Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:9]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)C(C)Oc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)Oc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 448.5 %

Procedure:
Hydrazine hydrate (41.7 μL, 0.4 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-hexanoic acid ethyl ester (566 mg, 2.14 mmol) in EtOH (4.5 mL). The mixture was stirred at 80° C. for 1 hour. Then, the mixture was stirred at room temperature for 16 hours. Hydrazine hydrate (20 μL, 0.2 mmol) was added and the mixture was stirred at 80° C. for 2 hours. More hydrazine hydrate (41.7 μL, 0.4 mmol) was added and the mixture was stirred at 80° C. for 2 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and solvents evaporated in vacuo to yield (rac)-5-(1-phenoxy-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (467 mg, 78% yield) as a colourless oil.
Reaction SMILES: C([NH:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]([C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O.[CH3:23]O>>[NH2:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]([C:15]([O:17][CH3:23])=[O:16])=[CH:7][CH:6]=1
Reactant: CO
Reactant: CC(=O)Nc1ccc(C(=O)O)c2c1OCCO2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)c2c1OCCO2
Reaction time: 20 h
Yield: 89 %

Procedure:
A stirred solution of 8-acetamido-1,4-benzodioxan-5-carboxylic acid (GB 1 571 278) (2.5 g, 0.0105 mole)in methanol (60 ml) was treated with concentrated sulphuric acid (2 ml) and the solution kept at room temperature for 20 hours, then concentrated in vacuo to approxiamately 10 ml volume. The residue was treated with water (30 ml), basified with potassium carbonate and a precipitate was produced. This was filtered off, washed with water and dried to afford methyl 8-amino-1,4-benzodioxan-5-carboxylate as a white solid (1.96 g, 89%). 1H NMR (CDCl3) δ:7.38(d,1 H), 6.28(d,1 H), 4.25-4.43(m,4 H), 4.12(br s,2 H), 3.83(s,3 H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH3:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][C:5]([CH3:6])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:16])[CH3:2]
Reactant: CCNCC(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CC(C)(C)c1ccc([N+](=O)[O-])cc1
Yield: 85.8 %

Procedure:
In a 100 mL round bottom flask was charged N-ethyl-2-methyl-2-(4-nitrophenyl)propan-1-amine (1.50 g, 6.75 mmol), anhydrous acetonitrile (22 mL), ethyl iodide (1.16 mL, 7.43 mmol), and potassium carbonate (1.87 g, 13.5 mmol). The reaction was brought to reflux for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water and ethyl acetate and layers were separated. The organic layer was washed with once each with water, and then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give N,N-diethyl-2-methyl-2-(4-nitrophenyl)propan-1-amine (1.45 g, 86.1%). LC/MS (ESI+) 251 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([CH:21]=[N:22][C:23]3[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[CH:32]([CH3:34])[CH3:33])[CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Li])([CH3:37])[CH3:36].O>CCOCC>[CH:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([CH:21]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH:35]([CH3:37])[CH3:36])[NH:22][C:23]3[C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][CH:26]=[CH:27][C:28]=3[CH:29]([CH3:30])[CH3:31])[CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2ccccc2CNC2CCCCC2)n1
Reactant: [Li]c1ccccc1C(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)c1ccccc1C(Nc1c(C(C)C)cccc1C(C)C)c1cccc(-c2ccccc2CNC2CCCCC2)n1
Temperature: 25 °C

