Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:15]1([C:21]2[C:22]([CH:26]=[O:27])=[CH:23][O:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[C:28]([O:27][CH:26]([C:22]1[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:25][O:24][CH:23]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: O=Cc1cocc1-c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(C)=O)c1cocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dodecylmagnesium bromide (a 1.0M solution in THF; 2.11 ml, 2.11 mmol) was added to a solution of 4-phenyl-3-furaldehyde (303 mg, 1.76 mmol) in THF at 0 degrees under argon and gradually allowed to warm to room temperature with stirring. When all of the aldehyde was consumed acetic anhydride (719 mg, 7.04 mmol) was added and stirring was continued for 2 hours more. The reaction was quenched with saturated ammonium chloride and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated to a yellow oil which was purified by flash chromatography on silica using 3% ethyl ether hexanes to give the title compound.
Reaction SMILES: [F:1][C:2]1([F:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:13]([CH3:15])[CH3:14])[C@:4]([CH2:17][C:18](O)=[O:19])([OH:16])[CH2:3]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][NH:34][CH3:35].N1C2C=CC=CC=2N=C1CCCN(C)C(=O)C[C@@]1(O)C([2H])([2H])C([2H])([2H])C2C(=CC=C(F)C=2)[C@@H]1C(C)C>>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][N:34]([CH3:35])[C:18](=[O:19])[CH2:17][C@@:4]1([OH:16])[CH2:3][C:2]([F:1])([F:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@@H:5]1[CH:13]([CH3:15])[CH3:14]
Reactant: CNCCCc1nc2ccccc2[nH]1
Reactant: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)O
Agent: [2H]C1([2H])c2cc(F)ccc2[C@H](C(C)C)[C@@](O)(CC(=O)N(C)CCCc2nc3ccccc3[nH]2)C1([2H])[2H]
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1

Procedure:
Intermediate 17d is prepared from 15c and 16e in a manner analogous to that of Example 2, step 1 for 17b.
Reaction SMILES: [C:1]([C:3]1([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].[OH-].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CO>[O:13]=[C:6]1[CH2:7][CH2:8][C:3]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: COC(=O)C1CC(C#N)(c2ncccn2)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1(c2ncccn2)CCC(=O)CC1
Yield: 68 %

Procedure:
The crude methyl 5-cyano-2-oxo-5-(pyrimidin-2-yl)cyclohexanecarboxylate was completely dissolved in THF/MeOH (1/1, 8 mL) and the clear solution was treated with 1 M aqueous KOH (3.0 mL, 1.2 equiv.) and H2O (2.5 mL). After being refluxed for 24 h, The organic solvent was removed under reduced pressure. The concentrated reaction was diluted (H2O), neutralized (10% citric acid) and extracted (3×DCM). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to provide 4-oxo-1-(pyrimidin-2-yl)cyclohexanecarbonitrile (333 mg, 1.66 mmol, 68% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][S:9](Cl)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:17][C:18](=[NH:21])[O:19][CH3:20])([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C1COCC1>[C:13]([NH:17][C:18](=[N:21][S:9](=[O:11])(=[O:10])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:19][CH3:20])([O:15][CH3:16])=[O:14]
Reactant: O=S(=O)(Cl)NCc1ccccc1
Reactant: COC(=N)NC(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NC(=NS(=O)(=O)NCc1ccccc1)OC
Temperature: 25 °C

Procedure:
A solution of benzylsulfamoyl chloride (168 g) in anhydrous THF (300 ml) is added dropwise to a stirred solution of N-carbomethoxy-O-methylisourea (107 g) and triethylamine (90 g) in anhydrous THF (800 ml) under nitrogen at -70° C. The resulting suspension is warmed to RT, filtered and the filtrate evaporated in vacuo. The residue is partitioned between methylene chloride and 0.5N aq. HCl. The organic layer is dried, filtered, and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1

