Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Li])CCC.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>O1CCCC1>[CH2:12]([C:4]1[S:3][C:2]([NH:1][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1)[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cc(CC)sc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate (Ber. 99, 94-100) (40 g, 0.2 mol) in dry tetrahydrofuran (150 ml) was stirred under nitrogen and cooled to -40° C. n-Butyl lithium (125 ml of 10.2% w/v solution in hexane, 0.2 mol) was added keeping the temperature below -30° C. The mixture was then stirred at -30° C. for a further 15 minutes. This solution was blown by nitrogen through an inverted "U" tube into a solution of o-fluoro-nitrobenzene (28 g, 0.2 mol) in dry tetrahydrofuran (100 ml) maintained at 15°-30° C. The mixture was stirred overnight. The resulting ink-blue solution was poured into three volumes of ice water, extracted with ether (3 × 500 ml), washed with water (2 × 500 ml), dried and then evaporated to dryness. The deep red oil was dissolved in ethanol (200 ml) and chilled overnight. Crystals of the title compound were filtered off and dried in vacuo at 50° C.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:22]/[O:23][C:24]([C:27]([O:29]CC2C=CC([N+]([O-])=O)=CC=2)=[O:28])([CH3:26])[CH3:25])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH3:16])[N:14]([S:17]([O-:20])(=[O:19])=[O:18])[C:13]2=[O:21])=[O:10])[N:7]=1>O.O1CCCC1.[Pd]>[Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:22]/[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH3:16])[N:14]([S:17]([O-:20])(=[O:19])=[O:18])[C:13]2=[O:21])=[O:10])[N:7]=1
Reactant: C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Yield: 32.9 %

Procedure:
115 mg (0.19 mmol) of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(p-nitro-benzyloxycarbonyl)-1-methylethoxy]imino]acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 40 ml of water/tetrahydrofuran (1:1) and the solution is hydrogenated for 12 hours over 300 ml of 10% palladium/carbon. The catalyst is filtered off and the solvent is evaporated under reduced pressure. The oil obtained is chromatographed (230-400 mesh, chloroform/methanol/n-propanol/water (4:6:1:4) as the solvent]. There are obtained 28.6 mg (33%) of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy]imino]acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:31]=[N:32][N:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:34]=34)[N:25]=2)[CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]4[CH:31]=[N:32][N:33]5[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:34]=45)[N:25]=3)[CH2:18]2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCC[C@@H](Nc3ccnc(-c4cnn5ccc(C#N)cc45)n3)C2)nc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 69.2 %

Procedure:
6-Chloronicotinonitrile (0.04 g, 0.29 mmol) and triethylamine (0.15 mL, 1.08 mmol) were added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 0.11 g, 0.24 mmol) in dichloromethane (3.3 mL) and the resulting mixture was stirred at 50° C. for 20 hours. The reaction mixture was then cooled to ambient temperature and dichloromethane and 4% aqueous sodium hydrogencarbonate solution were added. The organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography (200:1 to 60:1 chloroform/methanol) to give the title compound (0.07 g, 71%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[C:42]([O:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:48])=[CH:40][C:39]=2[CH3:49])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH:48][C:41]2[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:43][C:38]([CH:35]3[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[CH2:37][CH2:36]3)=[C:39]([CH3:49])[CH:40]=2)=[N:3][C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])(=[O:11])[CH3:10]
Reactant: CC(=O)c1c(Cl)nc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Product: CC(=O)c1c(Cl)nc(Nc2cc(C)c(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC(C)C)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 130 °C

Procedure:
To a solution of 1-(2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)ethanone (113 mg, 0.29 mmol) in EtOH (2 mL) was added tert-butyl-4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (203 mg, 0.58 mmol), and the reaction mixture was heated at 130° C. for 30 min The reaction was concentrated in vacuo, followed by purification by silica gel chromatography (EtOAC/Hexanes: 3/7) to afford Tert-butyl 4-(4-(5-acetyl-4-chloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-2-ylamino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate. MS (ES+): 700.3 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:17]([C:31]([NH2:33])=[O:32])[C:18]2[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=2)[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:17]([C:31]([NH2:33])=[O:32])[C:18]2[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=CC(=O)OCC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CCC(=O)OCC)cc1