Procedure:
Et2O (10 mL) was added to compound 9 (0.189 g, 0.417 mmol) to form a clear pale yellow solution. At −80° C., an Et2O (5 mL) solution of 2-isopropylphenyllithium (0.136 g, 1.08 mmol) was added dropwise to form a red-purple solution. The mixture was allowed to slowly warm to ambient temperature overnight. Water (50 mL) was then added followed by Et2O (50 mL). The organics were separated, dried with brine and then MgSO4. Evaporation of the volatiles afforded compound 10, which did not require any purification. Yield: 0.224 g, 76.2%. 1H NMR (CD2Cl2): δ 7.67 (t, 2H), 7.1-7.53 (m, 10H), 7.00 (m, 3H), 5.44 (d, 1H), 4.40 (d, 1H), 3.69 (s, 2H), 3.11 (sept, 1H), 2.91 (sept, 2H), 2.24 (m, 1H), 1.5-1.7 (m, 6H), 1.25 (d, 3H), 1.1-1.2 (m, 4H), 0.97 (d, 12H), 0.93 (d, 6H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C1(C)C=CC=CC=1>[O:11]([C@@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccccc2)CC1
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=O)[C@H]1CC[C@@H](Oc2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of cis-4-phenoxy-cyclohexanecarboxylic acid methyl ester (0.55 g, 2.3 mmol) and hydrazine hydrate (0.11 g, 2.3 mmol) was heated at 120° C. for 24 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.50 g, 92%) as light yellow foam, which was used in the next step without further purification.
Reaction SMILES: [NH3:1].CS(O[CH2:7][C@H:8]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)(=O)=O>C1COCC1>[NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1
Reactant: CS(=O)(=O)OCCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: N
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCCNC1)OCc1ccccc1
Reaction time: 46 h

Procedure:
Liquid ammonia (ca. 30 ml) was added to a solution of (2R)-2-{[(benzyloxy)carbonyl]amino}-5-[(methylsulfonyl)oxy]pentyl methanesulfonate (1 g) in THF (15 ml) at −78° C. in a bomb reaction vessel and then the resultant mixture was allowed to reach room temperature. After 46 h, the solution was concentrated under reduced pressure to give an off-white solid which was purified using SPE (silica, eluting with methanol, methanol:aqueous ammonia 95:5, 9:1) to give the title compound (0.587 g) as an off white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C@H:11]1[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:13]2[C:24]3[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([C:35]([O:37][CH3:38])=[O:36])=[CH:27][C:25]=3[N:26]=[C:12]12)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([C@H:11]1[NH:16][CH2:15][CH2:14][N:13]2[C:24]3[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([C:35]([O:37][CH3:38])=[O:36])=[CH:27][C:25]=3[N:26]=[C:12]12)([CH3:10])[CH3:9]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
TFA (4 mL) was added dropwise to a solution of containing (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (2.0 g, 4.4 mmol) in DCM (20 mL) at rt over 2 min. The mixture was stirred at rt for 3 h. TLC showed the starting material was consumed completely. The solvent was removed in vacuo at 30° C., and then DCM (10 mL) was added. The mixture was neutralized with sat. aq. NaHCO3 to pH=7. The mixture was extracted with DCM (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (1.5 g, 96.4% yield) as a white solid. LC-MS m/z 351.9 [M+H]+, 374.0 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.15 (s, 1H), 8.07 (s, 1H), 4.26-4.05 (m, 3H), 3.97 (s, 3H), 3.63-3.50 (m, 1H), 3.44 (s, 3H), 3.32-3.16 (m, 1H), 2.85-2.66 (m, 1H), 1.16 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C@@H:14]([F:15])[CH2:13][C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=O)(C)(C)C.C(OCC)(=O)C.Cl>>[NH2:8][C@@:9]1([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C@@H:14]([F:15])[CH2:13][C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17]
Reactant: C=CCOC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC=C)[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)OCC=C)[C@@H]21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
To (1S,2S,3S,5R,6S)-diallyl 2-((tert-butoxycarbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate (D-13-2, 1.49 g), a 4 mol/L hydrogen chloride-ethyl acetate solution (24 mL) was added at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction solution was thereafter concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. After the combined organic layer was washed once with brine and dried over anhydrous sodium sulfate, the insoluble was filtered off and the filtrate was concentrated under reduced pressure to give (1S,2S,3S,5R,6S)-diallyl 2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate (D-13-3, 949 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: Brc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1cccc2c1cnn2C1CCCCO1
Yield: 80.1 %