Procedure:
10.1 g of 1H-naphth[2,3-d]imidazole-2-thiol are suspended in 100 ml of alcohol in a 250 ml volume sulphonating flask equipped with a stirrer, thermometer, cooler and dropping funnel. A solution of 4.0 g of sodium hydroxide in 50 ml of water was then added dropwise, and a clear solution formed. The solution was then heated to boiling, 8.2 g of 2-chloromethyl-pyridine-hydrochloride were added, and the resulting mixture was boiled under reflux overnight. The reaction mixture was then concentrated by evaporation, the residue was taken up in 600 ml of ethyl acetate and 200 ml of water, and the ethyl acetate phase was washed twice with 200 ml of water, dried over sodium sulphate, and concentrated by evaporation in vacuo. The residue was recrystallised once from ethyl acetate/petroleum ether and provided 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a melting point of 165°-167°; the hydrochloride melts at 230°-231°.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[C:12]1([C:18]#[C:19][C:20]2[O:24][C:23]([C:25](ON3C(=O)CCC3=O)=[O:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C=O)C.C(N(CC)CC)C>C(OCC)C>[C:12]1([C:18]#[C:19][C:20]2[O:24][C:23]([C:25]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:26])=[CH:22][CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(C#Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
(R)-aminocarnitine (16 mg, 0.1 mmol) and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate (60 mg, 0.19 mmol) were dissolved into DMF (1 mL). Triethylamine (50 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The powder was purified by silica gel chromatography (elution 10% MeOH/CH2Cl2 to 100% MeOH) to give the title compound as a white powder (10 mg, 24%). 1H NMR (400 MHz, D2O) δ 7.35-7.33 (m, 2H), 7.25-7.16 (m, 3H), 7.02 (d, 1H, J=3.7 Hz), 6.58 (d, 1H, J=3.6 Hz), 4.90-4.80 (m, 1H), 3.63-3.55 (m, 1H), 3.47-3.42 (m, 1H), 3.04 (s, 9H), 2.51-2.41 (m, 2H); MS ESI 355.1 [M+H]+, calcd for [C20H22N2O4+H]+ 355.16.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].C(O[C:23](=[O:34])[C:24]([NH2:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:25][CH3:26])C>O1CCCC1>[CH2:25]([C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:33][C:8](=[O:9])[N:1]([C:2]2[S:3][C:4]([CH3:7])=[N:5][N:6]=2)[C:23]1=[O:34])[CH3:26]
Reactant: CCOC(=O)C(N)(CC)c1ccccc1
Reactant: Cc1nnc(N)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC1(c2ccccc2)NC(=O)N(c2nnc(C)s2)C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
2.30 g of 2-amino-5-methyl-1,3,4-thiadiazole were dissolved at room temperature in 40 ml of dry tetrahydrofuran in a nitrogen atmosphere and with exclusion of moisture. 3.24 g of 1,1'-carbonyldiimidazole were then added. The mixture was stirred for 30 minutes at 50° C. 4.15 g of 2-amino-2-phenylbutyric acid ethyl ester (product from Example 3, stage 1) in 10 ml of dry tetrahydrofuran were added dropwise to the resultant suspension and stirred for 20 hours at 50° C. Once the solvent had been removed by distillation, the residue was recrystallised from ethanol. 3.94 g of 5-ethyl-3-(5-methyl[l.3.4]thiadiazol-2-yl)-5-phenyl-2,4-imidazolidinedione (58% of th.) were obtained in the form of white crystals (mp 223-225° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: CCNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1nc(Cl)ccc1N
Temperature: 140 °C
Yield: 99.9 %

Procedure:
To a solution of 6-chloro-N-ethyl-3-nitropyridin-2-amine (1.82 g, 9.04 mmol) in ethanol (20 mL) is added iron powder (2.52 g, 45.2 mmol) followed by a solution of ammonium chloride (2.42 g, 45.2 mmol) in water (8 mL). The mixture is heated in a microwave reactor at 140° C. for 30 min. The mixture is diluted with EtOAc, filtered and evaporated to afford the title compound as a brown oil (1.55 g, 100%) which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:24]OC(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]3[O:21][CH:24]=[N:23][N:22]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(OC)OC
Reactant: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 10.5 %

