(C)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.8 g (0.063 mol) of acetyl chloride in 20 ml of dichloromethane were added dropwise at 0° C. to a solution of 12.1 g (0.05 mol) of 3-(7-isopropyl-1-methylazulen-4-yl)butanol and 7.9 g (0.1 mol) of pyridine in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. It was then extracted with 30 ml of 2N hydrochloric acid, and the organic phase was washed neutral and dried over sodium sulfate. The residue remaining behind after evaporating off the solvent was chromatographed (silica gel; 9:1 v/v petroleum ether/ethyl acetate). This gave 12.6 g (89%) of the acetate as a highly viscous blue oil. Physical data: IR (KBr): 2959, 2929 (CH); 1741 (C=O); 1555, 1463, 1436, 1387, 1365, 1241, 1047 cm-1. 1H-NMR (CDCl2): δ=1.38 (d, 6H); 2.05 (s, 3H); 2.16 (cm, 2H); 2.68 (s, 3H); 3.08 (cm, 1H); 2.22 (cm, 2H); 4.18 (cm, 2H); 6.95 (d, 1H); 7.30 (d, 1H); 7.40 (d, 1H); 7.64 (d, 1H); 8.18 (s, 1H) ppm. 13C-NMR (CDCl3); δ=1286; 20.85; 24.72 (2C); 30.17; 34.53; 38.28; 64.22; 112.19; 124.41; 125.46; 133.30; 135.13; 136.39; 136.59; 137.28; 140.04; 147.55; 170.90 ppm. MS: m/e=284.4 (C19H24O2+, 50%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[C:11]([C:15]([O:17]CC)=[O:16])=[CH:10]2)([O:3]C)=[O:2].[OH-].[Na+]>C(O)C>[CH3:14][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:1]([OH:3])=[O:2])[CH:10]=[C:11]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2cccc(C(=O)OC)c2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)O)cc2cccc(C(=O)O)c21
Yield: 107.7 %

Procedure:
A mixture of 5.20 g (19.9 mmol) of ethyl 7-carbomethoxy-1-methyl-2-indolecarboxylate, 90 ml of 2N sodium hydroxide and 150 ml of ethanol was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and ice water was added to the residue. 2N hydrochloric acid was added to acidify the reaction mixture. The precipitated solid was filtered and dried under reduced pressure to give 4.70 g (>99%) of 1-methylindole-2,7-dicarboxylic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:32][CH2:33][O:34][CH3:35]>>[NH2:31][C:22]1[C:21]2[N:20]=[C:19]([CH2:32][CH2:33][O:34][CH3:35])[N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1cc2ccccc2cn1
Yield: 57.1 %

