Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].B(Br)(Br)Br>>[CH3:16][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:14][C:5]1[CH:6]=[C:7]([OH:12])[C:8]([CH:9]([CH3:11])[CH3:10])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cc(C=C(C)c2ccccc2)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Product: CC(=Cc1cc(O)c(C(C)C)c(O)c1)c1ccccc1
Yield: 63 %

Procedure:
This compound was made from 1-(3,5-dimethoxy-4-i-propylphenyl)-2-phenylpropene (11) and BBr3 in 63% yield by the same procedure as described in example 1(c). 1HNMR (CDCl3, ppm): δ 1.42 (d, J=7.0 Hz, 6H), 2.32 (d, J=1.4 Hz, 3H), 3.49 (hept., J=7.0 Hz, 1H), 4.71 (s, 2H), 6.39 (s, 2H), 6.67 (m, 1H), 7.58-7.33 (m, 5H).
Reaction SMILES: O.P([O-])([O-])(O)=O.[Na+].[Na+].OO.Cl([O-])=O.[Na+].[Cl:15][C:16]1[C:25]([CH:26]=[O:27])=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].Cl.S([O-])(O)=[O:34].[Na+]>O.C(#N)C>[Cl:15][C:16]1[C:25]([C:26]([OH:34])=[O:27])=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: O=S([O-])O
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: OO
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)O)c1Cl
Temperature: 5 °C
Reaction time: 12 h

Procedure:
At 5° C., 13.8 g (0.11 mol) of sodium hydrogen phosphate monohydrate in 170 ml of water, 49.3 g (0.43 mol) of 30% strength hydrogen peroxide solution and 66.2 g (0.59 mol) of 80% strength aqueous sodium chlorite solution were added in succession to a solution of 115.3 g (0.42 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 2000 ml of acetonitrile. The reaction solution was then stirred for 1 hour at 5° C. and for 12 hours at room temperature. The pH was then adjusted to 1 using 10% strength hydrochloric acid, and 1500 ml of aqueous 40% strength sodium hydrogen sulfite solution were added. After stirring for 1 hour at room temperature, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with sodium hydrogen sulfite solution and dried. Removal of the solvent by distillation gave 102.0 g of methyl 2-chloro-3-hydroxycarbonyl-4-methylsulfonylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[C@@H:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:17]=1.[H-].[Na+].[Cl-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[CH2:42][N+:43]#[C-:44]>CN(C)C=O.O.C(O)(=O)C>[Cl:38][C:39]1[CH:40]=[C:41]([C:42]2[N:43]=[CH:44][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=4[C:7](=[O:16])[N:8]4[CH2:15][CH2:14][CH2:13][C@H:9]4[C:10]=23)[CH:45]=[CH:46][CH:47]=1
Reactant: O=C1Nc2ccc(F)cc2C(=O)N2CCC[C@@H]12
Reactant: [C-]#[N+]Cc1cccc(Cl)c1
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2-n2cnc(-c3cccc(Cl)c3)c2[C@@H]2CCCN12
Reaction time: 0.58 h

Procedure:
A suspension of 8.20 g (35 mmol) of (S)-7-fluoro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione in 40 ml of dry N,N-dimethylformamide is treated at -30° to -20° with 1.53 g (35 mmol) of sodium hydride (55 percent oil dispersion), the mixture is stirred at the above temperature for a further 35 minutes, and then at -60° there are added dropwise 7.25 ml (35 mmol) of phosphoric acid diphenyl ester chloride in 7 ml of dry N,N-dimethylformamide. The temperature is allowed to rise to -35°, the mixture is then again cooled to -70° and there is added a solution of 5.03 g (35 mmol) of 3-chlorobenzyl isocyanide in 5 ml of dry N,N-dimethylformamide, and subsequently there is added a solution of 3.92 g (35 mmol) of potassium t-butylate in 7 ml of dry N,N-dimethylformamide. After completion of the addition, the mixture is left to warm to 20°, neutralized by the addition of 1.5 ml of glacial acetic acid and poured into 250 ml of water. The mixture is extracted five times with methylene chloride, the combined organic extracts are washed three times with water, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate and recrystallized from ethyl acetate and n-hexane. There is obtained (S)-1-(m-chlorophenyl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one having a melting point of 182°-183°.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[ClH:18]>O1CCOCC1>[ClH:18].[CH3:17][C:15]1[N:14]=[CH:13][N:12]([C:4]2[C:3](=[O:2])[NH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=2)[CH:16]=1
Reactant: COc1nc(C(=O)[O-])ccc1-n1cnc(C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2) (34.3 g, 139 mmol) in aqueous hydrochloric acid (37%, 230 mL) and 1,4-dioxane (230 mL) was heated at reflux for 18 hours. After cooling to room temperature, the reaction was filtered and the solids were washed with 1,4-dioxane (2×100 mL). The solids were mixed with methanol (500 mL) and the volatiles were removed in vacuo. The residue was stirred with methanol (100 mL) for 15 minutes, and 1,4-dioxane (250 mL) was added. The resulting mixture was stirred for 15 minutes; the solids were collected by filtration and washed with 1,4-dioxane to provide the title compound as a beige solid. Yield: 35.4 g, 138 mmol, 99%. 1H NMR (300 MHz, DMSO-d6) δ 2.33 (d, J=0.9 Hz, 3H), 7.09 (d, J=7.5 Hz, 1H), 7.84-7.87 (m, 1H), 8.04 (d, J=7.5 Hz, 1H), 9.50 (d, J=1.6 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)=[CH:5][CH:4]=1)#[N:2].[Cl:32]CCl>>[ClH:32].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)=[CH:30][CH:31]=1)#[N:2]
Reactant: ClCCl
Agent: N#Cc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Product: Cl
Reaction time: 0.08 h