Procedure:
In a 50-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.920 g, 1.0 eq.) was dissolved in THF (23 mL, 25V), added trimethylorthoformate (0.328 g, 1.1 eq.) and added methanesulphonic acid (0.161 g, 0.5 eq.). The Reaction mixture was refluxed at 70° C. for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.60 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 35% to 40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (100 mg), Yield (10.54). 1H NMR (400 MHz, CDCl3) δ 10.25 (S, 1H), 8.5 (S, 1H), 8.04 (S, 1H), 7.89 (S, 1H), 7.51-7.54 (d, J=11.2 Hz, 1H), 7.28 (S, 1H), 7.23 (S, 1H), 6.27-6.30 (d, J=10.8 Hz, 1H), 3.35 (S, 3H): LCMS for C14H10F3N5O2 [M+1]+ 337.3 at 3.60 min (LCMS 93.43%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:15]([O:4][CH:1]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[Br:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1C(OC(c1ccccc1)c1ccccc1Br)c1ccccc1
Temperature: 60 °C

Procedure:
Potassium carbonate (9.12 g) was suspended in dimethylformamide (25 ml) and 2-bromophenol (3.46 g) was added portionwise. Benzyl bromide (3.76 g) was added and the mixture heated to 60° C. for 4 h. After cooling the mixture was added to water (250 ml) and extracted three times with diethyl ether. The organic layer was separated and washed with 2M sodium hydroxide solution (100 ml) before drying over sodium sulphate. After filtration, evaporation yielded (5.13 g) as a colourless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2.[CH3:25][C:26]([CH3:44])([CH3:43])[C@@H:27]([C:40](O)=[O:41])[NH:28][C:29]([O:31][C@@H:32]1[CH2:34][C@H:33]1[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:25][C:26]([CH3:44])([CH3:43])[C@@H:27]([C:40]([N:19]1[CH2:20][C@H:16]([O:15][C:4]2[C:3]([Cl:2])=[N:12][C:11]3[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=3)[N:5]=2)[CH2:17][C@H:18]1[C:21]([O:23][CH3:24])=[O:22])=[O:41])[NH:28][C:29]([O:31][C@@H:32]1[CH2:34][C@H:33]1[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])=[O:30]
Reactant: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(OC)ccc3nc2Cl)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 20 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
A solution (0.2 M) of methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride in DMF was treated with 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine (1.1 eq), DIEA (5 eq) and HATU (1.2 eq). The resulting mixture was stirred at 20° C. for 5 h, then diluted with EtOAc. The organic layer was separated and washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine. The dried organic phase was concentrated under reduced pressure to give a residue that was purified by flash chromatography (eluent 10-30% EtOAc/petroleum ether) to furnish the title compound (96%) as an oil. MS (ES+) m/z 604 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[C:4]=1[C:5](=[N:7]O)[NH2:6]>CO.ClCCl.C(O)(=O)C.[Ni]>[CH3:16][O:15][C:9]1[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH2:7])=[NH:6]
Reactant: COc1cc(OC)c(C(N)=NO)c(OC)c1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(C(=N)N)c(OC)c1
Reaction time: 2 h

