Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH2:15])[C:5]([F:8])=[N:6][CH:7]=1.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.[F-].[K+].O.CO.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:2]3[CH:3]=[C:4]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[NH2:15])[C:5]([F:8])=[N:6][CH:7]=3)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cnccc1-c1cc(Br)cnc1F
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Nc1cnccc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Temperature: 100 °C
Yield: 64.7 %

Procedure:
A degassed mixture of 5-bromo-2-fluoro-[3,4]bipyridinyl-3′-ylamine (861 mg, 3.21 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (816 mg, 3.72 mmol) and bis(triphenylphosphine)palladium(II) chloride (169 mg, 0.241 mmol) in acetonitrile (14 mL) and 1N aqueous potassium fluoride solution (8.0 mL) was heated under microwave irradiation at 100° C. for 25 minutes. The cooled reaction mixture was diluted with water and 20% methanol in DCM, the layers separated, and the aqueous phase extracted into 20% methanol in DCM. The combined organic phase was concentrated in vacuo, and the resultant residue dissolved in DCM/methanol, absorbed onto celite, and purified by flash chromatography (silica, 100 g column, Biotage, 0-20% methanol in DCM) to afford the title compound as a dark orange foam (753 mg, 65%). 1H NMR (DMSO-D6, 400 MHz): 8.58 (s, 1H), 8.20 (d, J=7.1 Hz, 1H), 8.13 (s, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.74 (m, 2H), 7.43 (m, 2H), 7.07 (d, J=4.9 Hz, 1H), 5.31 (s, 2H), 3.29 (s, 2H), 2.35 (m, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method B): RT=1.27 min, M+H+=363.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]=2[CH:20]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 90 °C
Yield: 15.6 %

