Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH3:29].C([C@H]1N(C(=O)C2C=CC=C(OC)C=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:26]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Product: CCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Yield: 76 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with 1-bromobutane according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) to yield (3R)-1-butyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (76%). MS (ESI) m/z 385 ([M+H]+).
Reaction SMILES: Cl.Br[CH:3]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C#N.[N:13](CCO)(CCO)[CH2:14]CO>>[C:14]([CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][N:7]1[CH2:6][CH2:3]1)#[N:13]
Reactant: CCCCCNCC(Br)C#N
Reactant: OCCN(CCO)CCO
Agent: Cl
Product: CCCC(C#N)CN1CC1
Yield: 43 %

Procedure:
reaction of 2-bromo-3-n-pentylaminopropionitrile hydrochloride (prepared by reacting 2,3-dibromopropionitrile with n-pentylamine; m.p. 133°-135° C.) with triethanolamine gives 2-cyano-n-pentylaziridine; b.p.0.3 : 50°-52° C.; yield 43% of theory;
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:32])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C>C1COCC1.[OH-].[Na+]>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:14]3[CH:13]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=4)[CH:17]=[CH:16][CH:15]=3)=[O:32])=[CH:21][CH:22]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(-c2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)cc1
Temperature: 25 °C

Procedure:
3′-(4-Morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester (850 mg) in THF (12 ml) and 1M NaOH (25 m) was heated to 100° C. for 3 hours then cooled to room temperature. THF was evaporated and the residue extracted with dichloromethane. The aqueous layer was acidified to pH 1 and a grey solid precipitated which was collected by filtration and dried (793 mg)
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C@@H:5]2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:2]1(=[O:1])(=[O:18])[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2[C@@H](CCS2(=O)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CC[C@H]2CNCCN21
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of tert-butyl (3aS)-1,1-dioxo-2,3,3a,4,6,7-hexahydroisothiazolo[2,3-a]pyrazine-5-carboxylate (360 mg, 1.303 mmol) in DCM (5 mL) at 0° C. was added TFA (1.25 mL, 16.22 mmol) dropwise and the reaction was stirred and warmed slowly to ambient temperature over 45 mins. The reaction mixture was concentrated in vacuo and the residue was adsorbed onto a pre-wetted (methanol/DCM (1:1), 10 mL) SCX-2 cartridge (10 g) and flushed with DCM/methanol (1:1, 50 mL) and then the basic components eluted with 2 M ammonia in methanol (50 mL). The basic eluent was evaporated to dryness to afford (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide as a colourless oil (192 mg, 84%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][O:20][CH:21]([O:31][CH3:32])[CH2:22][NH:23][CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH3:33][N:34]1[CH:38]=[C:37]([C:39]2[CH:40]=[C:41]([CH:50]=[CH:51][CH:52]=2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47](O)=[O:48])[N:36]=[N:35]1.C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C>[CH:24]1([N:23]([CH2:22][CH:21]([O:31][CH3:32])[O:20][CH3:19])[C:47](=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42][C:41]2[CH:50]=[CH:51][CH:52]=[C:39]([C:37]3[N:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[CH:40]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)nn1
Reactant: COC(CNC1CCCCCC1)OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cn(C)nn2)c1)C1CCCCCC1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of T3P (1.656 mL) dissolved in THF (1.57M) was added in one portion to a stirred solution of N-(2,2-dimethoxyethyl)cycloheptanamine (0.30 mL), 3-(3-(1-methyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoic acid [Example 5, Step ii)] (0.51 g) and triethylamine (2.17 mL) in acetonitrile (5 mL) at 25° C. The resulting solution was stirred at 25° C. for 15 min. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with saturated sodium hydrogen carbonate (50 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-70% ethyl acetate in isohexane to afford the subtitled compound (0.51 g). 1H NMR (400 MHz, CD3OD) δ 8.25 and 8.24 (2×s, 1H), 7.68-7.65 (m, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.32 and 7.31 (2×t, J=7.6 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 4.56 and 4.39 (2×t, J=5.1 Hz, 1H), 4.13 (s, 3H), 3.85-3.66 (m, 5H), 3.36-3.32 (m, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 3.22 (d, J=5.0 Hz, 2H), 2.92-2.85 (m, 2H), 2.63 and 2.60 (2×t, J=6.0 Hz, 2H), 1.83-1.32 (m, 10H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19](OCC)=[O:20])=[C:5]2[OH:24].C(N(C(C)C)C(C)C)C.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:18])[C:6]([C:19]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:20])=[C:5]2[OH:24]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
Ethyl 6,7-dichloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (550 mg, 1482 μmol) was dissolved in 1,4-dioxane (1482 μL), and N-ethyl-N-isopropylpropan-2-amine (774 μL, 4445 μmol). tert-Butyl 2-aminoacetate hydrochloride (373 mg, 2222 μmol) was added to the reaction, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (350 mg) as a white solid after flash chromatography. MS (m/z)=456 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:22])=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=1)=O.CO.[NH3:25]>>[Cl:22][C:8]1[N:7]=[N:6][C:5]([C:3]([NH2:25])=[O:2])=[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:9]=1
Reactant: N
Reactant: COC(=O)c1nnc(Cl)cc1Nc1ccc(OC)c(OC)n1
Solvent: CO
Product: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
6-Chloro-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid methyl ester (1.7 g, 5.2 mmol) was suspended in ammonia in methanol (7N, 30.0 mL, 210 mmol) and the flask sealed. After stirring for 6 h at room temperature the mixture was concentrated in vacuo to give 6-chloro-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (1.55 g, 96%) as a yellow powder. LC-MS: 310.4 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)OCC)C1CC(C)(C)NC(C)(C)C1

