Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:13])=[CH:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]2[CH2:25][CH3:26])=[CH:17][C:16]=1[F:31]>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:13])=[CH:5][C:6]=1[CH:7]1[NH:8][CH2:9][CH2:10][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]3[CH2:25][CH3:26])=[CH:17][C:16]=2[F:31])[CH2:12]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1cc(C2CNCCN2)c(C)s1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(C)sc4C)C3)cc21

Procedure:
A mixture of 2.35 g of 2-(2,5-dimethyl-3-thienyl)piperazine and 1.076 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was heated for 48 hours, then cooled and filtered. The filtrate was evaporated under reduced pressure and the residue triturated with chloroform:methanol (9:1),. giving mg of the desired product, mp 248°-250° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Br[CH2:27][C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>>[Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:27][C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(c1ccccc1)C2
Reactant: C[Si](C)(C)C#CCBr
Product: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2

Procedure:
Reaction of ethyl (6,7-dibromo-1-oxo-2-phenyl-5-indanyloxy)acetate with 1-bromo-3-(trimethylsilyl)-2propyne according to the procedure of Example 1, STEP (b), affords the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:15](=[O:16])[O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(SCCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCSc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of compound 1-HCl (0.466 g) in CH2Cl2 (20 mL) cooled to ˜0° C. was added methyl chloroformate (1.1 eq.) and triethylamine (2.5 eq.). The reaction mixture was stirred for 2 hours at 0° C. and washed with 1N HCl, and sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 7 as white solid with a yield of 480 mg, 98%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:3]=1[C:22]#[N:23].[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27]>>[NH2:23][C:22]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([C:30]([O:32][CH3:33])=[O:31])[N:1]=[C:2]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:3]=12
Reactant: CN(C)c1ccc(-c2nn(-c3ccccc3)c(N)c2C#N)cc1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1nc2c(c(-c3ccc(N(C)C)cc3)nn2-c2ccccc2)c(N)c1C(=O)OC

Procedure:
Using 1.57 mg (5 mmol) of 5-amino-3-(p-dimethylaminophenyl)-1-phenylpyrazole-4-carbonitrile [see Chem. Ber., 99, 3492 (1966)] and 0.85 g (6 mmol) of dimethyl acetylenedicarboxylate, the entitled product having a melting point of 207° to 208° C. was obtained in the same manner as in Example 2-(2).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])[CH2:4][CH2:3]1.[NH2:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22](O)=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22]([NH:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:23]
Reactant: Cc1cc(F)c(C(=O)O)cc1N
Reactant: CN1CCN(c2ccccc2CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising (2-(4-methylpiperazin-1-yl)phenyl)methanamine (413 mg, 2.010 mmol) and 5-amino-2-fluoro-4-methylbenzoic acid (step 2) (340 mg, 2.010 mmol) in DMF (3 ml) was treated with DIPEA (0.351 ml, 2.010 mmol) followed by HATU (764 mg, 2.010 mmol) and stirred at 25° C. for 24 hrs. The mixture was partitioned between water and EtOAc. The organic portion was washed with sat. aq. NaHCO3, 0.5 M LiCl and brine (each back extracted with EtOAc). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness to give a pink oil. Purification by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].C(=O)([O-])[O-].[K+].[K+]>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.C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(B(O)O)cc1C(F)(F)F
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 26.5 %