Procedure:
An amount of 0.60 gm (1.34 m mol) of ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate was hydrogenated in 10 ml of ethanol on 0.20 gm of 10% palladium/charcoal at ambient temperature under 5 bar of hydrogen. The mixture was filtered and concentrated by evaporation in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:26][C:27]([NH2:29])=[O:28])=[C:14]([CH3:25])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>CCO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:13]1[C:12]2[C:16](=[CH:17][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:10][CH:11]=2)[N:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]=1[CH3:25]
Reactant: CCOC(=O)CCCOc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(CC(N)=O)c2ccc(OCCCC(=O)O)cc2n1Cc1ccccc1
Yield: 47 %

Procedure:
A solution of 100 mg (0.245 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]butanoic acid ethyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 1.5 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH/CH2Cl2 to give 44 mg (47% yield) or 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]butanoic acid, mp, 180-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:21][CH2:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][C:17]=4[CH:26]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:27][NH:28][C:29]([O:31][CH3:32])=[O:30].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:21][CH2:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]=4[CH:26]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:27][NH:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)C=C(C(=O)OC)CO4)n2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)C=C(C(=O)O)CO4)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a solution of methyl 6-[3-[4-chloro-3-[[(methoxycarbonyl)amino]methyl]phenyl]-1H-pyrazol-1-yl]-2H-1-benzopyran-3-carboxylate (i.e. the product of Step C) (100 mg, 0.22 mmol) in 1:1 tetrahydrofuran/water was added NaOH (35 mg 0.85 mmol) and the reaction mixture was stirred at ambient temperature for 6 hrs. After TLC analysis (50% ethyl acetate/pet ether) showed completion of reaction, the organic solvent was concentrated. The resultant aqueous solution was cooled to 0° C., acidified with 1N HCl and extracted three times with ethyl acetate. The combined the organic phases were washed with water, brine, dried over Na2SO4. The solvent was concentrated under vacuum to give compound number 24, a compound of the present invention, (70 mg, 73% yield) as solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=2)[CH2:3]1.C([Si](C)(C)O[CH:20]1[CH:25]([O:26][CH3:27])[CH:24]([O:28][CH3:29])[CH:23]([O:30][CH3:31])[CH:22]([CH3:32])[O:21]1)(C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:27][O:26][C@@H:25]1[C@H:24]([O:28][CH3:29])[C@@H:23]([O:30][CH3:31])[C@H:22]([CH3:32])[O:21][C@H:20]1[O:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=2)[CH2:3]1
Reactant: COC1C(C)OC(O[Si](C)(C)C(C)(C)C)C(OC)C1OC
Reactant: CC(=O)c1ccc2c(c1)CC(O)C2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC2Cc3ccc(C(C)=O)cc3C2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution at 0-5° C. of 1-(2-hydroxy-indan-5-yl)-ethanone (Compound E-25; 440 mg, 2.50 mmol) and 92% w/w of tert-butyl-dimethyl-(3,4,5-trimethoxy-6-methyl-tetrahydro-pyran-2-yloxy)-silane (Compound E-23; 1.00 g, 2.87 mmol) in CH2Cl2 (6 mL) was added via syringe trimethylsilyl triflate (0.12 mL, 146 mg, 0.66 mmol). The contents were allowed to gradually warm to room temperature and were stirred overnight. The solution was diluted with CH2Cl2 and was washed once with saturated sodium bicarbonate (NaHCO3). The aqueous phase was extracted once with CH2Cl2, and the combined organics were dried (MgSO4). Concentration gave a pale green oil (783 mg, 86%): 1H NMR (CDCl3) δ 7.79 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 4.97 (s, 1H), 4.64 (m, 1H), 3.67-3.40 (m, 3H), 3.55 (s, 3H), 3.50 (s, 3H), 3.45 (s, 3H), 3.21-2.97 (m, 5H), 2.59 (s, 3H), 1.30 (d, J=6.3 Hz, H); IR (neat) 1683 cm−1.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.N1C2C=CC=CC=2N=N1.ClC1C=CC2=NN(C3C=C(C)C=CC=3O)N=C2C=1>>[OH:32][C:10]1[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[N:7]1[N:8]=[C:4]2[CH:3]=[CH:2][CH:34]=[CH:33][C:5]2=[N:6]1
Reactant: CCCCCCCCCCCCCCCCc1cc(C)cc(-n2nc3ccc(Cl)cc3n2)c1O
Agent: Cc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: c1ccc2[nH]nnc2c1
Product: CCCCCCCCCCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
In like manner, 5-chloro-2-(2-hydroxy-3-hexadecyl-5-methylphenyl)-2H-benzotriazole is prepared by substituting for the benzotriazole used above an equivalent amount of 5-chloro-2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:38]=[C:37]([CH2:39][C:40](O)=[O:41])[O:36][N:35]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[O:11][C:10](=[O:12])[C:9]([C:40](=[O:41])[CH2:39][C:37]3[O:36][N:35]=[C:34]([CH3:33])[CH:38]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(C(=O)Cc3cc(C)no3)C(=O)O2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a solution of 6-cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (52 mg, 0.15 mmol) from Step 2 below, triethylamine (0.075 mL, 0.68 mmol) and (3-Methyl-isoxazol-5-yl)-acetic acid (0.027 g, 0.196 mmol) in CH2Cl2 (1.5 mL) were added DMAP (1 mg), and EDC (37 mg, 0.196 mmol). The reaction was stirred at room temperature for 18 hours, and then diluted with CH2Cl2. The organic was washed with water, and the layers were separated. The organic layer was dried under vacuum, and then purified by preparatory HPLC to give the desired compound (26.2 mg, 37% yield). 1H NMR (CDCl3) δ: 1.47-1.75 (m, 8H), 1.85-1.91 (m, 2H), 2.21 (s, 3H), 2.26-2.32 (m, 1H), 2.48-2.53 (m, 2H), 2.71 (d, J=18.09 Hz, 1H), 2.86 (d, J=18.09 Hz, 1H), 3.69 (s, 3H), 3.71 (s, 3H), 4.40-4.57 (m, 2H), 6.00 (s, 1H), 6.31-6.36 (m, 2H), 6.91 (d, J=7.91 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1[OH:18])([O-:3])=[O:2].N(C1C(O)=C(N=O)C(O)=C(N=O)C=1O)=[O:20]>>[N+:1]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1[OH:18])([O-:3])=[O:2].[N+:15]([O-:17])([OH:20])=[O:16]
Reactant: O=Nc1c(O)c(N=O)c(O)c(N=O)c1O
Agent: O=[N+]([O-])c1c(O)c([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O
Product: O=[N+]([O-])O

