Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C(OCC)(=O)C>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: ClCn1nnc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cn1nnc2ccccc21

Procedure:
A solution of potassium phthalimide (5.55 g) and crude 1-(chloromethyl)benzotriazole (5.02 g) in 75 ml dimethylformamide was stirred at ambient temperature for 2 hours. An additional portion of potassium phthalimide (1.0 g) was added. After 2 hours an aqueous ethyl acetate extractive work up gave a crude solid. Recrystallization from acetonitrile gave a colorless solid, m.p. 177°-180° C. (5.49 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:15].O>CN(C=O)C>[Cl:15][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)nc1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of Example 85B (2.8 g, 15.8 mmol) in 20 mL of anhydrous DMF was added POCl3 (5 mL) at 0° C. The resulting mixture was warmed to room temperature and stirred overnight. The solution was poured into 20 mL of icy water. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=20:1) to afford the title compound (2.1 g, 68.2%). LC-MS: m/z 300 (M+H). 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.72 (s, J=8.0 Hz, 1H), 4.66 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8](NC2C(=O)N3C2CCOC3(C)C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:31]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]([NH2:41])[C:29]1=[O:42]>>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:31]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]([NH:41][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:29]1=[O:42]
Reactant: CC1(C)OCCC2C(NC(=O)Cc3ccccc3)C(=O)N21
Reactant: NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1
Product: O=C(Cc1ccccc1)NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1

Procedure:
Following the procedure described for the preparation of 7-phenylacetamido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo-[4.2.0]octane from 7-amino-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 6) and using 1-(2-tetrahydropyranyl)-3-amino-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone there is obtained 1-(2-tetrahydropyranyl)-3-phenylacetamido-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[C:12](OC)[CH2:13][O:14][CH3:15])[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].[NH4+:19].[OH-]>CCO.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5]([OH:11])=[CH:6][C:7]([OH:8])=[N:19][C:12]=1[CH2:13][O:14][CH3:15]
Reactant: [NH4+]
Reactant: COCC(OC)=C(C(=O)CC(=O)OC)C(=O)OC
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1nc(O)cc(O)c1C(=O)OC
Temperature: 60 °C

Procedure:
2-(1,2-Dimethoxy-ethylidene)-3-oxo-pentanedioic acid dimethyl ester (29.8 g, 115 mmol) is dissolved in a solution of EtOH (250 mL), water (250 mL) and concentrated NH4OH(aq) (30 mL). The mixture is heated to 60° C. for 5 hours. The reaction mixture is cooled to room temperature and the EtOH removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified with concentrated hydrochloric acid, at which time a white precipitate appeared. The precipitate is collected and dried in a vacuum oven to yield the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:17])[CH2:15]Cl)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:17])[CH2:15][N:2]([CH3:3])[CH3:1])([O-:6])=[O:5]
Reactant: CNC
Reactant: O=C(CCl)Nc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CN(C)CC(=O)Nc1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of dimethylamine in ethanol (40 ml. of a 33% w/w solution) was added to a suspension of N-(2-nitrophenyl)-2-chloroacetamide (14.9 g) [prepared by the method described by G. Tennant, J.C.S., (1963), 2428] in ethanol (70 ml) and the mixture was heated to reflux, with stirring, for 2hours. After cooling, the ethanol and excess dimethylamine were evaporated off under reduced pressure and the solid residue was treated with an aqueous potassium hydroxide solution (100 ml., 40% w/v). The resulting suspension was extracted with diethyl ether (3 × 100 ml) and the combined extracts dried over magnesium sulphate and evaporated to give N-(2-nitrophenyl)-2-dimethylaminoacetamide (13.8 g), m.p. 44°-47° C., sufficiently pure to be used in the next stage of the synthesis, the preparation of N-(2-aminophenyl)-2-dimethylaminoacetamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].CCN(C(C)C)C(C)C.[NH2:21][C@@H:22]([CH3:25])[CH2:23][OH:24]>CC(O)C.CN(C1C=CN=CC=1)C>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([NH:21][C@@H:22]([CH3:25])[CH2:23][OH:24])[C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: C[C@H](N)CO
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Nc1c(Cl)c(Cl)nc(Cl)c1Cl
Yield: 52 %