Procedure:
(S)-1-[6-Fluoro-1-(3-fluorophenyl)-1H-benzoimidazol-2-yl]ethylamine (0.45 g, 1.64 mmol) was dissolved in n-butanol (10 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.39 g, 1.64 mmol) and DIPEA (1.45 mL, 8.24 mmol) were added. The reaction mixture was heated at 90° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford crude product. This material was purified by column chromatography (silica gel, gradient 0-7.5% MeOH in DCM) to afford 185 as an off-white solid (100 mg, 20%). LCMS (Method K): RT 3.52 min [M+H]+ 392.0 1H NMR (DMSO-d6, 400 MHz): δ 8.09 (1H, s), 8.05 (1H, s), 7.91 (1H, s), 7.68 (1H, dd, J=8.80, 4.85 Hz), 7.58-7.47 (2H, m), 7.42 (1H, d, J=7.91 Hz), 7.32-7.23 (1H, m), 7.09 (1H, td, J=9.32, 2.48 Hz), 6.92 (1H, dd, J=8.93, 2.50 Hz), 5.63-5.47 (1H, m), 1.58 (3H, d, J=6.82 Hz)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25](=[O:30])[CH:26]=[CH:27][CH2:28]Br)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:31]#[N:32])[CH:10]=[CH:11][CH:12]=1.O.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25](=[O:30])[CH:26]=[CH:27][CH2:28][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:31]#[N:32])[CH:10]=[CH:11][CH:12]=1
Reactant: CCNCC
Reactant: N#Cc1cnc2ccc(NC(=O)C=CCBr)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CC=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A solution of 3.15 ml (30 mmoles) of diethylamine in 15 ml of tetrahydrofuran was cooled in an ice bath and a solution of 729 mg (1.5 mmoles) of 4-bromo-but-2-enoic acid [4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide in 5 ml of N, N-di-methylformamide was added dropwise. Stirring and cooling were continued for 2 hours. Then 25 ml of water and 15 ml of ethyl acetate were added. The layers were separated and aqueous layer was extracted with 2-15 ml portions of 1:1 tetrahydrofuran-ethyl acetate. The combined organic layers were absorbed onto silica gel and chromatographed on silica gel. The column was eluted with a gradient of 1:19 to 1:4 methanol-methylene chloride to give 367 mg (51%) of 4-Diethylamino-but-2-enoic acid [4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide. The compound melted at 141-145 deg: mass spectrum (electrospray, m/e): M+H 478.0,480.0.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.[C:22](OCC(Cl)(Cl)Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)(=O)CCCC.C(Cl)(O)C(Cl)Cl>N1C=CC=CC=1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCC(=O)OCC(Cl)(Cl)Cl
Agent: CCCCC(=O)Cl
Agent: OC(Cl)C(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
2-Amino-6-methoxy-9-β-D-arabinofuranosyl-9H-purine (1.0 g, 3.2 mmol) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2.0 mL of trichloroethyl valerate (Trichloroethyl valerate was synthesized by addition of 36 g of valeryl chloride (Aldrich) over 30 minutes to 45 g of trichloroethanol (Aldrich) in 50 mL of pyridine at 0° C. The product was purified by successive washing with 2×250 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H-NMR (200 MHz, CDCl3): δ4.74 (s, 2H, Cl3CH2 --), 2.48 (t, 2H, J=7.6 Hz, CH3CH2CH2CH2CO2 --), 1.68 (m, 2H, CH3CH2CH2CH2CO2 --), 1.53 (M, 2H, CH3CH2CH2CH2CO2 --), 0.93 (t, 3H, J=7.2 Hz, CH3CH2CH2CH2CO2 --)). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot #38F-0356), which had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 24 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (90:10) as the eluant. Product fractions were pooled and lyophilized from water to yield 0.85 g of the desired product as a white powder; m.p. 105° C.; TLC Rf =0.39 (silica gel; CH2Cl2:CH3OH (90:10)); UV λmax (ε;, mM- 1 cm-1) at pH 7.0, 279 nm (9.3); MS (Cl) 382 (M+1), 280 (M-C5H9CO2). 1H-NMR (200 MHz, DMSO-d6): δ7.83 (s, 1H, H8), 6.45 (s, 2H, 2-NH2), 6.15 (d, 1H, J=3.7 Hz, H1 '), 5.76(d, 1H, J=4.2 Hz, 2'--OH), 5.65 (d, 1H, J=3.5 Hz, 3'OH), 4.28 (m, 2H, H2' and H3'), 4.08(m, 2H H5'), 3.94 (s, 3H, --OCH3) 3.92 (m, 1H, H4'), 2.29 (t, 2H, J=7.1 Hz, CH3CH2CH2CH2CO2 --), 1.49(m, 2H, CH3CH2CH 2 CH2CO2 --) 1.28 (m, 2H CH3CH2CH2CH2CO2 --), 0.83 (t, 3H, J=7.2 Hz, CH3CH2CH2CH2CO2 --). Anal. Calcd. for C16H23N5O6.0.36 H2O: Calcd: C, 49.54; H, 6.16; N,18.05. Found: C, 49.52; H,6.15; N, 18.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][NH2:18])[CH2:15][NH2:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[S:20](N)(N)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][NH:16][S:20](=[O:22])(=[O:21])[NH:18][CH2:17]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(CN)CN)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1
Yield: 64.3 %

Procedure:
[4-(2-Amino-1-aminomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in Example 4, step (b), 30.4 mg, 0.114 mmol) and sulfamide (15.4 mg, 0.802 mmol) in pyridine (0.7 mL) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo, and the residue was purified on silica (20%-70% EtOAc-hexane) to obtain the title compound (24 mg, 64%): 1H-NMR (DMSO-d6; 400 MHz): δ 9.35 (br s, 1H), 7.45 (m, 2H), 7.15 (m, 2H), 6.73 (m, 2H), 3.52 (m, 2H), 3.27 (m, 2H), 2.85 (m, 1H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:12](Cl)=[O:13])([O-:8])=[O:7]>C(OCC)(=O)C>[CH2:1]([NH:5][C:12](=[O:13])[C:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 27.2 %

