Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2ccc(C)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A mixture of 230 mg of ethyl 4-hydroxy-6-methyl-3-quinolinecarboxylate (J. Chem. Soc., 893 (1948)) and 0.7 mL of 4-chlorobenzylamine is stirred for 1 h at 210 ° C. The mixture is cooled to 25° C. and it is diluted with 1.5 mL of toluene. The mixture is filtered and the filtrant is dissolved in a minimum volume of refluxing glacial acetic acid. The hot solution is treated with distilled water dropwise until it becomes cloudy, and it is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with a small amount of dilute aqueous acetic acid. The solid is dried for 48 h at 20 torr and 85° C. This procedure gives the title compound as 47 mg of a light tan solid.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:14][CH2:15][CH:16](N)[CH3:17]>C(=S)=S>[CH3:17][CH:16]1[CH2:15][NH:14][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1
Reactant: CC(N)CN
Reactant: CCCCCCCCCCCC#N
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NC(C)CN1
Yield: 74.9 %

Procedure:
18.13 g (100 mmoles) of undecyl cyanide, 9.3 g (125 mmoles) of 1,2-diaminopropane and 0.5 ml of carbon disulfide were heated to 125° C. for 24 hrs. and then worked up as mentioned under Example 23. Kugelrohr distillation at 163°-165° C./1.2-1.4 mm Hg gave 17.85 g (75%) of product.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18](=[O:24])[NH:19]3)=[CH:10][CH:9]=1)#[N:7].[OH-:25].[NH4+]>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18](=[O:24])[NH:19]3)=[CH:10][CH:9]=1)(=[O:25])[NH2:7]
Reactant: N#Cc1ccc(-c2nccc3[nH]c(=O)ccc23)cc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1ccc(-c2nccc3[nH]c(=O)ccc23)cc1
Reaction time: 0.5 h

Procedure:
To a 35 ml of concentrated sulfuric acid chilled in an ice bath was added 5 g of 5-(4-cyanophenyl)-1,6-naphthyridin-2(1H)-one. The resulting mixture was allowed to stand in an ice bath for 30 minutes and then at room temperature overnight. The mixture was poured onto ice and neutralized by adding aqueous ammonium hydroxide solution. The resulting white precipitate was collected, washed with distilled water, dried in a vacuum oven at 90°-95° C. to yield 4.8 g of 5-(4-carbamylphenyl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:26][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc(OC(F)(F)F)cc2)c1
Yield: 44.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (208 mg, yield: 44.8%).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].CS([C:26]1[C:31]2[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:30]=2[N:29]=[N:28][N:27]=1)(=O)=O.CS(C)=O>CO>[CH3:39][O:38][C:33]1[C:34]([O:36][CH3:37])=[CH:35][C:30]2[N:29]=[N:28][N:27]=[C:26]([N:18]3[CH2:19][CH2:20][CH:15]([N:5]4[C:6](=[O:14])[C:7]5[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=5)[N:3]([CH3:2])[C:4]4=[O:21])[CH2:16][CH2:17]3)[C:31]=2[CH:32]=1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: COc1cc2nnnc(S(C)(=O)=O)c2cc1OC
Agent: Br
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc2nnnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 67 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 4-methanesulfonyl-6,7-dimethoxy-1,2,3-benzotriazine was used in place of 4-chloro-6,7-dimethoxyquinazoline, DMSO was used as a reaction solvent in place of methanol, and the reaction was conducted at room temperature. As a result, 307.6 mg (yield: 67%) of Compound 75 was obtained as white crystals.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([O:9]C(C)(C)C)=[O:8])=[CH:5][N:6]=1.[CH3:14][O-:15].[Na+].[OH-].[Na+]>CC#N.CO>[CH3:14][O:15][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)s1
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: COc1ncc(C(=O)O)s1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 2-chlorothiazole-5-carboxylate (100 mg, 0.455 mmol) in MeCN (880 μl) and MeOH (880 ul) was added 5.4M NaOMe in MeOH (337 μl, 1.821 mmol) followed by 2M NaOH (881 μl, 1.762 mmol). The reaction mixture was heated to 80° C. overnight and, after cooling to RT, the mixture was evaporated under reduced pressure. The residue was acidified with a minimal volume of 6M aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in a high vacuum oven overnight to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:21]=2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(Nc4ccc(OCCN(C)C)nc4)c3n2)cc(Cl)c1O
Yield: 75.7 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[2-(dimethylamino)ethoxy]pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.052 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (22 mg, 74%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.33 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.74 (dd, J=8.8, 2.7 Hz, 1H), 7.29 (br s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.85 (br s, 1H), 4.70-4.64 (m, 2H), 3.95 (s, 3H), 3.62-3.56 (m, 2H), 2.99 (s, 6H), 2.83 (s, 3H); ESI MS m/z 508 [M+H]+; HPLC>99% (AUC), tR=9.36 min.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12]C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]2[C:8]([CH:11]=[O:12])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2sccc12
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1csc2cccc(Br)c12
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
4-Bromobenzothiophene (1.80 g, 8.45 mmol) and dichloromethyl methyl ether (1.46 g, 12.7 mmol) were dissolved in anhydrous DCM (100 mL). Titanium tetrachloride (2.40 g, 12.7 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×150 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 4-bromobenzothiophene-3-carboxaldehyde (0.910 g). The 4-bromobenzothiophene-3-carboxaldehyde (0.910 g, 3.77 mmol) and sulfamide (3.0 g, 31 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.157 g, 4.15 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[N:13]([C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=Nc1ccnc2c(F)cccc12
Yield: 93.2 %

