Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[NH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C1COCC1.C1(C)C=CC=CC=1>[C:2]1([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([NH2:13])[N:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccn1
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
To a solution of bromobenzene (4.43 mL, 42.06 mmol) in dry THF (100 mL) at −78° C. was added BuLi (394 mL, 63.08 mmol) and the mixture left to stir at −78° C. for 2 h. To this was added 2-aminopyrimidine (2.0 g, 21.03 mmol) in hot toluene (80 mL) over a 15 minutes period. The mixture was refluxed for 16 h and allowed to cool to room temperature and carefully quenched with aqueous NaHCO3. The mixture was filtered and the filtrate concentrated under vacuum. The residue was then dissolved in DCM and washed with aqueous NaHCO3, brine and dried (MgSO4). The solvent was removed to afford 350 mg of 47 (10%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=4.8 Hz, 1H), 7.97 (m, 2H), 7.45 (m, 3H), 7.02 (J=4.8 Hz, 1H), 5.27 (br s, 2H); MS (+)-ES [M+H]+ 172.2 m/z.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(O)(=O)C1(CCC(C(O)=O)C1(C)C)C.[NH2:35][NH2:36]>C(O)C>[C:14]1([C:5]2[C:4](=[O:3])[NH:35][NH:36][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)C(C(=O)c1ccccc1)c1ccccc1
Agent: CC1(C(=O)O)CCC(C(=O)O)C1(C)C
Solvent: CCO
Product: O=c1[nH][nH]c(-c2ccccc2)c1-c1ccccc1
Yield: 32.5 %

Procedure:
To 20 mL of an ethanol solution of 1.2 g (4.47mmol) of 3-oxo-2,3-diphenylpropionic acid ethyl ester was added 1.04 g (4.47 mmol) of camphoric acid and 140 μL(4.47 mmol) of hydrazine. After the mixture was refluxed for 20 min, the solvent was removed in vacuo, and the residue was triturated with 40% ethyl acetate/hexane (2 mL) three times to afford 343 mg of 4,5-diphenyl-1,2-dihydropyrazol-3-one in 27% yield.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccn(-c2ccc(F)c(O)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(F)c(OS(=O)(=O)C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To an ice cooled solution of trifluoromethanesulfonic anhydride (0.29 mL, 1.72 mmol) in DCM (10 mL) was added 2-fluoro-5-(3-methylpyrazol-1-yl)phenol (which may be prepared as described in Description 68) (288 mg, 1.5 mmol) followed by pyridine (0.6 mL, 7.49 mmol). The reaction was stirred at 00° C. for 10 minutes, then allowed to warm to room temperature over 1 hour, then the reaction was stirred overnight at room temperature. Additional trifluoromethanesulfonic anhydride (0.29 mL, 1.72 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM (30 mL) and subsequently poured into an aqueous solution of citric acid (10% w/w, 50 mL), and the layers were separated. The aqueous was then re-extracted with DCM (30 mL). The combined organics were dried through a phase separator, and concentrated in vacuo. The residue was loaded onto a silica column (10 g, SNAP cartidge), which was eluted with a gradient of EtOAc:isohexane, 0% to 30%. Fractions containing desired product were combined and concentrated in vacuo, to give [2-fluoro-5-(3-methylpyrazol-1-yl)phenyl]trifluoromethanesulfonate (D69) (308 mg, 0.9024 mmol, 60.2% yield);
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH3:9])[CH3:2].[CH2:10]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH3:20])[CH2:11][CH3:12].N[C:22](N)=[O:23]>>[CH2:1]([N:3]1[CH2:4][CH2:5][CH2:6][N:7]([CH2:8][CH3:9])[C:22]1=[O:23])[CH3:2].[CH2:18]([N:17]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:10][CH2:11][CH3:12])[C:22]1=[O:23])[CH2:19][CH3:20]
Reactant: NC(N)=O
Reactant: CCNCCCNCC
Reactant: CCCNCCCNCCC
Product: CCCN1CCCN(CCC)C1=O
Product: CCN1CCCN(CC)C1=O

Procedure:
Further, a process has been known wherein N,N'-diethyl-1,3-propanediamine or N,N'-dipropyl-1,3-propanediamine is reacted with urea to obtain 1,3-diethyltetrahydro-2(1H)-pyrimidinone or tetrahydro-1,3-dipropyl-2(1H)-pyrimidinone with a yield of 64.0% or 21.5%, respectively (J. Med. Chem., vol. 14, page 140 (1971)). These processes are also commercially unsatisfactory due to the low yields of the objective products.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:10][CH2:11][CH2:12][CH:13]([OH:31])[CH2:14][CH2:15][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][CH3:30])=[CH:5][CH:4]=1.[C:46]1(=[O:52])[O:51][C:49](=[O:50])[CH2:48][CH2:47]1.[CH2:53]([N:55]([CH2:58][CH3:59])[CH2:56][CH3:57])[CH3:54].CN1C=CN=C1>C(Cl)Cl>[CH2:53]([N:55]([CH2:58][CH3:59])[CH2:56][CH3:57])[CH3:54].[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:10][CH2:11][CH2:12][CH:13]([O:31][C:46](=[O:52])[CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:14][CH2:15][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][CH3:30])=[CH:43][CH:42]=1
Reactant: CCCCCCCCCCCCCCCCCC(O)CCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(CCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1-(bis(4-methoxyphenyl)(phenyl)methoxy)icosan-3-ol (6.8 g, 11.0 mmoles), succinic anhydride (1.1 g, 11.0 mmoles), triethylamine (4.6 mL, 33.0 mmoles) and 1-methylimidazole (0.44 mL, 5.5 mmoles) are dissolved in methylene chloride (68 mL). The reaction is stirred at ambient temperature for five days, during which time the solution darkened. The solution is then diluted with methylene chloride (100 mL) and washed twice with ice-cold aqueous citric acid (10% [w/v], 50 mL) and once with saturated aqueous sodium chloride (50 mL). The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and evaporated to a dark resin. The crude product is purified on silica gel (200 mL bed volume) eluting with methylene chloride:triethylamine (95:5 [v/v/v], 500 mL), then methylene chloride:methanol:triethylamine (93:2:5 [v/v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a resin. The resin is dried well in vacuo. The yield is 2.4 g (30%).
Reaction SMILES: [CH:1]1([O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])(=O)=O>C(O)(=O)C>[Cl:21][CH2:16][C:15](=[O:17])[C:9](=[N:8][O:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOC1CCCCC1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC1CCCCC1)C(=O)CCl
Yield: 58.9 %

Procedure:
Ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.3 g.), acetic acid (41.3 ml.) and sulfuryl chloride (23.8 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].C[Si]([N:15]=[N+:16]=[N-:17])(C)C>>[CH:5]1[CH:4]=[C:3]([N:8]2[NH:17][N:16]=[N:15][C:9]2=[O:10])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C=Nc1ccccc1Cl
Product: O=c1nn[nH]n1-c1ccccc1Cl
Yield: 78.1 %

Procedure:
2-Chlorophenylisocyanate (7 g) and trimethylsilyl azide (7.9 g) were mixed and heated under refluxing for eight hours. The excessive trimethylsilyl azide was distilled off under reduced pressure and to the residue there were added 40 ml of methanol. Thereafter, the methanol was evaporated and the residue was purified by flush column chlomatography (hexane:ethyl acetate=2:1) to obtain the desired 1-(2-chlorophenyl)-5(4H)-tetrazolinone (7 g) having a melting point in the range of from 124.5° to 125.5° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:25])[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(C)nc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)cn1
Temperature: 23 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (490 mg, 1.36 mmol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (172 mg, 4.1 mmol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (316 mg, 67%) as a brown solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.[OH-].[Na+].O1CCOCC1.Cl>C(OCC)(=O)C.O>[OH:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]=13)[O:7][C:6]([CH2:5][CH2:4][C:3]([OH:23])=[O:2])([CH3:22])[CH2:15][CH2:14]2
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCC3C1
Reaction time: 5 h
Yield: 73.3 %

Procedure:
1.0 gram (3.16 mmol) of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester, prepared as described in Example 13, was mixed with 20 mL of 2N NaOH and 20 mL of dioxane, the mixture was stirred for 5 hours and was acidified with dilute HCl. Water and ethyl acetate were added and the organic layer was separated, washed and dried over MgSO4. After the removal of solvents, the residue was further purified by flash column chromatography on silica gel (3:2 ethyl acetate/hexane) to afford 700 mg of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.29 (s, 1H), 4.70 (s, 1H), 3.52-3.46 (d, 2H), 2.69-2.55 (m, 2H), 2.52-2.47 (m, 2H), 2.00-1.64 (m, 8H), 1.43-1.15 (m, 5H); MS: 302 (M+H+, 73%), 325 (M+Na+, 100%)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1.[C:41]([O-])(=[O:43])C.[Na+]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)[CH:16]=2)=[O:43])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(C)c1cc(F)ccc1NC(N)=S
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(4-fluoro-2-isopropylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.140 g, 41%): 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.11 (s, 1H), 9.41 (s, 1H), 8.13-8.04 (m, 2H), 8.02-7.92 (m, 2H), 7.61 (dq, J=7.8, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.43-7.31 (m, 2H), 7.15 (dd, J=10.4, 3.0 Hz, 1H), 7.10 (t, J=5.6 Hz, 1H), 7.03 (td, J=8.5, 3.0 Hz, 1H), 3.26-3.10 (m, 2H), 2.97 (pd, J=6.9, 1.6 Hz, 1H), 2.73 (dd, J=8.5, 6.7 Hz, 2H), 1.90-1.76 (m, 2H), 1.15 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.97, −114.41; ESIMS m/z 601 ([M+H]+), 599 ([M−H]−).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:44])[CH2:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])=[O:10])[CH2:2]1.C(=O)([O-])[O-:46].[K+].[K+].[CH2:51](Br)[CH:52]=[CH2:53]>C(#N)C.C(Cl)(Cl)Cl>[CH2:51]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][C@@H:21]([OH:46])[CH2:20][N:19]2[C:23](=[O:44])[CH2:24][C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])=[O:10])[CH2:2]1)[CH:52]=[CH2:53]
Reactant: O=C([O-])[O-]
Reactant: C=CCBr
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C=CCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 37 mg of (2R)-N-((3S)-3-piperidylmethyl)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.9 ml of acetonitrile, 0.0055 ml of allyl bromide and 25 mg of potassium carbonate were added at room temperature, followed by 1.5 hours' stirring at 80° C. under heating. The reaction liquid was diluted with chloroform, washed successively with water and 1N aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. After distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1), to provide 23 mg of the title compound as a white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22]
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogen carbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(3-fluoro-4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.15 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.52 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 64%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]3[C:21]([O:22][CH3:23])=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:28]=[CH:27][N:26]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(F)ccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 67 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (160 mg, 0.44 mmol) in IPA (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (72 mg, 0.47 mmol) and DIPEA (229 μL, 1.34 mmol) and the reaction mixture heated at 90° C. for 72 hours. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 339 as a white solid (119 mg, 66%). 1H NMR 400 MHz δ (d6-DMSO): 7.80 (1H, s), 7.58 (1H, d, J=7.3 Hz), 7.55-7.47 (2H, m), 7.47-7.40 (3H, m), 7.39 (1H, dd, J=8.8, 4.0 Hz), 7.14 (2H, br s), 7.10 (1H, dd, J=12.2, 8.8 Hz), 5.24 (1H, quin, J=6.9 Hz), 3.32 (3H, d, J=0.7 Hz), 1.43 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.86 min, [M+H]+=404
