Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C1(CC[Mg]Br)CC1.[CH3:17][C:18]1[C:22]([C:23]2[CH:24]=[C:25]([C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[O:36])[C:26]3[N:30]=[C:29]([O:31][CH2:32][CH3:33])[NH:28][C:27]=3[CH:34]=2)=[C:21]([CH3:43])[O:20][N:19]=1>C(OCC)C.C1COCC1>[CH:7]1([CH2:6][CH2:5][C:35]([C:25]2[C:26]3[N:30]=[C:29]([O:31][CH2:32][CH3:33])[NH:28][C:27]=3[CH:34]=[C:23]([C:22]3[C:18]([CH3:17])=[N:19][O:20][C:21]=3[CH3:43])[CH:24]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[OH:36])[CH2:9][CH2:8]1
Reactant: BrCCC1CC1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Agent: Br[Mg]CCC1CC1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(CCC3CC3)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reaction time: 0.17 h

Procedure:
Magnesium metal (39.0 mg, 2.0 mmol) and iodine (one crystal) was taken up in dry diethyl ether (1.2 mL) and (2-bromoethyl)cyclopropane (200 mg, 1.3 mmol) was added dropwise until iodine color faded. The remainder was then added dropwise over 15 minutes to maintain a gentle reflux and then cooled to 0° C. (2-cyclopropylethyl)magnesium bromide (1.1 M, 0.38 mL, 0.41 mmol) was added to a cooled (0° C.) solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) in dry THF (1.0 mL) under argon and allowed to stir for 10 minutes. The reaction was quenched with water, extracted three times with EtOAc, and combined organic layers were concentrated and purified by reverse-phase HPLC to give 3-cyclopropyl-1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-1-(pyridin-2-yl)propan-1-ol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mL concentrated HCl and heated to 65° C. for 2 hours and concentrated to afford the desired product as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH3:36].C(=O)([O-])[O-]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[CH3:36])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (308 mg, 974 μmol) in DMF (2.43 ml) was added 1-(chloromethyl)-2-methylnaphthalene (223 mg, 1.17 mmol) and cesiuim carbonate (952 mg, 2.92 mmol). The reaction was stirred at rt for 2 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (364 mg, 80% yield) as an off-white oil. MS m/z 493 (MNa)+.
Reaction SMILES: [C:1]([C:6]1[C:15](=[O:16])[C:14]2[C:9]([C:10]3[C:11]([N:17]=[N:18][CH:19]=3)=[CH:12][CH:13]=2)=[N:8][CH:7]=1)([O:3]CC)=[O:2].Cl>[OH-].[Na+]>[C:1]([C:6]1[C:15](=[O:16])[C:14]2[C:9]([C:10]3[C:11]([N:17]=[N:18][CH:19]=3)=[CH:12][CH:13]=2)=[N:8][CH:7]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1=CN=c2c(ccc3c2=CN=N3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1=CN=c2c(ccc3c2=CN=N3)C1=O

Procedure:
3-Carbethoxy-4-oxo-pyrazolo[5,4-h]quinoline (0.05 mole) is added to a 10% sodium hydroxide solution (200 ml). The reaction mixture is refluxed for 3 hours, which time is required for complete dissolution to occur. The cold solution is made acidic with a dilute hydrochloric acid solution. The resulting 3-carboxy-4-oxo-pyrazolo[5,4-h]quinoline precipitates out. It is suction filtered, washed with water and dried in vacuo.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]=[C:13]([NH:15][C:16]3[C:21]([S:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)=[CH:20][C:19]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:18][N:17]=3)[S:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+:41]>CCO>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]=[C:13]([N-:15][C:16]3[C:21]([S:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=4)=[CH:20][C:19]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:18][N:17]=3)[S:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Na+:41].[Na+:41]
Reactant: COC(=O)c1ccc(Sc2cc(Oc3ccccc3)cnc2Nc2nc(C3CCN(C(C)=O)CC3)ns2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCC(c2nsc([N-]c3ncc(Oc4ccccc4)cc3Sc3ccc(C(=O)[O-])cc3)n2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl 4-(2-(3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-phenoxypyridin-3-ylthio)benzoate (0.15 g, 0.26 mmol) in EtOH was treated with NaOH (0.56 mL, 0.56 mmol). The solution was stirred at 60° C. for 1 hour. The solution was concentrated to give sodium (3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-yl)(3-(4-carboxylatophenylthio)-5-phenoxypyridin-2-yl)amide as a solid. To this salt was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.066 g, 0.35 mmol), 1-hydroxybenzotriazole hydrate (0.053 g, 0.35 mmol) in DMF (2 mL). N1,N1-dimethylethane-1,2-diamine (0.038 mL, 0.35 mmol) and DIEA (0.060 mL, 0.35 mmol) were added. The reaction stirred at 50° C. for 3 hours. The solution was then diluted with water, extracted with dichloromethane and concentrated. The crude material was purified via reverse phase HPLC to afford 4-(2-(3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-phenoxypyridin-3-ylthio)-N-(2-(dimethylamino)ethyl)benzamide (0.064 g, 36% yield). 1H NMR (CDCl3) δ 1.76-1.88 (m, 2H), 2.04-2.12 (m 2H), 2.10 (s, 3H), 2.25 (s, 6H), 2.50 (t, 2H), 2.82 (t, 1H), 3.00-3.06 (m, 1H), 3.20 (t, 1H), 3.48 (dd, 2H), 3.87 (d, 1H), 4.54 (d, 1H), 6.80 (bs, 1H), 7.02 (d, 1H), 7.14-7.19 (m, 3H), 7.38 (t, 2H), 7.67 (d, 1H), 7.71 (d, 2H), 8.30 (d, 1H), 9.20 (bs, 1H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)([O-:3])=[O:2].CO.[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>CC(O)=O>[N+:1]([CH2:4][CH2:5][C:6](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(N)=S
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: NC(=S)NN=C(CC[N+](=O)[O-])c1ccccc1
Yield: 60.4 %