Procedure:
A hydrogen chloride ether saturated solution was added to a solution of 0.4 g (1.0 mmol) of (R)-(+)-5,11-dihydro-5-[1-(4-cyanophenethyl)-2-pyrrolidinylmethyl ]dibenzo[b,e][1,4]oxazepine in 2 ml of dichloromethane, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of dichloromethane and diethyl ether to give 0.35 g (78%) of (R)-(+)-5,11-dihydro-5-[1-(4-cyanophenethyl)-2-pyrrolidinyl methyl]dibenzo[b,e][1,4]oxazepine hydrochloride as a colorless prism crystal in a yield of 78%.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C[O-].[Na+].[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH2:17][CH2:18]Br)=[C:13]([CH2:22][CH2:23][CH3:24])[C:12]=1[OH:25])(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH2:17][CH2:18][S:1][CH2:2][CH2:3][OH:4])=[C:13]([CH2:22][CH2:23][CH3:24])[C:12]=1[OH:25])(=[O:10])[CH3:9]
Reactant: OCCS
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: C[O-]
Agent: [Na+]
Product: CCCc1c(OCCCSCCO)ccc(C(C)=O)c1O

Procedure:
4.68 g. (60 mMole) 2-mercaptoethanol are stirred for 10 minutes at ambient temperature with 60 ml. 1M sodium methylate solution. Subsequently, 9.39 g. 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl bromide are added thereto and the reaction mixture is boiled under reflux for 5 hours. The reaction mixture is thereafter evaporated and the residue mixed with water and ethyl acetate. The ethyl acetate phase is successively shaken with 2M aqueous sodium hydroxide solution and with 2M hydrochloric acid and then dried and evaporated. After recrystallising the residue from diethyl ether/ligroin, there are obtained 6.4 g. (68% of theory) of the title compound; m.p. 72°-74° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:6]2[CH:28]=[C:29]([C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2ethyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH:16]=[O:17])[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12.[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][OH:17])[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12
Reactant: N#CC1=C(C=O)Nc2n[nH]cc2C1c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: N#CC1=C(CO)Nc2n[nH]cc2C1c1ccccc1Cl
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a suspension of 4-(2-chlorophenyl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (400 mg) in methanol (10 ml) was added sodium borohydride (53 mg) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. 10% Hydrochloric acid was added to the reaction mixture, and a saturated sodium hydrogencarbonate solution was added. The precipitated crystals were collected by filtration and washed with ethanol to give the title compound (295 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N+:18]([O-])([OH:20])=[O:19]>>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccccc1
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc([N+](=O)[O-])cc1
Temperature: -2 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1,3-Dihydro-5-methyl-6-phenyl-2H-imidazo[4,5-b]pyridin-2-one (Example 4c, 8.06 g) was added in small portions to 80 ml 90% nitric acid cooled to -2° C. The reaction mixture was stirred at 0° C. for 2 hours and then poured portion wise into ice-water. The solid product was collected, washed with water and ether, and dried in high vacuum at 110-130° C. to give 9.3 g (97%) of 1,3-dihydro-5-methyl-6-(4-nitrophenyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. above 300° C. Further purification was accomplished by repeated recrystallization from aqueous dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([CH2:21][C:22](OCC)=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[C:13]([CH2:21][C:22]([NH:6][C:5]1[CH:7]=[C:8]([Cl:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CC(=O)c1ccccc1)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
A mixture of 4,5-dichloro-2-nitroaniline (2.07 g, 10 mmol) and ethyl benzoylacetate (technical, 5 mL, approximately 22 mmol) was heated at 180° C. for 16 h under stirring. It was cooled to 150° C. and kept at this temperature under aspirator vacuum for 5 h, then cooled to room temperature. Chloroform (50 mL) was added and the mixture was evaporated, then diluted with ether (200 mL) and cooled to -10° C. Precipitate was filtered and washed with ether (5×50 mL) to give 2.12 g (60%) of the title compound as an orange solid: mp 177°-179° C. (from EtOH); IR (KBr) 3330, 1693, 1670, 1561, 1472, 1340, 1233, and 764 cm-1 ; 1H NMR (DMSO-d6) δ4.24 (s, 2H), 7.53 (m, 2H), 7.65 (m, 1H), 7.77 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 8.11 (s, 1H), 8.23 (s, 1H), 10.70 (s, 1H, N--H). HRMS Calcd for C15H10N2O4Cl2 : 352.0018. Found: 352.0020.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1>Cl>[C:11]1([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ncc(-c2ccccc2)c(OC)n1
Agent: Cl
Product: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Yield: 80 %