Procedure:
A stirred mixture 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (152 mg, 0.76 mmol), 4-methoxy-3-trifluoromethylphenylboronic acid (332 mg,1.51 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 10 mol %), potassium carbonate (418 mg, 3.03 mmol) and THF (5 ml) was degassed under a stream of nitrogen before heating in the Smith Creator microwave at 150° C. for 10 minutes. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give a dark brown oil. Mixture was flash chromatographed over silica (10 g Combiflash cartridge, 7:3 heptane/ethyl acetate to 1:1 heptane/ethyl acetate) to afford 68 mg of 4-amino-6-(4-methoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile as an orange solid. 1H NMR (DMSO) δ 8.25 (d, 1H), 8.18 (m, 2H), 7.62 (s, 2H), 7.46 (d, 1H), 3.99 (s, 3H). MS m/z 339.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].Cl[CH2:13][CH:14]=O>O>[CH3:10][C:8]1[N:9]2[CH:13]=[CH:14][N:1]=[C:2]2[C:3]([C:4]#[N:5])=[C:6]([CH3:11])[CH:7]=1
Reactant: Cc1cc(C)c(C#N)c(N)n1
Reactant: O=CCCl
Solvent: O
Product: Cc1cc(C)n2ccnc2c1C#N
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of compound 2-amino-4,6-dimethylnicotinonitrile (1 equiv.) in water was added chloroacetaldehyde (55% aq. solution) (1.2 equiv.) and reaction was heated at 80° C. for 16 h. On completion, it was quenched by 1N NaOH till pH 8. Solid precipitated was filtered and vacuum dried to afford the title compound (75% yield).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[H][H]>>[CH3:8][C@H:7]1[CH2:9][C:10](=[O:11])[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)CCO
Product: CC(C)[C@@H]1CC[C@@H](C)CC1=O

Procedure:
In another embodiment of the present invention, the present invention provides a process for producing menthol in good yields which comprises dehydrogenating citronellol in a reaction system containing a catalyst at a temperature of about 150° to about 260° C in an atmosphere of hydrogen under a pressure of 0 to about 5 kg/cm2.G to produce menthone, and then, in the same reaction system without separating the catalyst or adding additional catalyst, hydrogenating the menthone produced by decreasing the temperature to about 110° to about 130° C and increasing the hydrogen pressure to about 10 to about 50 kg/cm2.G to produce menthol.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[H-].[Na+].[Br:26]Br>O1CCCC1.ClCCl>[C:1]([C:4]([Br:26])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(CCCCCCCOC1CCCCO1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CCCCCCCOC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-acetyl-9-tetrahydropyranyloxy-nonanoate (20 g) in dry tetrahydrofuran (100 ml) was added dropwise to a stirred suspension of sodium hydride (2.01 g of 80% oil dispersion) in dry tetrahydrofuran (50 ml), under nitrogen. The mixture was warmed to reflux for 10 minutes. The clear solution was allowed to cool to room temperature then a solution of bromine (3.15 ml) in dry dichloromethane (50 mls) was added rapidly. After stirring for 30 minutes, during which time a yellow precipitate was formed, the mixture was partitioned between water and ether. The ether solution was washed with brine, dried and evaporated in vacuo at low temperature (<30° C.). The ethyl 2-acetyl-2-bromo-9-tetrahydropyranyloxy-nonanoate was obtained as a dark yellow oil (27.1 g.) which still contained a small amount of solvent.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:44])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41](=[O:43])[CH3:42])=[N:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:10](=[O:44])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41](=[O:43])[CH3:42])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (900 mg, 1.550 mmol) and triethylsilane (0.495 mL, 3.10 mmol) in DCM (14 mL) was treated with TFA (7.16 mL, 93 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc and the combined organics were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-10% MeOH/DCM) to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. For C17H18N6O2 [M+1]+ 339. found 339. 1H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.71 (s, 1H), 8.99 (s, 1H), 8.94 (s, 1H), 7.80-7.72 (br s, 1H), 7.50 (s, 1H), 7.36-7.29 (m, 4H), 7.26-7.19 (m, 1H), 4.91-4.81 (m, 1H), 2.09 (s, 3H), 1.39 (d, J=6.9, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)=O.C(N(CC)CC)C>C(#N)C>[CH2:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[N:5]=[C:3]([NH:2][CH3:1])[S:4][C:8]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: O=C(c1ccc2c(c1)CCC2)C(Br)c1cccnc1
Reactant: CNC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc(-c2ccc3c(c2)CCC3)c(-c2cccnc2)s1
Reaction time: 2 h
Yield: 80 %