Procedure:
A mixture of 4-bromo-1H-indazole (0.5 g, 2.53 mmol), p-TsOH.H2O (50 mg, 0.25 mmol), and 3,4-dihydro-2H-pyran (0.64 g, 7.61 mmol) in THF (20 mL) was degassed then heated to reflux overnight. After the solvent was removed, the residue was partitioned between DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0.5 to 1% MeOH) to afford 570 mg (81%) of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (196) as yellow solid: MS (ESI) m/z=282.2 [M+1]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH3:20])[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[N:17][N:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=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>[O:26]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([C:8]3[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]4[N:19]([CH3:20])[C:18]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)=[N:17][N:16]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:27]1
Reactant: Cn1c(SCc2noc(-c3cccc(I)c3)n2)nnc1-c1cccs1
Reactant: OB(O)c1ccoc1
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: COCCOC
Solvent: CCOC(C)=O
Product: Cn1c(SCc2noc(-c3cccc(-c4ccoc4)c3)n2)nnc1-c1cccs1
Temperature: 90 °C
Yield: 59.3 %

Procedure:
To 5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (50 mg, 0.10 mmol) in a vial was added 3-furan boronic acid (17 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.0052 mmol), ethylene glycol dimethyl ether (1 ml) and 2 M sodium carbonate (1 ml). The vial was then sealed and heated at 90° C. for 1 h with vigorous stirring. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. The residue was purified by flash column chromatography using 70% ethyl acetate in hexanes. Additional purification by trituration with a mixture of diethyl ether and hexanes and then filtration afforded the title compound as a beige solid 25 mg (57%). 1H NMR (CDCI3), δ (ppm): 8.18 (s, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.51 (m, 4H), 7.17 (m, 1H), 6.74 (s, 1H), 4.55 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[C:6](=[O:23])[NH:5][C:4](=[O:24])[C:3]=1[NH:25][C:26](=O)[CH:27]([CH3:29])[CH3:28].[OH-].[Na+]>O>[CH:18]1([O:17][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=2[O:15][CH3:16])[CH2:8][N:7]2[C:2]3[N:1]=[C:26]([CH:27]([CH3:28])[CH3:29])[NH:25][C:3]=3[C:4](=[O:24])[NH:5][C:6]2=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(Cn2c(N)c(NC(=O)C(C)C)c(=O)[nH]c2=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cn2c(=O)[nH]c(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Yield: 90.8 %