Procedure:
Into a round bottom flask containing 3-nitropropiophenone (1.02 g, 5.53 mmol), 30 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes. To the warm ketone solution, thiosemicarbazide (0.485 g, 5.33 mmol) and 1% solution of HOAc (0.4 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 30 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (50% EtOAc/50% hex) to obtain 0.8119 g (3.22 mmol) of the product in a 58% yield.
Reaction SMILES: BrC1N=C(/C=C(\C#N)/C(NC(C2C=CC(OCCN(CC)CC)=CC=2)CCC)=O)C=CC=1.[F:33][C:34]1[N:39]=[C:38]([CH:40]=O)[CH:37]=[CH:36][CH:35]=1.[C:42]([CH2:44][C:45]([NH:47][CH:48]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)=[CH:54][CH:53]=1)[CH2:49][CH2:50][CH3:51])=[O:46])#[N:43]>>[C:42](/[C:44](=[CH:40]\[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[N:39]=1)/[C:45]([NH:47][CH:48]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]2[CH2:62][CH2:63][O:64][CH2:65][CH2:66]2)=[CH:54][CH:53]=1)[CH2:49][CH2:50][CH3:51])=[O:46])#[N:43]
Reactant: O=Cc1cccc(F)n1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCOCC2)cc1
Agent: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccc(OCCN2CCOCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and 2-cyano-N-(1-(4-(2-morpholinoethoxy)phenyl)butyl)acetamide (32) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 37 (130 mg, 77%) as a light yellow oil: MS (ES+) m/z 453.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][C:57]([F:61])([F:60])[F:56])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 2,2,2-trifluoroethylamine (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (30 mg, 35%) as a white solid. MS: m/e=426.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.CS(C)=O.C1C=CC=CC=1.[F-:22].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:22]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
50 g of 3,4-dichloro-nitro benzene were added to a mixture of 120 ml of dimethylsulfoxide, 80 ml of benzene and 35 g of potassium fluoride and the mixture was stirred at 180°-185° C. for two hours. The water vapor was entrained and the distillate was extracted with isopropyl ether. The combined organic phases were dried and distilled at 40° C. under a pressure of 3 to 4 mm Hg. The residue was rectified at a pressure of 15 mm Hg to obtain 29 g of 3-chloro-4-fluoro-nitrobenzene melting at 41° to 43° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11](C(Cl)=O)[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC([C@H]2[C@@H](C3C=CC(Cl)=CC=3)N([C:54]([N:56]3[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][S:64]([CH3:67])(=[O:66])=[O:65])[CH2:58][CH2:57]3)=[O:55])C(C3C=CC=CC=3OCC)=N2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:54]([N:56]3[CH2:57][CH2:58][N:59]([CH2:62][CH2:63][S:64]([CH3:67])(=[O:65])=[O:66])[CH2:60][CH2:61]3)=[O:55])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and 1-(2-methanesulfonylethyl)-piperazine (example 11) in an analogous manner as described in example 8. LR-MS: 673.3 [(M+H)+].
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:10][C:3]1[C:2]([CH:19]=[O:20])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=O)c(Cl)n1
Temperature: 25 °C