Procedure:
In 40 ml of acetonitrile was dissolved 661 mg. of N-methyl thiourea. In the solution was suspended 2.9 g of 2-bromo-1-(5-indanyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added dropwise slowly 1 ml of triethylamine. The mixture was then stirred for 2 hours at refluxing temperature, followed by being left standing for cooling. The solvent was then evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and, then, the solvent was evaporated off. Recrystallization was conducted from ethyl acetate-isopropylether afforded 1.8 g (80%) of 4-(5-indanyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole, m.p. 169°-170° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])NC(C(=O)N)C)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[NH2:39][C@H:40]([C:44]([NH2:46])=[O:45])[CH:41]([CH3:43])[CH3:42].C(C(NC(C1C=CC2C(=CC=C(C3N(C4CCCCC4)C4C=CC(C(O)=O)=CC=4N=3)C=2)N=1)=O)C)(=O)N>>[C:44]([CH:40]([NH:39][C:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:9]4[CH:37]=[CH:38][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=1)=[O:30])[CH:41]([CH3:43])[CH3:42])(=[O:45])[NH2:46]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Agent: CC(NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1)C(N)=O
Product: CC(C)C(NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1)C(N)=O

Procedure:
The title compound (5 mg yield) was prepared as described for Compound 497a using L-valinamide in place of L-alaninamide, and hydrolyzed as described for Compound 497.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH3:18])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].CN(C)C1C=CC=CC=1>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:18])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1C)C(=O)CBr
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1C)c1csc(N)n1
Yield: 45.9 %

