Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[C:31]=3[Cl:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2-chloro-3-trifluoromethylphenol according to the procedure of Example 69. MS (ESI) m/z 572.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[S:7][CH:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.Cl>O.CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)CCNc1nc(C(C)C)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(C(C)C)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of 4-isopropyl-N-(3-methylbutyl)-1,3-thiazol-2-amine (313 mg), sodium hydride (60% oil, 50 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by preparative HPLC (gradient cycle A) to give the title compound (150 mg, yield 28%) as a yellow oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17]>C1COCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccncc1
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1ccncc1
Yield: 98.7 %

Procedure:
A mixture of isonicotinic acid (3 g), N-hydroxysuccinimide (2.79 g) and N,N-dicyclohexylcarbodiimide (5.52 g) was stirred in THF (200 mL) for 16 hours. The solid was filtered off and the solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate and more solid filtered off. The filtrates were concentrated under reduced pressure gave 2,5-dioxopyrrolidin-1-yl isonicotinate (5.27 g). MS: 221 [MH]+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: COCCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: COCCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 8.4 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-6-(2-methoxy-ethoxymethyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(2-methoxy-ethoxymethyl )-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140 g, 14.7%). 1H NMR δ(400 MHz, CDCl3) 8.60 (s, 1H), 8.34 (m, 1H), 7.95 (s, 1H), 7.69 (t, J=1.4 Hz, 1H), 7.42 (m, 1H), 5.91 (m, 1H), 4.53 (d, J=1.2 Hz, 1H), 3.78 (m, 1H), 3.63 (m, 6H), 3.43 (s, 3H), 3.11 (m, 4H), 2.35 (m, 2H), 2.08 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:28]([CH3:29])[CH3:27])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: CN(C)CCCCOC[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with dimethylamine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-[4-(4-dimethylamino-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 411 (MH+, 1Cl).
Reaction SMILES: N1C=CN=C1.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CN(C)C=O>[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.7 %

Procedure:
Imidazole (30.0 g) was added to a solution of 1-benzyl-3-hydroxymethylpyrrolidine (43.45 g) and t-butyldimethylsilyl chloride (48.5 g) in dimethylformamide(150 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and at ambient temperature for 15 hours. The mixture was poured into water (600 ml), extracted twice with ethyl acetate (200 ml and 100 ml), dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (500 g) and eluted with a mixture of methanol and dichloromethane (5:95 V/V) to give 1-benzyl-3-t-butyldimethylsilyloxymethylpyrrolidine (60.15 g).
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:13]CC(C1C=C(CC)C=CN=1)=O>>[Br:13][CH2:2][C:1]([C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: CCc1ccnc(C(C)=O)c1F
Product: CCc1ccnc(C(=O)CBr)c1F

Procedure:
The title compound was prepared from 2-acetyl-4-ethyl-3-fluoropyridine according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH:14]=O>C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
To a solution of t-butyl carbazate (4.99 g, 37.76 mmol) in ethyl acetate (10 mL) was added with vigorous stirring a solution of 3,4-dichlorobenzaldehyde (6.77 g, 38.6 mmol) in ethyl acetate (10 mL) followed by hexanes (40 mL). Crystallization occurred and the resulting slurry was stirred at rt for 15 min, then cooled to 0° C. and held at that temperature for 45 min. The solids were filtered, rinsed with cold hexanes and dried in vacuo at 60° C. to afford the title compound as a solid (10.10 g, 92.4%): mp 173.8-174.4° C. (dec); 1H NMR (DMSO-d6) δ 11.16 (br s, 1 H), 7.79 (s, 1 H), 7.62 (d, 1 H, J=1.8 Hz), 7.57 (d, 1 H, J=8.5 Hz), 7.55 (m, 1 H), 1.44 (s, 9 H); 13C NMR (DMSO-d6) δ 152.9, 141.1, 136.1, 132.3, 132.1, 131.6, 128.6, 127.0, 80.4, 28.7; IR (KBr mull) 3358, 3010, 2983, 1736, 1508, 1475 cm−1. A portion was recrystallized (ethyl acetate) for analysis. Anal. Calcd. for C12H14Cl2N2O2: C, 49.84; H, 4.88; Cl, 24.52; N, 9.69. Found: C, 49.59; H, 4.71; Cl, 24.43; N, 9.57.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1)=O.[H][H]>C(O)(=O)C.Cl(O)(=O)(=O)=O.[Pd].[C]>[CH3:1][C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1
Reactant: O=Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3