Procedure:
The general procedure was used with isobutyl amine (14.6 g, 0.200 mole) and 3,5-dinitrobenzoyl chloride (23.0 g, 0.100 mole) in ethyl acetate. Produced 7.28 g (26%) crystals, mp 149°-155° C. Proton NMR (90 MHz) shows resonances at 9.168 ppm (m, 1H; 4-aryl H); 8.955 ppm (d, 2 Hz, 2H; 2,6-aryl H's); 6.526 ppm (bs, 1H; N-H); 3.378 ppm (t, 6.4 Hz, 2H; N-CH2); 2.050 ppm (sep, 7 Hz, 1H; CH); 1.021 ppm (d, 6.2 Hz, 6H; CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][CH3:43])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].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>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][N:42]([CH3:43])[C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN(C)C(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)cc1OC
Yield: 47.1 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example 1d was reacted with [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine (58.6 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amide (57.3 mg, 48.26%) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]2[N:9]=[C:10]3[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:28][CH2:27]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
In the final step of the synthesis reaction, the title compound, 7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one was produced as follows: To a solution of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (1.06 g, crude from previous reaction) was added a solution of 2,3-dichlorophenylpiperazine (1.02 g, 4.40 mmol) in dichloroethane (5 mL). The solution was stirred for 15 min and NaBH(OAc)3 (1.21 g, 5.72 mmol, 1.3 equiv) was added as a powder. The reaction was stirred at room temperature for 3 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated to give a yellow foam/oil. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as a white foam (1.20 g, 2.67 mmol, 61% over 2 steps). The HCl salt was formed by dissolving the title compound (800 mg, 1.78 mmol) in Et2O (20 mL) and CH2Cl2 (2 mL) followed by the addition of 1N HCl in Et2O (1.75 mL). The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (801 mg). MS: APCI: M+1: 449.1 (Exact Mass: 448.14).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][N:12]=1>CN(C)C=O.C(OCC)(=O)C>[I:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Fc1cc(I)ccn1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccnc(Oc2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenol (0.464 g) in N,N-dimethylformamide (5 mL) was treated with sodium hydride (60% in mineral oil, 0.057 g). After the gas evolution ceased, 2-fluoro-4-iodopyridine (0.22 g) was added slowly to the solution. The mixture was heated at 100° C. overnight under nitrogen atmosphere, cooled, diluted with ethyl acetate and washed with aqueous NaOH. The organic layer was concentrated and purified by preparative TLC, eluting with petroleum ether/ethyl acetate (10/1).
Reaction SMILES: C(OC(N1C[C@@H](P(C2C=C(C)C(OC)=C(C)C=2)C2C=C(C)C(OC)=C(C)C=2)C[C@H]1CP(C1C=C(C)C(OC)=C(C)C=1)C1C=C(C)C(OC)=C(C)C=1)=O)(C)(C)C.C(N(CC)CC)C.[C:63]([NH:66][C:67](=[CH:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:68]([OH:70])=[O:69])(=[O:65])[CH3:64]>C(O)C>[C:63]([NH:66][C@@H:67]([C:68]([OH:70])=[O:69])[CH2:71][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)(=[O:65])[CH3:64]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: COc1c(C)cc(P(C[C@@H]2C[C@H](P(c3cc(C)c(OC)c(C)c3)c3cc(C)c(OC)c(C)c3)CN2C(=O)OC(C)(C)C)c2cc(C)c(OC)c(C)c2)cc1C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
0.005 m-mole of rhodium-dinorbornadieneperchlorate, 0.0065 m-mole of (2S,4S)-N-tert.-butoxycarbonyl-2-bis(3,5-dimethyl-4-methoxyphenyl)phosphinomethyl-4-bis(3,5-dimethyl-4-methoxyphenyl)phosphinopyrrolidine (Ii) and 0.25 m-mole of triethylamine were dissolved in 20 ml of ethanol and 5 m-mol of α-acetamidocinnamic acid was added to the solution. The mixture was stirred for 20 hours at 50° C. and under a hydrogen pressure of 20 atm. The reaction mixture was concentrated under reduced pressure and then dissolved in 0.5N aqueous solution of caustic soda. Insolubles were filtered off and the filtrate was made acid with diluted hydrochloric acid and extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off to obtain optically active (R)-N-acetylphenylalanine. Conversion 100%; optical yield 98%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]([NH2:30])=[NH:29].COCCO.[OH-].[Na+]>O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]1[N:30]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[CH3:17])[CH:4]=[CH:3][N:29]=1
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)/C=C/N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Cc1nc(N)sc1-c1ccnc(Cc2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N′-[5-((E)-3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (1 g), 2,6-dichlorophenylacetamidine (0.90 g) and 2-methoxyethanol (3.8 ml) is stirred at room temperature for 30 minutes. NaOH (0.3 g) is added and the mixture stirred at 125° C. for 1 hr. After cooling to room temperature water is added and the mixture evaporated to dryness and then purified by normal phase chromatography on silica gel eluting with a gradient from CH2Cl2 to EtOAc to give the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1F
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2F)cc1