Procedure:
To a solution of pentachloropyridine (30 g) in 2-propanol (300 ml) was added DIPEA (18 ml), DMAP (0.8 g) and (S)-(+)-2-amino-1-propanol (18 g), and the reaction mixture was heated under reflux for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methanol and filtered to give the title compound as a white solid (18 g).
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18]>C(O)C>[CH3:15][C:16]1[C:17](=[O:18])[NH:13][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:14][C:22]=1[CH3:24]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)[nH]c(=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a mixture of sodium ethoxide (31.3 g) and anhydrous ethanol (200 ml) is added benzamidine hydrochloride (23.9 g) at 0-5° C. The mixture is stirred at 0° C. for 30 minutes, and thereto is added dropwise a solution of ethyl 2-methylacetoacetate (20 g) and anhydrous ethanol (50 ml) at the same temperature. After addition, the mixture is stirred at room temperature for 30 minutes, and refluxed for six hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in water. The pH value of the mixture is adjusted to pH 4 by addition of conc. hydrochloric acid while the mixture is stirred at 0-5° C. The precipitates are collected by filtration, washed with water, further washed with diethyl ether, and recrystallized from ethanol to give the desired compound (14.3 g), m.p. 205-207° C.
Reaction SMILES: C1COCC1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C[O:14][C:15]1[CH2:19][CH2:18][C:17](=O)[CH:16]=1>C(OCC)(=O)C>[CH2:7]([C:17]1[CH2:18][CH2:19][C:15](=[O:14])[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCBr
Reactant: COC1=CC(=O)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCC1=CC(=O)CC1
Temperature: 60 °C
Yield: 81.3 %

Procedure:
Mg turnings (972 mg, 40 mmol) were placed into a dry Schlenk flask, then THF (20 mL) was added. 6-Bromo-1-hexene (5.3 mL, 40 mmol) was placed into a separate dry flask, dissolved in THF (20 mL), then added via syringe to the Mg solution. The resulting mixture was heated at 60° C. for 12 h, then cooled to room temperature. The solution of the Grignard reagent was then separated from remaining Mg solid by transferring the solution via syringe to another Schlenk flask. The general procedure for the preparation of substrates using 3-methoxycyclopentenone (2.24 g, 20 mmol) and the solution of the Grignard reagent described above gave, after 24 h and and flash chromatography (4:1 hexanes:ethyl acetate), the title compound as a colorless liquid (2.67 g, 81%). 1H NMR (300 MHz, CDCl3): δ5.95-5.92 (m, 1 H), 5.79 (dddd, J=17.1, 10.2, 6.6, 6.6 Hz, 1 H), 5.06-4.92 (m, 2 H), 2.66 -2.54 (m, 2 H), 2.48-2.37 (m, 4 H), 2.15 -2.04 (m, 2 H), 1.69-1.54 (m, 2 H), 1.53-1.39 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ6209.9, 182.9, 138.3, 129.4, 114.8, 35.4, 33.5, 33.4, 31.6, 28.6, 26.6. IR (neat): 2929, 2860, 1706, 1615, 1437, 1183, 994, 909, 839 cm−1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].[OH:21][C@@H:22]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH3:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C@H:22]([O:21][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26]
Reactant: O=[N+]([O-])c1ccc(OCc2cccnc2)cc1F
Reactant: Cc1ccccc1[C@H](O)CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H](CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1[N+](=O)[O-]
Yield: 28.8 %