Procedure:
Ethyl 4-bromo-(Z)-2-(trans-2-methylcyclohexyl-oxyimino)-3-oxobutyrate (2.5 g) was treated with thiourea (0.57 g) and N,N-dimethylaniline (0.95 ml) as described in Example 4d to give the title compound as a yellow gum (1.07 g) after silica gel chromatography. (Found: M+, 311.1297. C14H21N3O3S requires M, 311.1305); νmax (CH2Cl2) 3475, 3380, 1735, 1600 and 1525 cm-1 ; δH (CDCl3) 0.98 (3H, d, J 6 Hz), 1.35 (3H, t, J 7 Hz), ca 1.1-2.4 (9H, m), 3.84 (1H, m), 4.40 (2H, q, J 7 Hz), 5.88 (2H, broad s), 6.71 (1H, s).
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=1)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:32]3[CH:44]=[CH:45][CH:46]=[C:30]([F:29])[CH:31]=3)=[CH:40][CH:39]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccc(OCc2cccc(F)c2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
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: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3cccc(F)c3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 64.9 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0443 g, 0.097 mmol), (4-((3-fluorobenzyl)oxy)phenyl)boronic acid (0.036 g, 0.146 mmol) and 2M Na2CO3 (0.122 ml, 0.243 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.011 g, 9.73 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110 C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0361 g, 0.063 mmol, 64.3% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.39 (dt, J=5.8, 7.9 Hz, 1H), 7.24-7.27 (m, 1H), 7.22 (dd, J=2.1, 9.5 Hz, 1H), 7.17-7.20 (m, 1H), 7.02-7.10 (m, 4H), 6.03 (br. s., 1H), 5.12-5.20 (m, 2H), 4.23-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.7 Hz, 1H), 3.06-3.28 (m, 1H), 2.85 (br. s., 1H), 2.65 (br. s., 3H), 2.26 (br. s., 3H), 1.96-2.11 (m, 1H), 1.27 (t, J=7.1 Hz, 4H), 1.20 (s, 9H), 0.90 (br.s., 3H), 0.66 (br. s., 3H). 5H of piperidine were not resolved. LCMS (M+H)=577.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.N1CCNCC1>O1CCCC1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:3]=2[C:2]([Cl:1])=[N:8]1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Reactant: BrCc1ccccc1Br
Agent: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C(=O)C(Cc2ccccc2Br)N=C(Cl)c2cc(Cl)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
(E)-5,7-Dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (400 mg, 1.65 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under a nitrogen atmosphere, cooled to −78° C., then a 1 M solution of potassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes before a solution of the 2-bromobenzyl bromide (411 mg, 1.65 mmol) in tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at −78° C. for 20 minutes then the cooling bath removed and the mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 18 hours. piperazine (283 mg, 3.29 mmol) was added to remove excess 2-bromobenzyl bromide and the mixture was stirred at ambient temperature for 30 minutes, diluted with ethyl acetate, and washed with cold 1 M aqueous hydrogen chloride (2×40 mL). The organic layers were dried with sodium sulfate, decanted and concentrated in vacuo to approximately 20 mL of a red liquid. The product was purified on a short pad of silica gel eluting with 100 mL of ethyl acetate:hexanes (1:2) to yield (E)-3-(2-bromobenzyl)-5,7-dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.44 g, 65%). 1H NMR (300 MHz, CDCl3) δ 3.40 (s, 3H) 3.75 (m, 2H), 4.15 (m, 1H), 7.05-7.55 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (2.072 g.) and hydantoin (1.50 g.) in water (15 ml) was heated to 70° to give a clear solution. To this was added monoethanolamine (1.38 g.) and the magnetically stirred mixture was heated (90°-92°, bath temperature) for 4 hours. Within 10 minutes crystallization occurred. The product was allowed to cool to room temperature and was stored overnight. After immersing in an ice-bath, the mixture was acidified with ECl, refrigerated 5 hours, filtered, washed with cold (-10°) 1:1 methanol-water and dried. The title compound was obtained as a pale brown solid: 2.776 g, m.p. 300°-310°. (Trituration with hot absolute ethanol gave a pale brown solid in ca 65% recovery, m.p. 320° decomp.)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28](Cl)(=[O:30])=[O:29])=[CH:23][CH:22]=1>ClCCl>[C:24]1([CH2:27][S:28]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution/suspension of 3-pyrrolidinyl-carbamic acid, 1,1-dimethylethyl ester (0.5 g) and triethylamine (0.38 ml) in dichloromethane (30 ml) at 0° C. was added benzenemethanesulfonyl chloride (0.51 g). The mixture was stirred at 0° C. for 30 minutes then stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (20 ml) washed with water, saturated aq. NaHCO3(aq), dried (MgSO4) and concentrated in vacuo to give the sub-title compound (0.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][CH2:15][CH2:16][C:17](Cl)=[S:18]>>[CH3:14][CH2:15][CH2:16][C:17]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1)=[S:18]
Reactant: CCCC(=S)Cl
Reactant: Nc1cccc(-n2nnnc2S)c1
Product: CCCC(=S)Nc1cccc(-n2nnnc2S)c1

Procedure:
This compound was prepared from 1-(m-aminophenyl)-5-mercaptotetrazole and 3-methylthiopropionyl chloride [A. Mooradian et al., J. Am. Chem. Soc. 71, 3372 (1949)] according to the same reaction scheme as the one described hereinabove for compound 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:35][CH3:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1.[NH2:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46])[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:35][CH3:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1
Reactant: CCOC(=O)CCN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Reactant: CCC[C@H](N)CCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CCC(=O)OCC)cc1OC
Yield: 28.9 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (2.7 g) (S)-3-aminohexan-1-ol (1.6 g). The sub-title compound (670 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.93 (1H, s), 6.86 (1H, d), 6.76 (1H, d), 4.80-4.65 (3H, m), 4.09 (2H, q), 3.88 (3H, s), 3.65 (2H, s), 3.50 (2H, s), 3.42-3.37 (1H, m), 3.24 (1H, ddd), 2.77 (2H, t), 2.46-2.41 (4H, m), 2.02 (3H, s), 1.82-1.72 (1H, m), 1.42-1.29 (1H, m), 1.26-1.19 (5H, m), 1.07-0.96 (5H, m), 0.74 (3H, t).