Procedure:
A mixture of 4.64 g of 6-amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-5-isobutyrylamino-uracil, 100 ml of water and 50 ml of 1N NaOH was heated under reflux for 1 hour. The solution was filtered, treated with 0.25 g of charcoal, filtered again and neutralized to pH 8. The solid was collected, dried, and recrystallized from THF to give the title compound (4.03 g) as a white solid mp 282-3° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C@H:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=2)[C:10]1=[O:27]>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=2)[C:10]1=[O:27]
Reactant: CN1C(=O)N(c2cncn2C)C[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cncn2C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (801 mg, 4.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-1-methylimidazole (644 mg, 4.00 mmol) in 1,4-dioxane (30 ml) was added potassium phosphate (4246 mg, 20.00 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (0.631 ml, 4.00 mmol) and copper(I) iodide (762 mg, 4.00 mmol) and the mixture stirred at reflux overnight. The reaction mixture was diluted with dichloromethane and filtered through celite. The filter pad was washed with dichloromethane and the filtrate was reduced under vacuum. The residue was re-dissolved in dichloromethane, washed with 0.880 ammonia (×2), water then brine and passed through a hydrophobic frit and the solution was concentrated under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylate (393 mg, 32.6% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl (4S)-3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylate (390 mg, 1.391 mmol) in dichloromethane (4 ml) and stirred at room temperature for 2 hours, then allowed to stand overnight. The solvent was evaporated and the residue was co-evaporated with toluene and dried under heated vacuum (40° C.) overnight to give 3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.4 mmol) which was used which was used in the next step. LC/MS [M+H]+=225.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:25])[C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:29]>C(Cl)(Cl)Cl>[ClH:29].[ClH:1].[ClH:29].[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)([N:3]([CH3:25])[CH3:2])[CH2:5][CH2:6]1
Reactant: CN(C)C1(c2cccs2)CCN(CCNC(=O)OC(C)(C)C)CC1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2cccs2)CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
HCl gas was passed through a solution of 9 g (1 eq) tert-butyl 2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethylcarbamate in chloroform at 0° C. for ˜30 min. The reaction mixture was then stirred at room temperature for one hour. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and 9 g (97%) of product were obtained in the form of a white solid.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][N:17]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[Cl:46])[CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC=CC=3Cl)C=C(C3CCC4(OCCO4)CC3)C=2)CNC1=O>>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][N:17]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[Cl:46])[CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C=C4CCN(C(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: O=C1NCc2c(-c3ccccc3Cl)cc(C3CCC4(CC3)OCCO4)cc2N1c1c(Cl)cccc1Cl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(CC4CCN(C(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The title compound was prepared from 7-[(1-tert-butylpiperidin-4-ylidene)methyl]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as described in INTERMEDIATE 72. Mass spectrum (ESI): 676.6 (M+1).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][O:32][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)nc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted 6-chloro-3-pyridinemethanol according to the procedure described in Example 59 to afford 2-(6-chloro-3-pyridylmethoxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=476 (M++1); Rt=4.45 min; 1H-NMR 400 MHz (CDCl3): δ 5.51 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.20 (d, J=9Hz, 1H), 7.25-7.30 (m, 4H), 7.38-7.40 (m, 1H), 7.85 (m, 1H), 8.55 (d, J=2 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: [P:1]([Br:4])(Br)[Br:2].[CH3:5][N:6]([CH3:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1>N1C=CC=CC=1>[Br:2][P:1]([Br:4])[C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[N:6]([CH3:14])[CH3:5]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(N(C)C)cc1
Solvent: c1ccncc1
Product: Cc1ccc(N(C)C)c(P(Br)Br)c1

Procedure:
A solution of PBr3 (7.0 g, 26.0 mm) in 80 mL of pyridine was treated with N,N-dimethyl-p-toluidine (10.0 g, 74.0 mm) over a period of 5 min. The resulting mixture was then refluxed overnight. to give the crude 2-dibromophosphino-N,N-dimethyl-p-toluidine (31P NMR: δ149.1 ppm). This compound was used directly for the next step without further purification. Next, polymer-supported secondary amines prepared as in Example 1 (10.0 g, 1.06 mmol/g, 10.6 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with THF (2×50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported 2-P(Br)-1-NMe2-4-(Me)C6H3 31P NMR (122 MHz, CDCl3): δ157.0 ppm.
Reaction SMILES: Cl[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([C:27]#[CH:28])=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([C:27]#[C:28][N:2]3[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]3)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: ClN1C=CC=CN1
Reactant: C#Cc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#CN3C=CC=CN3)c2CC1
Yield: 19.8 %

Procedure:
Use a method similar to the General Procedure 8 to couple 2-chloro-pyridazine (98 mg, 0.86 mmol) with 3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (104 mg, 0.34 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give 3-tert-butoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (26 mg, 10%). MS (ES+) m/z: 384 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.Cl.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:16][CH:15]3[O:22][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (42, prepared as reported in WO2008/023159, 1.60 g, 6.64 mmoles) was dissolved in dichloromethane and cooled to 0° C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.990 g, 6.64 mmoles) in dichloromethane and triethylamine (1.94 mL, 13.94 mmoles) was slowly added over 15 minutes. The solution was allowed to warm to room temperature over 30 minutes then heated to reflux for 1.5 hours. The reaction mixture was stirred at room temperature for an additional 18 hours, then concentrated and purified by chromatography on silica gel (eluting with 2-3% methanol in dichloromethane) to provide 3-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (43) as a white solid. Yield: 1.72 g (82%). HRMS; [M+H]+ Obs'd=318.0669, [M+H]+ Calc'd=318.0674.