Procedure:
3-(3-Fluoro-4-nitrophenoxymethyl)pyridine (1.53 g) is added to a stirred suspension of sodium hydride (0.48 g, 60% dispersion in mineral oil) in THF (50 mL) at ambient temperature. A solution of tert-butyl (R)-4-hydroxy-4-(2-methylphenyl)butanoate (3.08 g) in THF (30 mL) is added dropwise to the mixture over 2 hours. The reaction mixture is concentrated under reduced pressure and the residue partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer is extracted three times with ethyl acetate (100 mL) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with ethyl acetate. Fractions homogeneous in the required product are combined and evaporated to give tert-butyl (R)-4-(2-methylphenyl)-4-(2-nitro-5-(3-pyridylmethoxy)phenoxy)butanoate (0.85 g) as a yellow gum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([C:22]1[N:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[N:25]=[C:24]([CH:31]=O)[CH:23]=1)[CH2:20][CH3:21]>>[C:27]([N:26]1[C:22]([CH2:19][CH2:20][CH3:21])=[CH:23][C:24]([CH2:31][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:25]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Product: CCCc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1C(C)(C)C
Yield: 95.6 %

Procedure:
Compound 50 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(Cl)(Cl)Cl.C(#N)C>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (19.6 g) and 1,2,4-triazole (30.5 g) in a mixture of chloroform (250 mL) and acetonitrile (50 mL) is stirred at reflux for 15 hours. The solution is cooled and washed with 3% aqueous sodium bicarbonate (200 mL) and the organic solution is then dried (MgSO4) and evaporated. The residue is chromatographed on silica gel (300 g). Elution with chloroform/isopropanol (10:1) affords 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, m.p. 77°-79°, which forms a hydrochloride salt, m.p. 200°-205°, when its solution in ethyl acetate is treated with ethereal HCl.
Reaction SMILES: C[Si](Cl)(C)C.[CH3:6][C:7]1[N:8]=[C:9]([NH:19]C(=O)C)[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[N:13]=1.Cl>C(O)C>[CH3:6][C:7]1[N:8]=[C:9]([NH2:19])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[N:13]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(C)n2)s1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCO
Product: Cc1nccc(-c2sc(N)nc2C)n1
Temperature: 50 °C
Reaction time: 46 h

Procedure:
Trimethylsilylchloride (0.3 ml) is added at room temperature to a suspension of N-[4-methyl-5-(2-methyl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (29 mg, prepared as described in WO 04/096797) in ethanol (2 ml) at room temperature. The mixture is heated at 50° C. for 18 hours, conc. HCl (0.2 ml) is added and the heating at 50° C. is continued for a further 46 hours. Following cooing the mixture is partitioned between saturated aqueous NaHCO3 and CH2Cl2 containing 10% methanol and extracted a further 2×CH2Cl2. Evaporation of the organic layers gives the title compound as a beige solid. 1H nmr (d4-methanol, 400 MHz) 8.44 (d, J=7 hz, 1H), 7.33 (d, J=7 Hz, 1H), 2.58 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.I[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CI
Reactant: Nc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CNc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
4-Chloroaniline (15.5 g, 122 mmol), ethyl iodoacetate (14.4 mL, 122 mmol) and sodium acetate (20.0 g, 244 mmol) were stirred in water (24 mL) at 90° C. for 3 hours. After cooling to room temperature the precipitate was collected by filtration, washing with water (40 mL), to yield the title compound (25.6 g, 98%) as brown prisms. 1H NMR (400 MHz, CDCl3) δ 1.29 (3H, t), 3.86 (2H, s), 4.22 (2H, q), 6.53 (2H, d), 7.14 (2H, d).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:44][C:41]2[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:39][CH:40]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (47.3 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 41% (0.058 g, 0.102 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)s1
Yield: 86.1 %

Procedure:
A mixture of 5-methylthiophene-2-carbonitrile (9.9 g, 80.5 mmol), benzoylperoxide (0.23 g, 0.95 mmol), and N-bromosuccinimide (15 g, 84.3 mmol) in carbontetrachloride (200 mL) was heated at reflux for 6 h. The resulting suspension was filtered and the filtrate diluted with dichloromethane (400 mL), washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1:4) to give the title compound as a yellow oil (14.0 g, 86%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([O:5][CH2:6]1)[CH2:3][NH:2]2.[N:8]1[O:9][N:10]=[C:11]2[CH:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[CH:13][C:12]=12>>[N:8]1[O:9][N:10]=[C:11]2[CH:16]=[C:15]([C:17]([N:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][O:5]4)=[O:18])[CH:14]=[CH:13][C:12]=12
Reactant: C1OC2CNC1C2
Reactant: O=C(Cl)c1ccc2nonc2c1
Product: O=C(c1ccc2nonc2c1)N1CC2CC1CO2