Procedure:
A process for the production of trinitrophloroglucinol comprising adding a liquid suspension containing from about 4 to about 20 percent weight/volume of trinitrosophloroglucinol over a period of time sufficient to form trinitrophloroglucinol to a nitric acid solution containing between 45 and 100 percent by weight of nitric acid, said solution being maintained at a temperature in the range from about 45° to 100°C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][N:28]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=[C:29]1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:40]2[CH2:41][CH2:42][N:37]([C:29]3[N:28]([CH3:27])[C:36]4[N:35]=[CH:34][CH:33]=[CH:32][C:31]=4[N:30]=3)[CH2:38][CH2:39]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2cccnc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2cccnc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 3-methyl-2-(piperazin-1-yl)-3H-imidazo[4,5]pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:18])=[C:15]([NH2:17])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]([NH:30][C:31](=[N:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])SC)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.[Hg](Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([NH:17]/[C:31](/[NH:34][C:35](=[O:36])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:30]/[C:28](=[O:29])[O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14]([CH3:18])=[N:13][CH:12]=1)=[O:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N
Agent: Cl[Hg]Cl
Solvent: ClCCl
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of tert-butyl[3-(5-amino-6-methylpyridin-3-yl)propyl]carbamate (2.99 g, 11.3 mmol), 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (3.41 g, 9.51 mmol), and mercury(II) chloride (3.37 g, 12.4 mmol) in DCM (100 mL) was added TEA (5.19 mL, 37.3 mmol) dropwise via syringe. The reaction mixture was allowed to stir at rt overnight. The reaction mixture was filtered over a pad of Celite® and the resulting filtrate was concentrated. The residue was purified by column chromatography to give dibenzyl {(Z)-[(5-{3-[(tert-butoxycarbonyl)amino]propyl}-2-methylpyridin-3-yl)amino]methylylidene}biscarbamate (3.34 g, 61%) as a white solid. LCMS (FA): Rt=1.90 min, m/z=576.0 (M+H).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([O:13][C:14](=[O:22])[NH:15][C@@H:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21])([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([O:13][C:14]([NH:15][C@@H:16]([CH2:20][CH2:19][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:17]([OH:21])=[O:18])=[O:22])([CH3:12])([CH3:11])[CH3:10]
Reactant: Sc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCOC1=O
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCSc1ccccn1)C(=O)O
Temperature: 100 °C
Yield: 26.8 %