Procedure:
The 3-bromo-2-chloro-6-methoxy-pyridine (0.50 g, 2.26 mmol) obtained in (19-1) above was dissolved in toluene (dehydrated) (11 mL), and thereafter, n-butyllithium (1.46 mL, 2.3 mmol, 1.57 mmol/L hexane solution) was added dropwise to the solution at −78° C. in an argon atmosphere. The obtained mixture was stirred at the same temperature as described above for 30 minutes, and DMF (1.0 mL) was then added to the reaction solution. The obtained mixture was further stirred for 30 minutes. Thereafter, a saturated ammonium chloride water (20 mL) was slowly added to the reaction solution, and the temperature of the mixture was then increased to room temperature. The mixture was extracted with diethyl ether (20 mL) twice, and organic layers were gathered. The resultant was dried over anhydrous sodium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was purified by silica gel column chromatography (SiO2 30 g, hexane:ethyl acetate=95:5 to 80:20), so as to obtain 180 mg of 2-chloro-6-methoxy-3-pyridinecarboxaldehyde.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]#[N:13])[CH2:11][NH:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>C(Cl)Cl>[CH2:23]([S:26]([N:10]1[CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)([C:12]#[N:13])[CH2:11]1)(=[O:28])=[O:27])[CH2:24][CH3:25]
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CC1(c2ccccn2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(C#N)(c2ccccn2)C1
Reaction time: 4 h

Procedure:
A suspension of 3-pyridin-2-ylazetidine-3-carbonitrile hydrochloride (365 mg, 1.9 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with i-Pr2NEt (1.1 mL, 6.3 mmol) and n-PrSO2Cl (0.35 mL, 3.1 mmol) dropwise. After 4 h, the reaction was quenched with the addition of 2 M aqueous NaOH (10 mL) and stirred 72 h before being extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 1-(propylsulfonyl)-3-pyridin-2-ylazetidine-3-carbonitrile (II-1) as an orange oil. Analytical LCMS: single peak (214 nm), 2.664 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[C:4]=2[CH:3]=[CH:2]1.CC1(C)C(C)(C)OB(C2C3C=COC=3C=CC=2)O1.[CH3:36][O:37][C:38](=[O:57])[NH:39][C:40]1[CH:45]=[C:44]([C:46]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=2)=[O:47])[CH:43]=[C:42](Br)[CH:41]=1>>[CH3:36][O:37][C:38](=[O:57])[NH:39][C:40]1[CH:45]=[C:44]([C:46]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=2)=[O:47])[CH:43]=[CH:42][C:41]=1[C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Oc1cccc2occc12)C(F)(F)F
Reactant: COC(=O)Nc1cc(Br)cc(C(=O)c2ccnc(OC)c2)c1
Agent: CC1(C)OB(c2cccc3occc23)OC1(C)C
Product: COC(=O)Nc1cc(C(=O)c2ccnc(OC)c2)ccc1-c1cccc2occc12

Procedure:
Trifluoro-methanesulfonic acid benzofuran-4-yl ester was converted to 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran using conditions described in Wang, Y.-C. and Georghiou, P. E., Org. Lett. 4: 2675-78 (2002). The Suzuki coupling of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran to [3-bromo-5-(2-methoxy-pyridine-4-carbonyl)-phenyl]-carbamic acid methyl ester was carried out as described in Example 75 to give [3-benzofuran-4-yl-5-(2-methoxy-pyridine-4-carbonyl)-phenyl]-carbamic acid methyl ester. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.38 (dd, J=5.2, 0.5 Hz, 1H), 8.29 (t, J=1.6 Hz, 1H), 8.06 (t, J=1.7 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.75 (t, J=1.6 Hz, 1H), 7.62-7.56 (m, 1H), 7.48-7.42 (m, 2H), 7.29 (dd, J=5.2, 1.3 Hz, 1H), 7.15 (dd, J=2.1, 1.0 Hz, 1H), 7.08 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[C:23]([F:22])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cccc(F)c1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cccc(F)c3)ncc21

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.32 mmol), 3-fluoroaniline (54 mg, 0.48 mmol), i-PrOH (2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give the title compound. The final compound was purified by reverse phase HPLC and basified to give the free base (50 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.96 (m, 8H) 4.04 (t, J=14 Hz, 2H) 4.78 (m, 1H) 6.59-6.87 (m, 1H) 7.16-7.33 (m, 1H) 7.38 (d, J=8 Hz, 1H) 7.79 (d, J=12 Hz, 1H) 8.26 (s, 1H) 9.66 (br. s., 1H). [M+H] calc'd for C19H20F3N5O, 392. found 392.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)#[N:8]>O.CO>[C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:21])=[O:1])[N:15]=1)#[N:8]
Reactant: O=S([O-])OO
Reactant: CSc1nccc(-c2[nH]ncc2C#N)n1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1nccc(-c2[nH]ncc2C#N)n1
Reaction time: 20 h

