Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:8]3[C:12](=C)[CH:11]=[CH:10][CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)C>O1CCCC1>[C:1]12([C:8]3[CH2:12][CH:11]=[CH:10][CH:9]=3)[CH2:7][CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: C=C1C=CC=C1C12CCC(CC1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CCC(C23CCC(CC2)C3)=C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of norbornylfulvene (14.37 g, 90.8 mmol) dissolved in 100 mL tetrahydrofuran was cooled to 0° C. before LiAlH4 (5.00 g, 132 mmol) was added over 2 minutes. After stirring at room temperature for 17 hours, the reaction was cooled to 0° C. and 100 mL water were added dropwise over 1 hour. Then, 200 mL water/50 mL concentrated aqueous HCl and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The organic layers were dried over MgSO4, filtered, and rotavapped to provide the crude product as a light yellow oil in quantitative yield.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].N(OC(C)(C)C)=O.[CH3:18][S:19]SC>O1CCOCC1>[OH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[S:19][CH3:18]
Reactant: CSSC
Reactant: N#Cc1ccc(O)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: C1COCCO1
Product: CSc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-amino-4-hydroxybenzonitrile (1.00 g, 7.46 mmol) in dioxane (15 ml) was added t-butyl nitrite (1.12 ml, 14.9 mmol) and the resulting mixture was stirred under nitrogen at room temperature for 15 min. Dimethyl disulfide (5 ml) was then added and the resulting mixture was heated to 90° C. for 3 h. The reaction mixture was purified by flash column chromatography to afford the title compound. Mass spectrum (ESI) 164.1 (−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[CH2:55]([O:57][C:58](=[O:65])[C@H:59]([CH3:64])[CH2:60][C@H:61](N)[CH3:62])[CH3:56].C(N(CC)CC)C>CN(C=O)C>[CH2:55]([O:57][C:58](=[O:65])[C@H:59]([CH3:64])[CH2:60][C@@H:61]([CH3:26])[CH2:62][C:9](=[O:10])[CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:25])[CH3:56]
Reactant: CCOC(=O)[C@H](C)C[C@@H](C)N
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)C[C@@H](C)CC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester (100 mg, 0.29 mmol) in DMF (10 mL) is added HOBt (45 mg, 0.29 mmol) and EDCl (56 mg, 0.29 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4R)-4-amino-2-methyl-pentanoic acid ethyl ester trifluoroacetate (47 mg, 0.29 mmol) and triethylamine (89 mg, 0.87 mmol) is added and the mixture is stirred at room temperature for 5 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to give (2R,4R)-7-biphenyl-4-ylmethyl-2,4-dimethyl-6-oxo-nonanedioic acid 9-tert-butyl ester 1-ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][CH3:11])[CH:7]([C:12]#[N:13])[CH2:6]1)=[O:4].C(O)C.C(Cl)(Cl)[Cl:18]>O=[Pt]=O>[ClH:18].[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][CH3:11])[CH:7]([CH2:12][NH2:13])[CH2:6]1)=[O:4]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)C1CC(C#N)C(OC)C1
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)C1CC(CN)C(OC)C1
Product: Cl
Reaction time: 8 h

Procedure:
To a stirred solution of (1SR,3RS,4SR)-3-cyano-4-methoxy-cyclopentanecarboxylic acid methyl ester (595 mg) in ethanol/chloroform 5:1 (6 ml) was added PtO2 (60 mg). The reaction mixture was hydrogenated overnight. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to give (1SR,3RS,4SR)-3-aminomethyl-4-methoxy-cyclopentanecarboxylic acid methyl ester hydrochloride (704 mg) as white amorphous semisolid. MS 188.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C(Cl)Cl>[NH3:11].[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:29])[CH2:27][CH3:28])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC(CNc2ccccc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCCN(C(=O)OCc2ccccc2)C1)c1ccccc1
Product: N
Temperature: 0 °C