Procedure:
A solution of 5.0 g of 5-formyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole (Example 69) in 120 ml of acetic acid and 10 ml of perchloric acid was hydrogenated in the presence of 1.5 g of 10% Pd/carbon catalyst at 25°, 50 psi hydrogen pressure, overnight. The mixture was filtered and the solvent was evaporated to leave the product, 5-methyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13]>[OH-].[Na+].C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:14])[CH:11]([CH3:15])[CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
4-Bromo-benzaldehyde (available from Aldrich, 10.0 g, 54.3 mmol) was added to a solution of 3-methyl-butan-2-one (available from Aldrich, 4.7 g, 54.7 mmol) in 10 mL of 10% NaOH(aq) and 20 mL of ethanol. After stirring at room temperature for 3 h, the reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (3×20 mL). The organic layer was then washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (95:5 hexane/ethyl acetate) yielded the title compound (7.98 g, 58% yield) as a light yellow oil:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[CH3:27][NH:28][CH3:29].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:28]([CH3:29])[CH3:27])[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Product: CN(C)C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 170.2 %

Procedure:
Using a similar procedure to that described in Example 27, N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and dimethylamine (2.0 M solution, 2.7 mL, 5.4 mmol) yielded, after treatment with HCl, 100 mg of the title compound as a hydrochloride salt.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[CH:7]=[CH:8][N:9]3[CH:15]=[CH:14][CH:13]=[C:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1)#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:17]=[CH:16][C:6]2[CH:7]=[CH:8][N:9]3[CH:15]=[CH:14][CH:13]=[C:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1)(=[O:21])[NH2:2]
Reactant: CC(=O)O
Reactant: N#Cc1ccc2ccn3cccc3c(=O)c2c1
Agent: Cl
Product: NC(=O)c1ccc2ccn3cccc3c(=O)c2c1
Temperature: 25 °C

Procedure:
9-Cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid is refluxed for 2 hours. It is then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution is left to cool to room temperature and filtered to afford 9-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[N:9]=1>CO.O>[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[NH:10][N:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(Br)c3cc(N)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cnc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
K2CO3 (0.233 g, 1.68 mmol) was added to a solution of 3-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.206 g, 0.56 mmol) in MeOH/H2O (3:1, 8 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The resulting residue was taken up in water (10 mL), and the pH was adjusted to about 7 with acetic acid. The aqueous layer was extracted with ethyl acetate (3×50 mL) The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:4) to give 3-bromo-1H-pyrazolo[3,4-b]pyridin-5-amine (0.036 g, 30%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:12]1[CH:11]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1
Reactant: O=c1cc(C2CC2)nc(-c2cccc(Cl)c2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
A 250-mL round bottom flask was charged with 2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4(3H)-one (2.46 g, 9.97 mmol). POCl3 (11.0 mL, 120 mmol) was cautiously added at 0° C. The resulting mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) treated with aqueous sodium bicarbonate until the pH˜8. The aqueous layer was extracted with dichloromethane (4×25 mL). The combined organic extract was washed the saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography using hexanes/dichloromethane (3:1) as eluent to afford the title compound (2.55 g, 96%) as a white solid. MW=265.14. 1H NMR (CDCl3, 500 MHz) δ 8.38 (t, J=1.5 Hz, 1H), 8.28 (dt, J=8.0, 1.5 Hz, 1H), 7.44 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12 (s, 1H), 2.04-1.97 (m, 1H), 1.33-1.27 (m, 2H), 1.18-1.13 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
Following procedure A, 3,4-difluoronitrobenzene (401 mg, 2.52 mmol, 1.00 eq) and 4-tert-butylphenol (477 mg, 3.18 mmol, 1.26 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (522 mg, 3.78 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 19 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as colourless oil (722 mg, 2.52 mmol, 99% yield). Rf=0.54 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C16H17FNO3+ [M+H]+ 290.1187. found: 290.1194. 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=10.3, 2.7 Hz, 1H, aromatic H), 7.96 (ddd, J=9.1, 2.7, 1.5 Hz, 1H, aromatic H), 7.49-7.38 (m, 2H, aromatic H), 7.09-6.99 (m, 2H, aromatic H), 6.96 (dd, J=9.1, 8.0 Hz, 1H, aromatic H), 1.35 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 153.35, 152.23, 151.93, 151.82, 150.84, 148.70, 142.40, 142.33, 127.29, 120.68, 120.64, 119.38, 117.73, 117.71, 113.28, 113.05, 34.65, 31.54.
Reaction SMILES: COC1C=CC=CC=1C([O:7][C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11](=[O:19])(=[O:18])[N:10]([CH3:20])[C:9]=1[C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[N:23][N:22]=1)=O.C[O-].[Na+]>>[OH:7][C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11](=[O:19])(=[O:18])[N:10]([CH3:20])[C:9]=1[C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[N:23][N:22]=1
Reactant: COc1ccccc1C(=O)OC1=C(c2nnc(-c3ccccc3OC)o2)N(C)S(=O)(=O)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Product: COc1ccccc1-c1nnc(C2=C(O)c3ccccc3S(=O)(=O)N2C)o1
Yield: 94 %