Procedure:
The title compound was prepared from 2-aza-5-oxabicyclo[2.2.1]heptane and [2,1,3]-benzoxadiazole-5-carbonylchloride as described for Example 7: mp=102-104° C., LC-MS, MH+=246; 1H NMR (300 MHz, CDCl3) δ 7.98-7.90 (m, 2H), 7.58 (dd, J=1.2 and 9.3 Hz, 1H), 5.08 and 4.78 (s, total 1H), 4.66 and 4.47 (s, total 1H), 4.05 (m, 1H), 3.89 (m, 1H), 3.73-3.63 (m, 1H), 3.52 (s, 1H), 2.06-1.95 ppm (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:15]2[C:16](=[O:17])[C:8]3([CH2:7][C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:9]3)[NH:13][C:14]2=[O:18])=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Reactant: COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)NC3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.4 g, 5.66 mmol, described in Intermediate 6), 4-methoxybenzyl alcohol (0.94 g, 6.80 mmol), diethyl azodicarboxylate (1.48 g, 8.49 mmol), and triphenylphosphine (2.23 g, 8.49 mmol) in THF (15 mL) was stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound as a yellow solid. MS: m/z=368 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]([CH3:20])[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[S:8][C:6]=2[N:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[CH3:20][N:12]([CH2:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[CH:10]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cncnc1
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 168. NMR (CDCl3): 1.59-1.81 (4H, m), 1.96-2.03 (2H, m), 2.25 (3H, s, Me), 2.28 (3H, s, Me), 2.44-2.52 (1H, m), 2.90-2.95 (2H, m), 3.80-3.88 (6H, m, CH2), 3.90-3.94 (4H, m, CH2), 7.10 (1H, s, Ar), 9.16 (1H, s, Ar) and 9.60 (2H, s, Ar). MS: (ESI+): MH+440.22
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8](O)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[ClH:4].[C:8]([Cl:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalic chloride (800 μL) is added dropwise to a solution of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoic acid, hydrochloride (2.33 g) in dichloromethane (20 mL) containing one drop of N,N-dimethylformamide. The mixture is stirred for two hours at room temperature and concentrated under reduced pressure. Cyclohexane is added and evaporated under reduced pressure to afford 2.55 g of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoyl chloride, hydrochloride used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[N:28]([CH3:37])[S:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)(=[O:31])=[O:30])=O)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([S:54][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][C:22]=4[N:28]([CH3:37])[S:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC3(O)CCN(Cc4ccccc4)CC3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5ccccc5)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 4.9 %

Procedure:
To a solution of N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.30 g) in a mixed solvent of toluene (60 ml) and tetrahydrofuran (30 ml) was added Lawesson's reagent (1.94 g), and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=5:95-40:60), and recrystallized from ethyl acetate-hexane to give the title compound (0.063 g, yield 5%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH3:30][CH:31]([NH2:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1[NH:33][CH:31]([CH3:32])[CH3:30]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(NC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 31 mg (0.07 mmol) of tert-butyl 3-(4-(5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 15, Step A) and 120 μL (1.4 mmol) of 2-propylamine in 5.0 mL of THF was heated to 100° C. in a sealed tube overnight. The mixture was cooled to rt and concentrated. Chromatography on a Biotage 40S cartridge using 1:9 v/v Et2O/hexanes as the eluant gave 28 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.32 (d, J=6.4, 6H), 1.43 (s, 9H), 2.57 (t, J=7.7, 2H), 2.64 (s, 3H), 2.94 (t, J=7.7, 2H), 4.41 (m, 1H), 5.32 (d, J=7.5, 1H), 7.16-7.17 (m, 2H), 7.99 (d, J=8.5, 1H), 8.18 (d, J=1.8, 1H), 8.85 (d, J=1.8, 1H).