Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO.O>[C:13]1([C:12]#[C:11][C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([OH:19])=[O:3])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncc(C#Cc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
To a solution of 5-phenylethynyl-nicotinic acid ethyl ester (1.17 g, 4.64 mmol) in methanol (10 mL) was added 5 N aqueous sodium hydroxide (2 mL, 10 mmol). The mixture was stirred at room temperature for approximately 20 h, before the reaction mixture was diluted with water (3 mL) and extracted with hexanes/EtOAc (95/5) (10 mL). The aqueous solution was acidified with 1 N HCl to pH 4. The white precipitate that formed was collected by filtration, washed with water (2 mL), and dried under vacuum to provide the title compound as a white solid (987 mg, yield 95%). 1H NMR (300 MHz, d6-DMSO) δ 9.02 (d, J=1.8 Hz, 1H), 8.94 (d, J=2.4 Hz, 1H), 8.34 (dd, J=1.8, 2.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.48-7.44 (m, 3H); ESI-MS m/z 223.9 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH3:14])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:13][CH3:14])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([Cl:23])=[O:5]
Reactant: CCC(C)C(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(C)C(C(=O)Cl)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 3-methyl-2-phenylvaleric acid (1.23 g; 6.2 mmol) and a catalytic amount of dry dimethylformamide (ca. 20 μL) in 5 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (4.8 mL of 2.0 M solution in methylene chloride) dropwise. After 45 minutes, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:34])=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-oxo-3-phenyl-propyl)-phenyl]-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-3-[4-(3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-1 -phenyl-propan-1-one trifluoroacetate as a white powder; MS: 450 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)=[N:12]1)[CH2:8]2.B(I)(I)I.O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:12]1)[CH2:8]2
Reactant: COc1ccc(C2=NC(=C3C4CC5CC(C4)CC3C5)c3ccccc3O2)cc1
Agent: IB(I)I
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(C2=NC(=C3C4CC5CC(C4)CC3C5)c3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6 mmol 4-adamantylidene-2-(4'-methoxyphenyl)-4H-1,3-benzoxazine in 20 ml absolute methylene chloride is added dropwise to a solution of 12 mmol boron triiodide while stirring at -25° C. with the exclusion of air and water. The mixture is heated to room temperature within one hour and stirred for a further 4 hours. After admixing with 50 ml water the organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation. The oily residue is separated by column chromatography (silica gel: ethyl acetate/petroleum ether 1:3).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19](N(OC)C)=[O:20])#[N:2].[CH3:25][Mg]Br.CCOCC>O1CCCC1>[C:19]([C:4]1[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6]2[C:11]([C:3]=1[C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:20])[CH3:25]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-cyano-1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (90 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added 3.0 M methylmagnesium bromide in ether (0.93 mL, 2.8 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-15% EtOAc/hexane) to give the desired product (43 mg, 56%). LCMS calculated for C17H12FN2O(M+H)+: m/z=279.1. Found: 279.0.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]4)=[CH:18][C:17]=3F)=[N:13][C:12]=2[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C(Cl)=O)=CC=1)=O>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH2:26]4)=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(Cc2ccc(-c3nc4cc(Cc5ccccc5)ccc4o3)c(F)c2)C1
Agent: O=Cc1ccc(C(=O)Cl)cc1
Product: O=C(O)C1CN(Cc2ccc(-c3nc4cc(Cc5ccccc5)ccc4o3)cc2)C1

Procedure:
Synthesized in a manner analogous to 1-((4-(5-benzylbenzo[d]oxazol-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid, except employing 4-formylbenzoyl chloride. white solid [hS1P1 EC50=364 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (d, J=8.0 Hz, 2H), 7.61-7.72 (m, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.25-7.35 (m, 5H), 7.15-7.24 (m, 1H), 4.08 (s, 2H), 3.64 (s, 2H), 3.19-3.48 (m, 5H). MS (ESI) m/z: Calculated: 398.2; Observed: 399.2 (M++1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)=[CH:24][N:23]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cn2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