Procedure:
The N-butyl-N-ethoxycarbonyl-2,2,6,6-tetramethyl-4-piperidylamine is prepared by reacting N-butyl-2,2,6,6-tetramethyl-4-piperidylamine with ethyl chlorocarbonate at 15°-25° C. in toluene in the presence of an aqueous solution of K2CO3. The product obtained, which is 99.2% pure, is employed directly, without any purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)(=[O:3])[CH3:2].O[C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=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>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:28]2[CH:41]=[CH:40][C:31]3[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=3[CH:29]=2)[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4COC(C)=O)c3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
(R)-(3′-(Hydroxymethyl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)biphenyl-2-yl)methyl acetate 35d (127 mg, 0.36 mmol) was dissolved in 10 mL of dichloromethane, followed by addition of methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (89 mg, 0.43 mmol) and triphenylphosphine (112 mg, 0.43 mmol). The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (87 mg, 0.43 mmol). The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure to obtain the crude title compound methyl 2-((S)-6-((2′-(acetoxymethyl)-6′-methyl-4′-(((R)— tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 35e (189 mg) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([I:13])[CH:4]=1.O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([I:13])[CH:4]=1)=[O:1]
Reactant: CC(=O)Nc1ccc(CO)cc1I
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of IBX (0.93 g, 3.3 mmol) in dimethylsulfoxide (3.5 mL) was added N-(4-hydroxymethyl-2-iodo-phenyl)-acetamide (0.87 g, 3.0 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added and the solid was separated by filtration, and washed with ethyl acetate (20 mL). The filtrate was collected and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave N-(4-formyl-2-iodo-phenyl)-acetamide as a light brown solid. Yield: 0.82 g (95%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=3)[CH2:30][CH2:31]2)[N:19]=1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: COc1cc(OC)nc(N2CCNCC2)n1
Product: COc1cc(OC)nc(N2CCN(Cc3ccc(C(C)(C)NC(C)=O)cc3)CC2)n1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4,6-dimethoxypyrimidin-2-yl)piperazine obtained in Example 90(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=199-202° C.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:4]1=[O:29])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:4]1=[O:29])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(CC(F)(F)F)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(CC(F)(F)F)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 73 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-2(1H)-one (73%). [α]D25=−137° (c=0.010 G/ML, CHCl3); MS (ESI) m/z 397 ([M+H]+); MS (ESI) m/z 395 ([M−H]−); HRMS: calcd for C19H16F4N2O3, 396.1097; found (ESI_FT), 397.11588.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:16])=[C:4]([NH2:15])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC(O)=O.[N:21]([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[C:3]2[NH:16][N:21]=[N:15][C:4]=2[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN1CCN(c2ncc(Br)c(N)c2N)CC1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(c2ncc(Br)c3[nH]nnc23)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (1.2 g, 4.2 mmol) and CH3COOH (10 mL). To the above was added dropwise a solution of NaNO2 (0.30 g, 4.3 mmol) in water (1 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the reaction mixture was basified to pH 8 by saturated aqueous Na2CO3 and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2Cl2, to afford 1.1 g (88%) of the product as a white solid. MS m/z: 297 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[C:12]([CH2:14][N:24]([CH3:25])[CH3:23])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1ccc(-c2cc(C=O)nc(Cc3ccccc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2cc(CN(C)C)nc(Cc3ccccc3)n2)cc1
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of the product from Step B (0.102 g, 0.35 mmol) in CH2Cl2 (2 mL) was added the Dess-Martin periodinane (0.228, 0.53 mmol). After 30 min, the mixture was diluted satd. aq. NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were dried, concentrated, and filtered through a small plug of SiO2 (25% EtOAc in hexanes). The filtrate was concentrated to give 2-benzyl-6-p-tolyl-pyrimidine-4-carbaldehyde (0.55 g, 54%). To a solution of this aldehyde in CH2Cl2 (3 mL) was added dimethylamine (2 M in THF; 0.15 mL, 0.30 mmol) and NaBH(OAc)3 (0.058 mg, 0.27 mmol). After 15 h, the reaction was diluted with CH2Cl2 and washed with 1 N NaOH. The aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.050 g (79%) of the title compound. MS (ESI): exact mass calcd. for C21H23N3, 317.19; m/z found, 318.4 [M+H]+. 1H NMR (CDCl3): 8.02 (d, J=8.2, 2H), 7.66 (s, 1H), 7.22 (d, J=7.5, 2H), 7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 4.33 (s, 2H), 3.58 (s, 2H), 2.41 (s, 3H), 2.32 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([C:34]([O:36]C)=[O:35])=[O:33])=[CH:22][CH:21]=2)[C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([C:34]([OH:36])=[O:35])=[O:33])=[CH:24][CH:25]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 70.9 %