Procedure:
Using the general method of Example 188 isoquinoline-3-caboxylic acid (1.05 g, 6.06 mmol) was reacted with 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) to provide 1.30 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide as a white foam, m.p. 198.0-198.5° C. Analysis: Calculated for C26H26N6O2: % C, 68.71; % H, 5.77; % N, 18.49. Found: % C, 68.39; % H, 5.83; % N, 18.63.
Reaction SMILES: Cl.[O:2]=[C:3]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7].O=[C:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>CO>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([N:28]2[CH2:29][CH2:30][CH:25]([N:10]3[CH2:11][CH2:12][C@@H:8]([C:6]([NH:5][CH2:4][C:3](=[O:2])[NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)=[O:7])[CH2:9]3)[CH2:26][CH2:27]2)=[CH:40][CH:39]=1
Reactant: O=C(CNC(=O)[C@@H]1CCNC1)Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N2CCC(N3CC[C@@H](C(=O)NCC(=O)Nc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of (3R)—N-(2-oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl)pyrrolidine-3-carboxamide hydrochloride (130 mg, 0.370 mmol) in MeOH (1 mL) was added methyl 4-(4-oxopiperidin-1-yl)benzoate (95 mg, 0.407 mmol) and NaBH3CN (70 mg, 1.11 mmol). After overnight, the mixture was washed with EtOAc and NaHCO3 (sat. aq.), the organic phase was dried over MgSO4, concentrated, and subjected to flash chromatography (EtOAc) to generate the title compound as a white solid (45% yield, 2 steps). 1H-NMR (CDCl3) δ: 1.55-1.75 (m, 2H), 1.85-2.06 (m, 3H), 2.10-2.22 (m, 1H), 2.24-2.40 (m, 1H), 2.42-2.62 (m, 2H), 2.81-3.02 (m, 5H), 3.65-3.85 (m, 5H), 4.05-4.20 (m, 2H), 6.81 (d, J=8.9 Hz, 2H), 7.20-7.40 (m, 2H), 7.65-8.00 (m, 5H), 9.57 (s, 1H). MS m/z: 533 (M+1)
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:16]([O:15][C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109°-110°C. (0.37 mm).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:11][C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-fluoro-5-nitro-6-picoline (3.0 g, 19.2 mmol) in DMSO (26 mL) were added morpholine (3.35 mL, 38.4 mmol) and potassium carbonate (6.64 g, 48.0 mmol). The reaction mixture was allowed to stir overnight, at 70° C. The reaction mixture was then partitioned between EtOAc (40 mL) and water (40 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×40 mL). The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-(6-methyl-5-nitropyridin-2-yl) morpholine (4.0 g, 99%), as a muddy green solid. LCMS (FA): Rt=1.59 min, m/z=224.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ClCCN1CCCCC1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.6 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 40 ml of a 10% aqueous sodium hydroxide solution and 40 ml of methanol is added dropwise a solution of 5.5 g of 1-chloro-2-piperidinoethane hydrochloride in 20 ml of water over a period of 15 minutes, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-(2-piperidinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from 99% ethanol to obtain 10.5 g of 2-(2-piperidinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 196°-198° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)CC(O)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-bromophenyl)-3-methylbutan-1-ol (500 mg, 2.06 mmol), phenol (252 mg, 2.69 mmol) and triphenyl phosphine (1.06 g, 4.04 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred at room temperature under nitrogen atmosphere. After 1 hour, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (500 mg, 2.48 mmol) was added dropwise and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, pure ether) to 1-bromo-4-(3-methyl-1-phenoxybutyl)benzene (300 mg, 46%).
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]=[CH:15]OCC)[N:9]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>CO>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:15]=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][CH:3]=[N:2][NH2:1])[S:6][CH:7]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC=NCCSCc1csc(NC=NN)n1
Solvent: CO
Product: NN=CNc1nc(CSCCN=CNS(=O)(=O)c2ccc(Br)cc2)cs1
Temperature: 25 °C

Procedure:
To the crude product composed by ethyl N-[2-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]ethyl]formimidate, 7.7 g of p-bromobenzenesulfonamide in 50 ml of methanol are dropwise added under stirring and at room temperature. The mixture is kept under stirring for 1 hour at room temperature, the solvent is removed by distillation under reduced pressure, and the obtained residue is purified by 60-silicagel column chromatography. 13.5 g of N-p-bromobenzene-sulphonyl-N'-[2-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]ethyl]formamidine are obtained.
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[CH2:22][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20]C)=[O:19])[CH:17]=[C:12]1[CH2:11]2.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:22][C:13]1=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]1[CH2:11]2
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 23 °C