Procedure:
A mixture of 2.08 g (0.0114 mol) of 4-chloro-8-fluoroquinoline, 1.12 g (0.0172 mol) of sodium azide, and 4.10 g ((0.0127 mol) of tetrabutyl ammonium bromide in 70 mL of dichloromethane and 25 mL of water was refluxed overnight. The layers were then separated and the organic layer was washed once with water, passed through phase separating paper, and concentrated to an oil, which was triturated with ether. The solid was filtered and the filtrate was concentrated to give 2.0 g of the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:42][C:25]([CH3:41])([CH3:24])[CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]5=[O:22])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:29]=[N:28]1
Reactant: CC1(C)COC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)OCC4(C)C)nc2-3)cn1
Yield: 22 %

Procedure:
3-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-yl)-4,4-dimethyloxazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 356. Yield 22%. MS (ESI+): 455.1. 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=8.3, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.37 (dd, J=8.3, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.71 (s, 1H), 4.32 (d, J=6.9, 4H), 4.05-4.00 (m, 2H), 3.25 (t, J=5.0, 2H), 1.76 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:7]=2)[CH:3]=1.[CH:41]1(B(O)O)[CH2:43][CH2:42]1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:41]1([C:2]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[C:8]3[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])[N:7]=3)[CH:3]=2)[CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C3CC3)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 4-(((5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (42 mg, 0.07 mmol), cyclopropyl boronic acid (17.2 mg, 0.2 mmol), and tetrakis(triphenylphosphine) palladium(0) (7.7 mg, 0.007 mmol) were combined in dry tetrahydrofran (2 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, 0.24 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel to afford 34 mg (86%). 1H-NMR (CDCl3, 300 MHz) δ 7.86 (s, 1H), 7.32 (m, 1H), 7.14-7.23 (m, 5H), 6.94 (m, 1H), 5.32 (s, 2H), 4.65 (s, 2H), 3.61-3.85 (m, 2H), 3.39 (s, 2H), 3.32-3.38 (m, 2H), 2.95-3.02 (m, 2H), 2.06-2.11 (m, 2H), 1.93-1.96 (m, 1H), 1.71-1.80 (m, 2H), 1.39 (s, 9H), 0.92-0.97 (m, 2H), 0.64-0.78 (m, 4H), 0.13 (s, 9H). Mass spec.: 592.24 (MH)+.
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24](OC)=[O:25])[CH:22]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[C:7]([CH3:28])[CH:6]=1>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH3:28])[C:8]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][OH:25])[CH:22]=3)[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[C:9]([CH3:11])[CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CO)cc32)c(C)c1