Procedure:
3.4 g of 2,4,6-trimethoxybenzamidoxime are dissolved in 120 ml of a methanol/dichloromethane/acetic acid mixture (2/2/1; (v/v/v)) in an autoclave and hydrogenation is carried out at a pressure of 2×106Pa in the presence of 1 g of Raney nickel. After hydrogenation for 2 hours, the catalyst is separated out and the mixture is concentrated to dryness.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[N:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:12][O:11][C:9]([C:4]1[C:5]([S:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)(=[O:21])=[O:20])=[CH:27][CH:26]=2)=[CH:6][CH:7]=[C:2]([NH:1][S:37]([C:31]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=2[Cl:29])(=[O:39])=[O:38])[N:3]=1)=[O:10]
Reactant: COC(=O)c1nc(N)ccc1Br
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: COC(=O)c1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-methoxycarbonylpyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.02 (1H, d, J 11 Hz, A-ring CH ortho to SO2NH), 7.63 & 7.42 (2×2H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 7.43 (1H, s, A-ring CH ortho to 2×Cl) 7.32 (1H, d, J 11 Hz, Ar CH), 3.88 (3H, s, CH3) 2.98-2.76 (4H, m, CH2NCH2),), 1.62-1.53 (4H, m, CH2CH2CH2CH2CH2), 1.41-1.30 (2H, m, CH2CH2CH2CH2CH2) further 2 aromatic protons were obscured by a solvent peak around 7.28 ppm. Hplc (Luna 2, Gradient 5): rt=6.55 minutes. LC/MS rt=7.23 minutes, 616/618 (MH+).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13]([C:17]1[C:21]([CH2:22]Cl)=[C:20]([CH3:24])[O:19][N:18]=1)[CH2:14][CH2:15][CH3:16]>CN(C=O)C.O>[CH2:13]([C:17]1[C:21]([CH2:22][N:6]2[C:2](=[O:12])[C:3]3[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]2=[O:7])=[C:20]([CH3:24])[O:19][N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCc1noc(C)c1CCl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 78 %

Procedure:
Phthalimide potassium was suspended in DMF (35 mL) and the reaction mixture heated to 90° C. A solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (970 mg, 5.2 mmol) in DMF (25 mL) was added. After 45 min the reaction mixture was cooled, evaporated and the residue obtained was diluted with water then extracted with ether. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (1.21 g, 78%) as an off white solid that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]O)[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.S(Cl)(Cl)=O.[Cl-].[CH2:34]([NH:38][CH3:39])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][N:38]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH3:39])[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: CNCC(C)C
Reactant: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CN(C)CC(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 282) (196 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with isobutyl-methyl-amine in DMF according to the general procedure of Example 288. Obtained as a light brown solid (141 mg, 61%).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2c(C)nc3cccnc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(Cn2c(C)nc3cccnc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 54.6 %

Procedure:
A 5N sodium hydroxide solution (0.4 mL) was added to a stirred mixture of the product of Step D (53.5 mg, 0.104 mmol) in methanol (4 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 2 h. The solution volume was reduced to ~10% in vacuo then 5% citric acid solution was added. The mixture was extracted with ethyl acetate (3 times). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed (8, 10% methanol/methylene chloride) to give the titled compound (28.5 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1[nH]c(=O)c(Br)cc1=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nn(C)c(=O)cc1Br
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution 4-bromo-1-methyl-1,2-dihydropyridazine-3,6-dione (216 mg, 1.05 mmol) in DMF (3.0 mL) was added K2CO3 (437 mg, 3.16 mmol), CH3I (299 mg, 2.11 mmol), the reaction mixture was stirred at 50° C. for 30 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified with silica gel column (Petroleum ether:ethyl acetate=4:1) to obtain product (120 mg, yield: 52.2%): LC/MS m/z=219.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:8][C:7]1=[O:19].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[ClH:1].[CH3:12][C:10]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][C@H:32]3[C@:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=4)([CH2:33]3)[CH2:29]2)[CH:11]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1cn(CCCCCl)c(=O)nc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)nc1-c1cccnc1
Product: Cl
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of 1-(4-chloro-butyl)-5-methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (Prep12, 86 mg, 0.31 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 63 mg, 0.28 mmol), KI (2 mg) and K2CO3 (43 mg, 0.31 mmol) in DMF (2 ml) was placed in a microwave oven and irradiated at 115° C. for 1 hour. After cooling, the solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated The solvent was removed under vacuum and the residue was redissolved in DCM and filtered, the filtrate was stirred in the presence of PS-isocyanate (350 mg) for 3 hours. The mixture was filtered and the solvent removed under vacuum. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (99-1-0.1) to give the title compound (17 mg, 4% yield) as a free base.