Procedure:
Et(iPr)2N (0.24 mL, 1.38 mmol) was added to a stirring solution of crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148) in CH2Cl2 (2.3 mL) under N2. The reaction was cooled to 0° C. in an ice bath, then propionyl chloride (0.22 mL, 2.53 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was then judged complete by TLC. It was concentrated in vacuo and EtOAc and 10% NaOH (aq) were added. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, and purified by automated silica gel chromatography with 96:2:2 Hexanes:CH2Cl2:2N NH3 in EtOH to obtain 3-[(phenyl-propionyl-amino)-methyl]-azepane-1-carboxylic acid benzyl ester (149) (0.3266 g) in 72% yield for two steps.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH:21]2[N:15]([N:16]([CH3:49])[C@@H:17]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41]CC4C=CC=CC=4)=[CH:37][CH:36]=3)[C:18](=[O:33])[N:19]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:20]2)[C:14](=[O:50])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.CCCCCC>C(O)(=O)C.Br>[CH2:1]([NH:8][C:9]([N:11]1[CH:21]2[N:15]([N:16]([CH3:49])[C@@H:17]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)[C:18](=[O:33])[N:19]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:20]2)[C:14](=[O:50])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)N(Cc2cccc3ccccc23)CC2N(C(=O)NCc3ccccc3)CCC(=O)N21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1[C@@H](Cc2ccc(O)cc2)C(=O)N(Cc2cccc3ccccc23)CC2N(C(=O)NCc3ccccc3)CCC(=O)N21
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
(2S)—N-benzyl-2-(4-(benzyloxy)benzyl)-1-methyl-4-(naphthalen-1-ylmethyl)-3,9-dioxooctahydropyrimido[1,2-b][1,2,5]triazepine-6(7H)-carboxamide (Compound 1-267) 33 mg (0.05 mmol) was dissolved in 25% HBr acetic acid solution 0.2 ml and the mixture was stirred at room temperature for 5 hr. Ether 1.2 ml and n-hexane 0.8 ml were added to the reaction mixture and the mixture was concentrated in vacuo. The precipitation was purified on silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound 7.3 mg (yield 25%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][NH:31][CH2:32]2)([O-:27])=[O:26].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][N:31]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:32]2)([O-:27])=[O:26]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 35.7 %

Procedure:
200 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 102 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.Br[CH2:29][C:30]([OH:32])=[O:31].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH2:26][O:27][CH2:29][C:30]([OH:32])=[O:31])[CH:13]=1
Reactant: O=C(O)CBr
Reactant: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(CO)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(COCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 530.1 %