Procedure:
A solution of Oxone (475 mg, 0.77 mmol, 1.2 equiv) in water(10 mL) was added to a solution of 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine (4-3, 670 mg, 2.86 mmol, 1 equiv) in methanol (150 mL), and the resulting mixture was stirred under ambient condition for 20 hours. The reaction was concentrated and the resulting residue was sonicated in water and filtered to provide 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidine (4-4) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 9.11(dd, 1H, J=5 Hz), 8.83 (br s, 1H), 8.10 (dd, 1H, J=5 Hz), 3.04 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][O:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][O:26][NH:27][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NOCCCOCc1ccccc1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=CNc1nc(Cl)c(NC=O)c(NOCCCOCc2ccccc2)n1
Yield: 50.1 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (5.4 g, 23.0 mmol), 3-benzyloxyprop-1-oxyamine (4.14, 23.0 mmol), triethylamine (10 ml) and dioxan (50 ml) was stirred at reflux temperature for 3 hours, cooled, filtered and evaporated to dryness. Column chromatography on silica gel (eluted with chloroform-ethanol, 25:1) gave the title compound (4.38 g, 50%). IR: υmax (KBr) 3248, 1692, 1589, 1570, 1473, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 1.88 (2H, quintet, J=6.3 Hz, CH2CH2CH2) 3.57 (2H, t, J=6.3 Hz, CH2OCH2Ph), 3.95 (2H, t, 6.3 Hz, CH2ONH), 4.47 (2H, s, CH2Ph), 7.32 (5H, m, Ph), 8.14 (1H, s, CHONH), 9.26 (1H, s, CHONH), 9.42 (1H, br.s, D2O exchangeable, NHOCH2), 10.83 (2H, br.s, 2×NHCHO).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH:20]C(OC(C)(C)C)=O)=[C:16]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][O:28][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][C:17]=1[NH2:20]
Reactant: CC(C)(C)OC(=O)Nc1ncc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1OCc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(N2CCNCC2)nc1OCc1cccc(Cl)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
5′-tert-Butoxycarbonylamino-6′-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3q (50 mg, 96 μmol) was dissolved in CH2Cl2 (1 mL) and trifluoroacetic acid (1 mL) was added with stirring at room temperature. The solution was stirred at room temperature for 3 h then diluted with CH2Cl2 (20 mL). The CH2Cl2 solution was washed with saturated aqueous NaHCO3 (3×50 mL) and brine (25 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated in vacuo to give the title compound 3-O as a reddish-brown solid (29 mg, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14]O)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][N:42]=[N+:43]=[N-:44])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(CN=[N+]=[N-])o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
99.4 mg of (5-hydroxymethyl-furan-2-ylmethyl)-carbamic acid tert-butyl ester was added to 4.5 mL of toluene, added successively with 83.7 mg of 1,8-diazabicyclo[5,4,0]undec-7-ene and 151.6 mg of diphenylphosphoryl azide, and stirred at room temperature under nitrogen atmosphere for 1 hour and 45 minutes. Then the solvent was evaporated, followed by purification and separation by silica gel column chromatography, to afford 88.6 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[CH2:13]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=1)[CH3:14].Cl>ClCC(Cl)(Cl)Cl>[CH2:7]=[C:6]([CH2:8][C:9](=[O:10])[C:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][C:15]=1[CH2:13][CH3:14])[C:5]([OH:12])=[O:11]
Reactant: C=C1CC(=O)OC1=O
Reactant: CCc1cc2ccccc2o1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Product: C=C(CC(=O)c1c(CC)oc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
At room temperature, 8.0 g of anhydrous aluminum chloride and 3.59 g of itaconic acid anhydride were dissolved in distilled tetrachloroethane, 20 ml, with vigorous agitation. Then the solution was cooled on an ice-water bath and to this, 2-ethybenzofuran, 4.39 g, dissolved in 10 ml of tetrachloroethane were added dropwise. After three hours stirring in an ice-water bath followed by 12 hrs. stirring at room temperature, the reaction mixture was poured into ice-water, 80 g, containing 20 ml of HCl and extracted with ethyl acetate. The ethyl acetate layer was extracted with 50 ml of a 10% NaCO3 solution and then the aqueous layer was acidified with 10% HCl again and extracted with ethyl acetate. After washing with water, drying and removal of the solvent, the resulting viscous oily substance was extracted with ligroin (20 ml×3). Needle-like crystals were obtained after overnight standing at room temperature.