Procedure:
Following a procedure similar to that described in Example 1(b), but using 878 mg of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carboxylate [prepared as described in step (a) above] and 364 mg of lithium hydroxide monohydrate, 571 mg of the title compound were obtained as a powder, softening at 140° C. and melting at 165°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Product: COc1ccc(-c2oncc2C(=O)N2CCCC2)cc1

Procedure:
The title compound was prepared from 5-(4-methoxyphenyl)isoxazole-4-carboxylic acid (11.0 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (15.1 mg). MS (pos) m/z 273.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]#[N:8])[NH:5][CH:6]=1.[H-].[Na+].[NH2:11]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:11][N:5]1[CH:6]=[C:2]([Cl:1])[CH:3]=[C:4]1[C:7]#[N:8]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(Cl)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cn1N
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a rapidly stirred solution of 4-chloro-1H-pyrrole-2-carbonitrile (3.6 g, 28.4 mmol) in DMF (75 mL) was added NaH (1.7 g, 42.7 mmol) portion wise over 20 min. The dark brown solution was allowed to stir for an additional 10 min. The aminating reagent ((aminooxy)(diphenyl)phosphine oxide) (10 g, 42.7 mmol) was added in one portion. The mixture was heated to 80° C. for 6 hours. The reaction was quenched with distilled water (100 mL). EtOAc (50 mL) was added to the reaction and the solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated in vacuo to yield 3.4 g of the above compound (24.02 mmol, yield 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[ClH:47]>C(O)CCC.C(Cl)Cl>[ClH:23].[ClH:47].[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[CH2:12][CH2:11]2)=[CH:21][CH:20]=1
Reactant: CC(C)C(=O)c1ccc(OCCCCl)cc1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCO
Product: CC(C)C(=O)c1ccc(OCCCN2CCC(C(Nc3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
A mixture of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (4.63 g, 0.0153 mol), 1-[4-(3-chloropropoxy)phenyl]-2-methyl-1-propanone (3.69 g, 0.0153 mol), and potassium carbonate (2.76 g, 0.02 mol) was heated at reflux 16 h in 350 mL 1-butanol containing sodium iodide (0.2 g). The reaction was concentrated to dryness and partitioned between chloroform and water. The chloroform layer was then extracted with 5% sodium hydroxide and dried (Na2SO4). The chloroform was removed to give a red oil. This material was subjected to flash chromatography on silica gel using 2% methanol in methylene chloride to accomplish elution. Fractions of similar purities were combined, and solvents removed to give an oil. The oil was converted to the HCl salt and recrystallized from methanol-diethyl ether to give a white solid. This solid was dried 16 h at 78° C. in vacuo. The procedure utilized here furnished 5.26 g (59%) of white crystalline product, mp 221° -223° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8]>CCO.[Pd]>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of 5-fluoro-N-methyl-2-nitrobenzamide (Compound 102B) in EtOH (10.0 mL) was charged with Palladium 10% wt on activated carbon (0.316 g, 0.297 mmol). The reaction mixture was evacuated and purged with hydrogen gas (3 times). The reaction mixture was allowed to stir under hydrogen at rt for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to yield a light yellow semi-solid. The material was purified by silica gel chromatography using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 0.500 g (100% yield). 1H NMR (CDCl3, 400 MHz): δ=2.98 (d, J=4.80 Hz, 3 H), 5.30 (d, J=5.31 Hz, 1 H), 6.64 (dd, J=8.84, 4.80 Hz, 1 H), 6.96 (ddd, J=8.91, 7.89, 2.91 Hz, 1 H), 7.02 (dd, J=9.22, 2.91 Hz, 1 H). MS (ES+): m/z 169.08 [MH+] (TOF, polar).