Procedure:
A solution of (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol (640 mg, 1.65 mmol) and bromo-acetic acid (0.25 g, 1.82 mmol) in N,N′-dimethylformamide (5 mL) is treated with sodium hydride (60%, 0.28 g, 6.94 mmol) at −30° C. The mixture is allowed to warm to room temperature over 1 hour, stirred for an additional 1 hour and quenched with water. The mixture is diluted with water, and washed with ether. The aqueous phase is acidified to pH 3.8 and the resulting solid is filtered and dried to give (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzyloxy)-acetic acid [3.9 g, 53%, Example 56]. The filtrate is extracted with ethyl acetate, and the combined extracts are washed with water, dried over magnesium sulfate, and concentrated to afford additional quantity of (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzyloxy)-acetic acid (0.43 g, Example 56). LCMS: RT=2.43 minutes, MS: 446 (M+H). IC50=0.6 nM
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([C:11]1[C:12]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH3:29])[C:20]=2[CH3:30])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1)(O)=[O:9].[CH2:31]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]([CH3:45])[CH3:44])[CH:38]=1)[CH2:32][CH2:33][CH2:34][CH3:35].C1(C)C=CC=CC=1>CO>[CH3:44][N:43]([CH3:45])[C:39]1[CH:40]=[CH:41][C:42]([C:17]2([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][CH3:29])[C:20]=3[CH3:30])[C:12]3[C:11](=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8](=[O:9])[O:18]2)=[C:37]([O:36][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:38]=1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Reactant: CCCCCOc1cccc(N(C)C)c1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCOc1cc(N(C)C)ccc1C1(c2c(C)n(CC)c3ccccc23)OC(=O)c2cccnc21
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Into 75 ml of acetic anhydride, 9.2 g of (1-ethyl-2-methylindol-3-yl) (3-carboxypyridin-2-yl) ketone and 7050 g of 1-n-pentyloxy-3-dimethylaminobenzene were added, and the resultant mixture was stirred for 4 hours at 60° to 65° C. After cooling the reaction mixture to room temperature, the cooled reaction mixture was poured into 500 ml of ice water and the resultant mixture was treated with toluene and methanol by the same manner as in Synthetic Example 1. As a result, 11.9 g of the objective compound were obtained as pale blue crystals (melting point: 169° to 171° C.). The elementary analytical data of the product were as follows.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and benzyltriethylammonium chloride (189.1 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 655.2 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[NH2:14].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCOC(C)=O>ClCCl>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([NH:14][S:22]([CH3:21])(=[O:24])=[O:23])[CH:5]=[C:6]([C:10]([F:12])([F:11])[F:13])[CH:7]=1
Reactant: COc1c(N)cc(C(F)(F)F)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(F)(F)F)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
2-Methoxy-5-trifluoromethylbenzene-1,3-diamine (2.32 g, 11.3 mmol) was dissolved in 50 mL anhydrous dichloromethane. The solution was cooled to 0° C., and pyridine (3.64 mL, 45.0 mmol) and methane sulfonyl chloride (0.89 mL, 11.5 mmol) were added. The reaction was left to stir overnight at room temperature. A few more drops (˜0.1 mL) of methane sulfonyl chloride were added and the reaction stirred an extra day. Then 200 mL EtOAc, was added and the solution washed once with 100 mL water, twice with 15 mL saturated aqueous NH4Cl solution and finally with brine. The organic solution was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexanes eluent mixtures, providing N-(3-amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide (1870 mg, 6.58 mmol, 58% yield) as an orange solid.
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=C)[CH3:2].C[N+]1([O-])CC[O:27]CC1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=[O:27])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC(CCOCc1ccccc1)O[Si](CC)(CC)CC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)OC(CC=O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.0 g (31.2 mmol) of 4-Triethylsilyloxy-6-benzyloxy-1-hexene in 310 mL of tetrahydrofuran at 0°C. were added 4.38 g (37.4 mmol) of 4-methylmorpholine N-oxide, 6.24 mL (1.248 mmol) of osmium tetroxide (0.2M in benzene) and 45 mL of water and stirred overnight at room temperature. To the mixture at 0° C. were added 185 mL of water and 20.02 g (93.6 mmol) of sodium periodate and stirred at room temperature for 1 hour, followed by partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated for the next reaction. 1H NMR (CDCl3): δ 9.79 (t, J=2.4 Hz, 1H, CH═O), 7.35-7.31 (m, 5H, ArH), 4.51 (d, J=12.0 Hz, 1H, ArCH2O), 4.46 (d, J=12.0 Hz, 1H, ArCH2O), 4.40 (p, J=6.0 Hz, 1H, CH—O), 3.55 (m, 2H, CH2—O), 2.56 (m, 2H, CH2C═O), 1.85 (m, 2H, CH2), 0.94 (t, J=8.1 Hz, 9H, TES CH3), 0.59 (q, J=8.1 Hz, 6H, TES CH2). 13C NMR (CDCl3): δ 201.94, 138.14, 128.31, 127.60, 127.55, 72.99, 66.31, 65.49, 51.14, 37.71, 6.84, 4.88.
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=2)=[C:8]([F:23])[CH:7]=1)[NH2:2].[OH:25]/[CH:26]=[C:27](\[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)/[C:28](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:23][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][O:3][C:1]2[NH:2][CH:28]=[C:27]([CH2:32][C:33]3[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=3)[C:26](=[O:25])[N:24]=2)[CH:11]=[CH:10][C:9]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]=1
Reactant: COC(=O)/C(=C/O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C(F)(F)F)n4)c(F)c3)nc2=O)cn1
Temperature: 160 °C
Yield: 21.7 %

Procedure:
A mixture of 2-(3-fluoro-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}phenyl)ethyl imidocarbamate (44 mg, 0.089 mmol), methyl (2E)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (30.1 mg, 0.134 mmol), and K2CO3 (37.1 mg, 0.268 mmol) in NMP (15 mL) was heated with a microwave reactor at 160° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (10 mg, 21.63% yield). LCMS: rt=3.13 min, [M+H+]=518
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:26])([F:1])[F:25])[CH:4]=1)=[N:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: NCCc1ccncc1
Product: N#CNC(=NCCc1ccncc1)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.4 %