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[CH:12]1(O)[CH2:16][CH:15]=[CH:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH:15]2[CH2:14][CH:13]=[CH:12][CH2:16]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: OC1CC=CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)ccc1OC1CC=CC1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 2-nitro-4-chlorophenol (3.46 g, 20 mmol), 3-cyclopenten-1-ol (2.1 g, 24 mmol), triphenylphosphine on polystyrene (3.0 mmol per gram, 10 g, 30 mmol) and di-tert-butyl azadicarboxylate (6.9 g, 30 mmol) in THF (200 mL ) was shaken for 1 hour and filtered. The resin was washed with dichloromethane (4×50 mL). The combined organic solutions were mixed with 20 g of silica gel and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 4.08 g (85%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.8, 2.7 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.75 (br s, 2H), 5.03–5.13 (m, 1H), 2.87 (d, J=6.8 Hz, 1H), 2.82 (d, J=6.8 Hz, 1H), 2.65 (br s, 1H), 2.59 (br s, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]([CH3:12])=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:13])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18](S(C)(=O)=O)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[S:11][CH:10]=[C:9]([CH3:12])[C:8]=3[C:3]=2[CH:1]=[O:2])[N:17]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1csc2ccc(O)c(C=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C=O)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture comprising 2.1 g of 4-formyl-5-hydroxy-3-methylbenzothiophene, 2.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.8 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for 3 hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.1 g (yield: 86%) of the desired compound.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:11])=[O:9])[C:4](=[O:24])O1.[CH2:26]=O.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:26][N:36]([CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:4](=[O:24])[C:5]=2[OH:6])=[O:9])=[C:14]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:15]=1
Reactant: CN(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCCN1CCOCC1
Reactant: C=O
Product: CN(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 69 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine as described in Method 44B to give the title compound as a white solid (0.032 g, 69% yield). 1HNMR (300 MHz, DMSO) δ: 9.65 (1H, bs), 7.74 (1H, dd, J=8.41, 2.56 Hz), 7.64–7.59 (1H, m), 7.43–7.38 (1H, m), 4.99 (2H, s), 4.15 (2H, s), 4.00–3.53 (10H, m), 3.43 (2H, s), 3.38 (3H, s), 3.11 (3H, s).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([O:13][CH3:14])=[O:12].[CH2:15]1[N:20]2[CH2:21][CH2:22][N:17](CC2)C1.[N:23]([CH:26]1[CH2:31][C:30]([CH2:33][N:34]=[C:35]=[O:36])([CH3:32])[CH2:29][C:28]([CH3:38])([CH3:37])[CH2:27]1)=[C:24]=[O:25]>C(Cl)(Cl)Cl>[CH3:14][O:13][C:11]([NH:10][C:2]1[N:3]([C:24]([NH:23][CH:26]2[CH2:31][C:30]([CH2:33][NH:34][C:35]([N:17]3[C:22]4[CH:9]=[CH:4][CH:5]=[CH:6][C:21]=4[N:20]=[C:15]3[NH:10][C:11]([O:13][CH3:14])=[O:12])=[O:36])([CH3:32])[CH2:29][C:28]([CH3:38])([CH3:37])[CH2:27]2)=[O:25])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:12]
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C1CN2CCN1CC2
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1C(=O)NCC1(C)CC(NC(=O)n2c(NC(=O)OC)nc3ccccc32)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of methyl 2-benzimidazolecarbamate (19.1 parts) and triethylenediamine (0.1 part) in chloroform (300 parts) was slowly added 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethylcyclohexane (11.1 parts). The reaction mixture was stirred at room temperature overnight, filtered and the solvent removed from the filtrate under reduced pressure. The residue from the filtrate was triturated with hexane and the product methyl 1-{5-[2-(methoxycarbonylamino)-1-benzimidazolylcarbonylamino]-1,3,3-trimethylcyclohexylmethylcarbamoyl}-2- benzimidazolecarbamate (28.5 parts) was collected by filtration. It exhibited a melting point of 82°-83°C.