Procedure:
Clean sodium metal (0.205 g, 8.95 mmol) was added, in portions, to anhydrous methanol (20 mL) in a thick walled tube. The suspension was stirred under anhydrous nitrogen until all the metal had dissolved, then pyridine-2-thiol (1.0 g, 8.95 mmol) was added. After stirring for 20 min, (2-oxotetrahydro-furan-3(R)-yl)-carbamic acid tert-butyl ester (1.8 g, 8.95 mmol) was added as a solid and the tube was capped and heated to 100° C. for 16 h. The reaction mixture was concentrated, then purified via flash chromatography (MeOH, CH2Cl2 as eluent) to give 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid (0.75 g) as a clear oil.
Reaction SMILES: C(C1(C)N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)C.C(=O)([O-])[O-:16].[Na+].[Na+]>Cl>[NH2:4][C:5]([CH3:11])([CH2:12][CH3:13])[CH2:6][C:7](=[O:16])[CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Agent: Cl
Agent: [Na+]
Product: CCC(=O)CC(C)(N)CC

Procedure:
196.3 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine were added dropwise to 300 ml of concentrated hydrochloric acid at 30° - 40° C, with stirring. When the addition was complete, the mixture was stirred for a further 4 - 5 hours and then neutralized with sodium carbonate and extracted with benzene. The resulting benzene solution was washed with, in turn, a 5% aqueous solution of sodium carbonate and water, and was then dried over potassium carbonate. After removal of benzene, the residue was distilled under reduced pressure, giving 72.4 g of 5-amino-5-methyl-3-heptanone (bp 46° - 48° C/2.5 mmHg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C([N:27]=[C:28]=[S:29])(=O)C1C=CC=CC=1.O>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:28]([NH2:27])=[S:29])=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of Compound 2 (0.06 g, 0.26 mmol) in acetone mL) was added with benzoyl isothiocyanate (0.10 mL, 1.5 mmol), followed by stirring at room temperature for 1 hour. The crude product obtained by adding water to the mixture was collected by filtration, dissolved in ethanol (1 mL) and added with 1 mol/L aqueous sodium hydroxide solution (1 mL), followed by stirring at room temperature for 1 hour. The mixture was neutralized by adding 6 mol/L hydrochloric acid and the precipitated solid was collected by filtration. The residue was triturated in ethanol to obtain Compound 161 (54 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:16])([S:6]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])(=[O:8])=[O:7])[CH:3]([F:5])[Cl:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([NH:22][C:23]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([S:6]([C:2]([F:1])([F:16])[CH:3]([F:5])[Cl:4])(=[O:7])=[O:8])[CH:10]=1)=[O:24])=[O:21]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)C(F)Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cccc(S(=O)(=O)C(F)(F)C(F)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
In 20 ml of toluene was dissolved 20 g of 3-(1,1,2-trifluoro-2-chloroethylsulfonyl)aniline, amd 1.4 g of 2,6-difluorobenzoyl isocyanate was added to the solution, followed by stirring at room temperature (20° to 25° C.) for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crystals which separated out were recovered by filtration, and washed with cyclohexane to give 3.3 g of N-(2,6-difluorobenzoyl)-N'-(3-(1,1,2-trifluoro-2-chloroethylsulfonyl)phenyl]urea (Compound No. 38), m.p. of 192°-194° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].Cl[C:13]([C:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O>>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([C:30]1[O:11][C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:13])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1O
Product: CC1(c2nc3cccc(C(=O)O)c3o2)CCCN1C(=O)OCc1ccccc1

Procedure:
2-(1-(Benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxylic acid is prepared from 3-aminosalicylic acid and benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate using identical conditions described in Example 3A. MS (ESI) m/e 381 [M+H]+.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14]([C:17]1[NH:18][CH:19]=[NH+:20][C:21]=1[O-:22])(=[O:16])[NH2:15]>N1C=CC=CC=1>[C:1]12([C:11]([O:22][C:21]3[N:20]=[CH:19][NH:18][C:17]=3[C:14](=[O:16])[NH2:15])=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Product: NC(=O)c1[nH]cnc1OC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 1-adamantanecarbonylchloride (2.980 g) in pyridine (26 ml) was added 4-carbamoylimidazolium-5-olate (1.271 g) and the reaction temperature was kept at 40°-43° C. for 4 hours. Unreacted starting material was recovered by filtration (210 mg). The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (30 ml) and water (30 ml), and stirred at room temperature for 1 hour. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (1.602 g, α form, m.p. 207°-209° C. (dec.)).