Procedure:
By following a procedure analogous to the one described in EXAMPLE 1b, N-(3,5-bis(trifluoromethyl)-phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg) was treated with 4-(2-aminoethyl)pyridine (1.15 mmol, 140.5 mg) to give 110 mg (27%) of the title product;
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[CH3:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1>C(O)CO.O>[Zn:2].[CH3:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1
Reactant: [Zn+2]
Agent: Cc1ccc(N)c(C(=O)O)c1
Agent: [Cl-]
Solvent: OCCO
Solvent: O
Product: [Zn]
Temperature: 130 °C
Reaction time: 2 h

Procedure:
27.3 g (0.2 mol) of zinc chloride was dissolved in 500 ml of ethylene glycol. To the solution was gradually added 60.4 g (0.4 mol) of 5-methyl-anthranilic acid. After the addition, the mixture was stirred for 2 hours at 130° C. and then dispersed in 3 liters of water. The dispersion was subjected to filtration and the precipitate was washed with water until the filtrate water reached neutrality. The precipitate was then dried at 90° C. to obtain about 40 g of white powder.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[F:17][C:18]([F:25])([F:24])[CH:19]([OH:23])[C:20]([OH:22])=[O:21].[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[F:17][C:18]([F:25])([F:24])[CH:19]([O:23][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])[C:20]([OH:22])=[O:21]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)C(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OC(C(=O)O)C(F)(F)F
Reaction time: 2 h
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, 50 mL of dehydrated THF, 5.56 g (55.0 mmol) of triethylamine and 305 mg (2.5 mmol) of dimethylaminopyridine were added to 7.20 g (50.0 mmol) of 3,3,3-trifluorolactic acid at a room temperature. Thereafter, 5.75 g (55.0 mmol) of methacrylic acid chloride was added dropwise over 10 min, and then the mixture was stirred for 2 hrs. After disappearance of the raw material was confirmed by TLC, an aqueous sodium bicarbonate solution was added to stop the reaction. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times. The organic layer thus obtained was washed with water, saturated brine each once, and dried by adding anhydrous sodium sulfate. Thereafter, the solvent was distilled off under a reduced pressure, and the resulting product was purified by column chromatography to give 3.71 g of 3,3,3-trifluoro-2-(methacryloyloxy)propionic acid represented by the following formula in the form of pale yellow oil (yield: 35%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:7]2.O.[NH2:37][NH2:38]>O1CCOCC1.C(OCC)(=O)C>[NH:37]([C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:7]2)[NH2:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Cl)nccc4cc3-c3ccccc3)cc2)CCC1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {1-[4-(8-chloro-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-4) (288 mg, 0.593 mmol) in 1,4-dioxane (4 mL) was added hydrazine monohydrate (286 mL, 5.93 mmol). The mixture was stirred at 100° C. for 1 h. The mixture was cooled to room temperature, suspended in ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl{1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) as an orange solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2.O>CS(C)=O>[O:17]1[CH2:2][C:11]21[CH:12]1[CH2:15][CH2:16][N:9]([CH2:14][CH2:13]1)[CH2:10]2
Reactant: O=C1CN2CCC1CC2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1CN2CCC1C1(CO1)C2
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2 mmol) and a dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen for 30 minutes. Quinuclidin-3-one (II) (7.05 g, 56.3 mmol) was then added as a solid portionwise, and the resulting mixture was stirred at 65–70° C. under nitrogen for 1 hour. The reaction mixture was cooled, water was added (200 ml), and the resulting solution was extracted with chloroform (3×200 ml). The chloroform extracts were combined, and back-extracted with water (4×200 ml). The chloroform layer was then dried (MgSO4), filtered, and evaporated under reduced pressure to afford spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (6.51 g, 46.8 mmol, 83%) as a clear, colorless liquid. To a stirred solution of spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (5.3 g, 38.1 mmol) in anhydrous tetrahydrofuran (100 ml) at 0° C. was added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38.1 ml, 38.1 mmol), and resulting solution was stirred at 0° C. under nitrogen for 30 minutes. Brine (100 ml) was added cautiously to the reaction solution, and the resulting aqueous mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (II) (4.3 g, 28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M−H]+, 15).