Procedure:
A mixture of methyl (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (30.0 g, 102 mmol) and aqueous 6 N sodium hydroxide solution (50.8 mL, 305 mmol) in MeOH (920 mL) was heated at reflux for 1 h. The mixture was allowed to cool to 23° C. before it was acidified to pH 6 with aqueous 1 N hydrochloric acid solution, resulting in a black precipitate which was removed by filtration. The filtrate was concentrated under reduced pressure to ˜100 mL and then partitioned between water (500 mL) and 2-methyltetrahydrofuran (2-MeTHF, 250 mL). The aqueous layer was extracted with 2-MeTHF (5×250 mL), and the combined organic layers were dried over sodium sulfate and concentrated to provide the title compound. MS: m/z 282.0 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Li]C.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH:26]([C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C=O)n1
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
To a solution of tert-butyl (6-bromopyridin-2-yl)carbamate (15.960 g, 58.43 mmol, 1 eq.) in 300 ml of THF cooled to −78° C. was added MeLi (1.6 M, 36.52 ml, 58.43 mmol, 1 eq.) dropwise and stirring allowed for 30 min. Then BuLi (1.6 M, 40.17 ml, 64.27 mmol, 1.1 eq.) was added dropwise and stirring allowed for 1 h. DMF (9.36 g, 128.55 mmol, 2.2 eq.) was added and the mixture was stirred 30 min at −78° C. and 1 h at r.t. The reaction was quenched with sat. aqueous NH4Cl, and DCM was added. The aqueous layer was extracted with DCM and then organics were combined, dried over MgSO4 and concentrated to give tert-butyl (6-formylpyridin-2-yl)carbamate (13.46 g) as a clear oil that was used directly in next step.
Reaction SMILES: C([NH:8][CH:9]([CH:12]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13]1)[CH2:10][F:11])C1C=CC=CC=1.[H][H]>CO.[Pd].S(=O)(=O)(O)O>[F:11][CH2:10][CH:9]([NH2:8])[CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: FCC(NCc1ccccc1)C1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: NC(CF)C1CCNC1
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of benzyl[1-(1-benzylpyrrolidin-3-yl)-2-fluoroethyl]amine (2.5 g, 8.0 mmol, Example 17) in methanol (50 mL) was added 20% palladium on carbon (200 mg). Hydrogen was introduced to the reaction mixture at high pressure (48 psi) for 24 hours, at which time sulfuric acid (3 drops) was added. After an additional 24 hours, the reaction mixture was filtered through Celite, washed with methanol, and the combined filtrates concentrated under vacuum to afford the title compound (1.0 g): MSCI: m/z 133 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9]2)=[O:5])[CH3:2].[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:14]=1)[NH:11][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9]2)=[O:5])[CH3:2]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Product: CCOC(=O)c1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid ethyl ester prepared in Step A and cyclopentanone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][N:3]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC>C1COCC1.O>[F:1][C:2]1[C:7]([B:18]([OH:23])[OH:19])=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(C(C)c2ccc(F)nc2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(C)c2cnc(F)c(B(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (1.078 g, 4.359 mmol) and triisopropyl borate (2.50 mL, 10.9 mmol) were dissolved in THF (11.5 mL). In a separate flask, 2,2,6,6-tetramethylpiperidine (1.11 mL, 6.54 mmol) was dissolved in THF (12 mL) and the flask was cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 3.8 mL, 6.1 mmol) was added via syringe, and the yellow solution was stirred under nitrogen for 15 min. Then, the contents were transferred via syringe to the other flask, which was pre-cooled in a dry ice/acetone bath. After completing the transfer, the reaction was stirred under nitrogen at −78° C. for 1 h. Then, the reaction was allowed to slowly warm up to room temperature while being stirred overnight. The reaction was treated with water (30 mL) and stirred for about 30 min. The layers were separated, and the organic phase was extracted with 1 N aqueous NaOH (15 mL). The organic phase was discarded, and the aqueous phase was treated with aqueous 5N HCl to lower the pH to around 5-6. The aqueous phase was extracted with 10:1 DCM/MeOH. The extracts were combined, concentrated, and dried under high vacuum to afford 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g). 1H NMR (400 MHz, CDCl3) δ 8.17-8.05 (m, 2H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 2H), 4.16 (q, J=7.37 Hz, 1H), 2.47 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, +ve ion) 292 (M+H)+.
Reaction SMILES: C(OC([O:6][C:7]1[CH:30]=[CH:29][C:10]([CH:11]=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=O)C.N1CCCC1>C(Cl)(Cl)Cl>[OH:6][C:7]1[CH:30]=[CH:29][C:10]([CH:11]=[CH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH2:20]2)=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cc1
Solvent: C1CCNC1
Solvent: ClC(Cl)Cl
Product: O=C(C=Cc1ccc(O)cc1)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
The piperazine compound was dissolved in 150 ml of chloroform, and to the solution was added 2.30 g of pyrrolidine. The resultant mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was evaporated, and the residue was subjected to chromatography using a silica gel column and purified with a mixed solvent of chloroform and methanol (10:1), thereby obtaining 11.1 g (a stoichiometric amount) of 1-(4-hydroxycinnamoyl)-4-(pyrrolidinocarbonylmethyl)piperazine as a colorless oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:18]3[N:17]=2)=[CH:9][C:8]([F:28])=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:28][C:8]1[CH:9]=[C:10]2[C:5](=[N:6][CH:7]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:27])[C:24]1=[C:18]3[N:17]=[C:16]([CH:21]=[CH:20][N:19]3[N:22]=[CH:23]1)[N:12]1[C@@H:11]2[CH2:15][CH2:14][CH2:13]1
Reactant: NCCCc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCCc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Reaction time: 3 h
Yield: 39 %

Procedure:
To (R)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (16 mg, 0.042 mmol) in DMF (5 mL) was added HATU (63 mg, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (22 mg, 0.17 mmol). The reaction mixture was stirred for 3 hours and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using 100% EtOAc to afford the title compound (6.0 mg, 39% yield). MS (apci) m/z=367.3 (M+H).