Procedure:
The ester derivative of (a) was treated with sodium methoxide according to the procedure of Example 4 to give the title compound in 94% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:32][CH3:33]>>[CH2:32]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21])[CH3:33]
Reactant: CCI
Reactant: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Product: CCN(Cc1ccc(C)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.88,(1H, d), 7.76,(1H, s), 7.56-7.45,(5H, m), 7.25-7.13,(4H,m), 4.66-4.48,(2H, m), 3.37-3.18,(2H, m), 2.55,(3H, s), 2.31-2.28,(6H, m), 1.05,(3H, b). LCMS; retention time 3.70 min, MH+ 426.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17]C)=[O:16].O[Li].O.Cl>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)[C@@H]1CCCN1c1nc2ccccc2o1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.66 G (S)-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride salt and 1.15 mL of 2-chlorobenzoxazole in 6 mL CH2Cl2 was subjected to microwave heating at 120° C. for 0.5 h. Solvent was evaporated. Purification by chromatography (SiO2, EtOAc/heptane) provided 2.283 g (93% yield) of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester as a waxy white solid, m/z 247.16 (MH+). A mixture of 2.0 g of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester and 1.02 G LiOH H2O in 15 mL MeOH and 15 mL water was stirred overnight at room temperature. The reaction was acidified with 1N HCl, was extracted three times with MeOH/CH2Cl2, was dried over Na2SO4 and was evaporated to provide the title compound. m/z 233.17 (MH+).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)OC1.CCOCC>C(O)C.Cl>[ClH:1].[ClH:1].[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:4]2[C:5]=1[C:6]([NH2:8])=[N:7][C:17]1([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[NH:3]2
Reactant: N=C(N)c1c(N)cccc1F
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC1=NC2(CCNCC2)Nc2cccc(F)c21
Yield: 169.3 %

Procedure:
To a solution of 2-amino-6-fluorobenzamidine dihydrochloride (Example C, 226 mg, 1 mmol) and 4-piperidone ethylene ketal (143 mg, 1 mmol) in dry ethanol (10 ml) was added IN HCl in ether (1 ml, 1 mmol) and the resulting mixture was heated at reflux for 36 h. The solid which separated on cooling was collected by filtration and recrystallised from ethanol to give the title compound (260 mg) as yellow crystals, m.p. 305°-307° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution (10 mL) of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.14 g) in methanol was added sodium borohydride (0.011 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.09 g, 66%).