8.0 mg (0.31 mmol) of 95% sodium hydride were added at 0° C. to a solution of 65 mg (0.28 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 3.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 76 mg (0.28 mmol) 2-chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at r.t overnight. After addition of 6 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1. The residue was purified by chromatography on silica (eluent: ethyl acetate) to give 91 mg (70%) of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([O:12][C:13]1[NH:14][N:15]=[C:16]([CH3:27])[C:17]=1[N:18]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]1)[CH3:11]>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:27])[C:17]([N:18]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]3)=[C:13]2[O:12][C:10]=1[CH3:11]
Reactant: Cc1n[nH]c(OC(C)C(=O)c2ccc(Cl)cc2Cl)c1-n1ccc(C(F)(F)F)n1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1-n1ccc(C(F)(F)F)n1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
1-(2,4-Dichloro-phenyl)-2-(5′-methyl-3-trifluoromethyl-2′H-[1,4′]bipyrazolyl-3′-yloxy)-propan-1-one (150 mg, 0.346 mmol) is dissolved in 1,2-dichloroethane (1.39 ml) and titanium tetrachloride (0.046 ml, 0.416 mmol) is added; the reaction mixture is stirred at 85° C. under N2 for 3 hours. The reaction mixture is allowed to cool to RT and quenched with sat. ammonium chloride then added to a further 50 ml solution of ammonium chloride. The crude product is extracted with EtOAc (2×50 ml). The combined organics are washed with water, brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude product by ISCO combiflash chromatography, eluting with 0 to 100% (EtOAc/Iso-hexane) on a 24 g SiO2-column afford the title compound as a solid MS: m/z 415.25 [M+H]+; 1H NMR (400.13 MHz (CDCl3) δ 7.69 (1H, dd), 7.60 (1H, d), 7.54 (1H, d), 7.43 (1H, dd), 6.72 (1H, d), 2.37 (3H, s), 2.35 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[C:13]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.28 mmol) in methanol (20 ml) was added a solution of sodium hydroxide (44 mg, 1.10 mmol) in water (3 ml). The reaction was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo to give a residue, which was dissolved in water (20 ml) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (101 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](=O)[CH3:18])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[CH:17]([NH2:26])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc2cccnc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 133.3 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethanone (0.24 g, 0.94 mmol) and ammonium acetate (0.73 g, 9.5 mmol) in methanol (3.0 mL) and acetonitrile (3.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.18 g, 2.8 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was then cooled to room temperature and quenched with saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the crude amine (0.32 g), which was used directly in the next step. LCMS calculated for C15H15FN3(M+H)+: m/z=256.1. Found: 256.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:37]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:38])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CC(C)N=C=O
Product: Cc1c(N2CCN(C(=O)NC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure P using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and isopropylisocyanate to give 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N-isopropylpiperazine-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 1.07 (d, J=6.8 Hz, 6H), 2.08 (br s, 3H), 3.04-3.06 (m, 4H), 3.24 (br s, 4H), 3.46-3.50 (m, 4H), 3.68-3.70 (m, 4H), 3.78 (m, 1H), 6.26 (d, J=7.6 Hz, 1H), 6.49 (br s, 1H), 7.12-7.18 (m, 1H), 7.28-7.32 (m, 1H), 7.53 (s, 1H), 7.78 (d, J=2 Hz, 1H), 8.35 (s, 1H). Mass Spectrum (ESI) m/e=526.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C>[O:20]([C:18]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc2cnccc2s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1nc2cnccc2s1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.1 %

Procedure:
To a mixture of 2-aminothiazolo[4,5-c]pyridine (302 mg, 2 mmoles) and pyridine (0.2 ml) in 5 ml of DMF was added phenyl chloroformate (400 mg, 2.5 mmoles), and the mixture was stirred at room temperature for 1.5 days. The crystalline precipitate was collected by filtration to afford 386 mg (71%) of the title compound. Mp. >290° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[NH:28][N:27]=[N:26][N:25]=1)[C:20]([O:22][CH3:23])=[O:21].N1C(CC(OCC)=O)=NN=N1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1nnn[nH]1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCOC(=O)Cc1nnn[nH]1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1nnn[nH]1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(1H-tetrazol-5-yl)acetate (prepared from ethyl 1H-tetrazole-5-acetate [CAS 173367-99-2] using procedures essentially the same as those described in S. Kukolja, J. Med. Chem., 1985, 28, 1886-1896), the title compound was prepared as a solid. The reaction was product was purified by tituration using EtOAc/hexanes.