Procedure:
Lithium borohydride (0.232 g, 0.0107 mol) was added at 0° C., under argon, to a solution of methyl 1-(4-methoxy-2,6-dimethylphenylsulfonyl)indoline-6-carboxylate (1 g, 0.0027 mol) in dry THF (30 ml), and the resulting reaction mixture was refluxed for 2 h. The solvent was removed in vacuo, water was added to the residue, and extraction with ethyl acetate was carried out. The organic phase was washed with water and saturated sodium chloride solution, then dried (Na2SO4) and concentrated in vacuo. The resulting crude product was used in the next stage without further purification. Yield: 0.9 g (97%).
Reaction SMILES: [N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[CH:20](O)=O>O>[CH3:20][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(N2CCCNCC2)nc1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCN(C)CC2)nc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 1.50 g of methyl 6-homopiperazinylnicotinate (compound 13), 0.68 g of 35% formaldehyde and 1.2 g of formic acid was stirred at 70°-80° C. for 2 hours. The resulting mixture was poured into 120 ml of water and extracted with ethyl acetate. The extract was washed twice with water and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; ethyl acetate : methanol=1:2) gave 1.35 g of methyl 6-(4-methyl-1-homopiperazinyl)nicotinate (yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:39])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:39][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0.1M solution of the alcohol of Step 6 in CH2Cl2 at -40° C. was added 1.3 equiv. of methanesulfonyl chloride and 1.5 equiv. of Et3N and the mixture was stirred 30 min at -40° C. and 1 h at 0° C. Saturated NaHCO3 was then added and the title mesylate was extracted in CH2Cl2, dried over Na2SO4, concentrated and stripped twice with toluene. The residual title compound was used for subsequent reactions without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.C(Cl)CCl.[NH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1 g, 3.62 mmol) in dry dichloromethane (30 mL) was added dimethylaminopyridine (884 mgL, 7.24 mmol), EDC (1.388 g, 7.24 mmol), and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (742 mg, 3.98 mmol) sequentially at room temperature under nitrogen. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](F)[CH:4]=[C:3]([CH2:8][CH:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.N[C@H](C(O)=[O:24])CC1C=CC=CC=1>>[CH:1]1[CH:6]=[C:5]([OH:24])[CH:4]=[C:3]([CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](Cc1cccc(O)c1)C(=O)O

Procedure:
DL-3-fluorophenylalanine and L-phenylalanine were purchased from Sigma (UK).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>C1C=CC=CC=1>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:27]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C1CCCN1Cc1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: F[B-](F)(F)F
Solvent: c1ccccc1
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g.; 0.025 mole - assuming 100% conversion) by adding 5 ml. of 50% of NaOH to an aqueous slurry of the salt and benzene extraction. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 3.84 g. (0.025 mole) of m-chlorophenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 2 hours and then taken to dryness in vacuo to give an oily residue which eventually crystallizes. Recrystallizations from acetone-petroleum ether affords a pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(m-chlorophenyl)urea, m.p. = 91°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH2:13][N:34]3[CH2:35][CH2:36][CH:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:26]=4)[CH2:32][CH2:33]3)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C=O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using ethyl 5-(4-chlorophenyl)-2-formyl-3-furoate and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 509.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[C:26]([CH3:31])([CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])=[CH:11][C:10]=1[O:23][CH2:25][C:26]([OH:24])([CH3:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCc2ccccc2)c(O)c1
Reactant: C=CCCC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCC(C)(O)COc1cc(C(C)(C)CC(C)(C)C)ccc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
A mixture of 7.4 g (23.7 mmole) of 2-benzyloxy-5-t-octylphenol, 5.3 g (47.4 mmole) of 1,2-epoxy-2-methyl-5-hexene and 3.27 g (23.7 mmole) of potassium carbonate was heated at 120° C., with stirring, under nitrogen, for 48 hours. The cooled reaction mixture was extracted with ethyl acetate, and the resulting solution was washed with water followed by saturated sodium chloride solution. Evaporation of the washed ethyl acetate solution in vacuo, followed by purification of the residue by column chromatography on silica gel, eluting with 9:1 toluene-ethyl acetate, gave 8.33 g of the title compound as an oil.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([O:47][C:48](OC3C=CC([N+]([O-])=O)=CC=3)=[O:49])[CH2:43][CH2:42]2)=[O:40])=[O:30])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([O:47][C:48](=[O:49])[NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:43][CH2:42]2)=[O:40])=[O:30])=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)NC2CCCCC2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.5 %

Procedure:
A solution of cyclohexylamine (442 mg, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature for approximately 48 hours. The reaction mixture was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.92 g of a waxy yellow solid. Purification of the solid on silica gel (230-400 mesh) using 20% ethyl acetate-methylene chloride as the eluent gave 884 mg (47%) of the title compound as a white crystalline solid, mp 138°-142° C.