Procedure:
69 mg of pale yellow solid 3-{4-[3-(2-fluoro-3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].C(O)C>O>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:10][CH:11]([OH:12])[CH2:13][OH:14])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: OCC1CO1
Solvent: CCO
Solvent: O
Product: CCN(CC(O)CO)c1ccccc1
Temperature: 120 °C
Yield: 94.7 %

Procedure:
A mixture of N-ethylaniline (1.21 g, 10 mmol), glycidol (1.11 g, 15 mmol) and ethanol (1 ml) was heated by microwave irradiation for 10 min at 120° C. The mixture was dissolved in water (10 ml) and extracted with ethyl acetate (3 times 25 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/heptane=1:2) to yield a colorless liquid (1.85 g, 94%); MS (ISP): 196.3 ((M+H)+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O:15]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 68.4 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 2.2 g of 4-phenoxyaniline. After stirring the reaction under an inert atmosphere for 18 hr, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 2.35 g (69%) of 6-fluoro-4-(4-phenoxy-phenylamino)-[1,7]naphthyridine-3-carbonitrile as yellow needles: melting point 211-213° C.; mass spectrum (m/e): M+H 356.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.I[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1>[Cu]I.O1CCOCC1>[C:1]([O:5][C:6]([N:8]([C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)cc(I)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)cc(N(C(=O)OC(C)(C)C)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 96.7 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), N-tert-butoxycarbonylaniline (200 mg, 1.04 mmol), K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 10 mol %), 5-iodo-m-xylene (190 μL, 1.32 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting pale yellow suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 20:1; 20 mL fractions). Fractions 12–20 provided 299 mg (97% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 7.36–7.30 (m, 2H), 7.27–7.16 (m, 3H), 6.87 (s, 2H), 6.85 (s, 1H), 2.30 (s, 6H), 1.48 (s, 9H). 3C NMR (100 MHz, CDCl3): δ 153.9, 143.2, 142.7, 138.3, 128.6, 127.5, 126.9, 125.4, 124.8, 80.9, 28.2, 21.2. Anal. Calcd for C19H23NO2: C, 76.74; H, 7.79. Found: C, 76.61; 7.87.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCOCC1.O>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([O:1][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Hydroxyphenyl)ethanol (400 mg, 2.90 mmol) was dissolved in a mixture of 4 ml of dioxane and 4 ml of water, and sodium hydrogencarbonate (2.43 g, 29 mmol) was added followed by acetic anhydride (2.96 g, 29 mmol) with ice cooling. The mixture was stirred overnight at room temperature and then partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the crude title compound which was used without further purification.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH2:7]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:24].[ClH:5].[CH2:7]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:3])[CH2:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCCN1CCN(CCc2ccccc2)CC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: SCCCN1CCN(CCc2ccccc2)CC1
Yield: 81.6 %

Procedure:
The procedure described in Example 1(b) was followed, using 15.2 g of thiourea, 32.6 g of 1-phenethyl-4-(3-chloropropyl)piperazine dihydrochloride, 20.0 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 26.4 g (79% of theory) of 3-(4-phenethylpiperazin-1-yl)propanethiol dihydrochloride as an off-white crystalline solid, M.p. 269°-272° C.