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:24]([CH3:35])[CH:23]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of ethyl [4-({butyl[6-(4-methoxyphenyl)-5-methylpyrimidin-4-yl]amino}methyl)-2-methylphenoxy]acetate (62 mg, 0.13 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M sodium hydroxide (1 mL). After shaking for 1 h at room temperature the solvent was removed. The residue was then acidified with 0.5M HCl aq. (20 mL), before extraction into EtOAc (2×25 mL). The organic solution was washed with brine, dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow solid (58 mg).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[NH:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@@H:16]([OH:26])[C@H:15]([O:27][CH2:28][CH2:29][S:30][CH3:31])[C:14]=3[CH:13]=[CH:12][N:11]2[C:32]=1[CH3:33]>O.CO>[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[NH:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@@H:16]([OH:26])[C@H:15]([O:27][CH2:28][CH2:29][S:30]([CH3:31])=[O:2])[C:14]=3[CH:13]=[CH:12][N:11]2[C:32]=1[CH3:33]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc2c3c(ccn2c1C)[C@@H](OCCS(C)=O)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
130 mg of sodium metaperiodate, dissolved in 1 ml of water, is added to a solution of 200 mg of (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h]-[1,7]naphthyridine in 5 ml of methanol. After two hours stirring at room temperature, 50 ml of water are added. The mixture is extracted three times with dichloromethane, the organic phases are collectively washed with water and dried over sodium sulphate. The solvent is removed in vacuo and the remaining residue is purified by chromatography on silica gel (eluent: ethylacetate/methanol=10/1). 100 mg of the title compound of m.p. 105-106° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>CC1C=CC=CC=1C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3F)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)C2(CC(c3ccccc3F)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 90 °C
Yield: 5.2 %

Procedure:
Pd(PPh3)4 (3.84 mg, 0.1 mmol) was added to the solution of 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 0.1 mmol) and 3-cyanophenylboronic acid (18.3 mg, 0.12 mmol) in dimethyl-benzene (6.6 mL) and an aqueous solution of Na2CO3 (2 M, 0.23 mL). The mixture was heated at 90° C. in an oil bath overnight. The mixture was concentrated to give the crude product which was purified by prepared HPLC to give the desired product 3-(2′-amino-2-(2-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.2 mg, 0.5%). 1H-NMR (MeOD): 2.5 (d, 1H), 3.30 (t, 1H), 3.5 (s, 3H), 6.35 (d, 1H), 7.2 (t, 2H), 7.3 (d, 2H), 7.65 (t, 3H), 7.75 (s, 2H), 7.85 (d, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH:16]=O)=[CH:6]1)(=[O:4])=[O:3].C([CH2:25][NH2:26])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][S:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][NH:26][CH3:25])=[CH:6]1)(=[O:4])=[O:3]
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)n(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution (5 mL) of 1-(methylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg) in tetrahydrofuran was added benzylmethylamine (117 mg), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (435 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), 10% palladium carbon (50% water-containing product, 200 mg) and 1 mol/l hydrochloric acid (1 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated; and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→ethyl acetate) to give the title compound as a colorless oil (yield 62 mg, 37%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@H:27]1[CH2:36][C@@H:35]2[N:30]([C:31](=[O:52])/[C:32](=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)/[CH2:33][CH2:34]2)[C@H:29]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)[CH2:28]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[F:59][C:56]1[CH:57]=[CH:58][C:53]([C@@H:29]2[CH2:28][C@@H:27]([OH:26])[CH2:36][C@@H:35]3[N:30]2[C:31](=[O:52])/[C:32](=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=2)/[CH2:33][CH2:34]3)=[CH:54][CH:55]=1
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H](c4ccc(F)cc4)N3C2=O)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@@H]3C[C@H](O)C[C@@H](c4ccc(F)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
TBAF (1.0 M solution in THF, 1.15 mL) was added to a solution of (E)-(6S*,8S*,9aR*)-8-(tert-butyldimethylsilanyloxy)-6-(4-fluorophenyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one (330 mg) in THF (5.0 mL), and the reaction solution was stirred at room temperature overnight. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 232 mg of the title compound. The property values of the compound are as follows.