Procedure:
2,4-Dimethoxy-5-phenyl-pyrimidine was suspended in 6N HCl and heated to 100 C for 24 h. Solution was cooled in an ice bath to afford title compound as a white solid 119 mg (80% yield). HNMR (500 MHz, dmso); δ11.25 (1H, s), 11.15 (1H, d), 7.65 (1H, d), 7.55 (2H, d), 7.35 (2H, m), 7.25 (1H, t).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]3[C:23]=2[CH3:24])=[CH:8][C:7]=1[OH:25].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CC(C)=O.O.O1CCCC1>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]3[C:23]=2[CH3:24])=[CH:8][C:7]=1[OH:25])(=[O:3])[CH3:2]
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(CCc2nc3cc(C)ccn3c2C)cc1O
Reaction time: 0.5 h

Procedure:
Acetyl chloride (1.5 ml) was dropwise added to a mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (5.0 g) and sodium bicarbonate (3.0 g) in acetone (30 ml) and water for 10 minutes under ice-cooling and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added a solution of ethyl acetate, tetrahydrofuran and water, and separated organic layer was washed with brine. The mixture was dried over magnesium sulfate and concentrated to give 2-[2-(4-acetamido-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (3.51 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:35][C:34](=[O:36])[NH:33][N:32]=2)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:32][N:33]=[C:34]([O:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:35]=2)=[CH:29][CH:30]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4ccc(Cl)cc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Yield: 72.9 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (140 mg, 0.415 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-one (202 mg, 1.04 mmol) in the presence of sodium hydride (41.5 mg, 1.04 mmol, prewashed with THF) in DMF (2.5 ml) to give 4-(5-(4-chlorophenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 73%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])C)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25].C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:6][NH:7][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13]
Reactant: CN(CCNC(=O)c1nc(Cl)c(N)nc1N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A mixture comprising {2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester in DCM:TFA (60 mL of a 5:1 DCM/TFA solution) is stirred at RT for 3 h. The solvent is removed in vacuo and the resulting yellow oil is dissolved in water with heating. Any undissolved material is removed by filtration and the filtrate is concentrated in vacuo to afford the title compound. [M+H]+245.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.Cl[C:19]1[N:20]=[N:21][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:23][CH:24]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:19]4[N:20]=[N:21][C:22]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)=[CH:23][CH:24]=4)[CH2:15][CH2:16]3)[C:7]=2[CH:17]=1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Agent: Cl
Product: Cn1cc(-c2ccc(N3CCC(c4noc5ccc(F)cc45)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method B, reacting 5-fluoro-3-(piperidin-4-yl)benzisoxazole HCl salt and 3-chloro-6-(1-methyl-1 H-pyrazol-4-yl)pyridazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[C:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: OB(O)C1=CCCCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnccc1C1=CCCCC1
Yield: 82 %

Procedure:
A solution of 4-chloro-3-nitro pyridine (1 eq.), cyclohexenyl boronic acid (1.7 eq.), and Pd(dppf)Cl2—CH2Cl2 (0.05 eq) in 3:1 DME/2M Na2CO3, at a concentration of 0.1 M was heated at 95° C. for 16 hours. Upon cooling the reaction was partitioned between EtOAc and H2O, was washed with NaCl(sat.), dried over MgSO4, was filtered and the volatiles were removed in vacuo. The material was purified by SiO2 chromatography (20% EtOAc/hexanes eluant) to yield 4-cyclohexenyl-3-nitropyridine (82%). LCMS (m/z): 205.0 (MH+); LC Rt=3.84 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:19]1([CH:22]([NH2:26])[CH2:23][O:24][CH3:25])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][CH:22]([CH:19]2[CH2:21][CH2:20]2)[CH2:23][O:24][CH3:25])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: COCC(N)C1CC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: COCC(Nc1nc(Cl)nc2c1CCC2c1ccc(F)cc1)C1CC1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[S:28][CH:27]=[C:26]([C:29](OC)=[O:30])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[S:28][CH:27]=[C:26]([CH2:29][OH:30])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: COC(=O)c1csc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cc(CO)cs2)C1c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To a solution of 600 mg of methyl 5-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}thiophene-3-carboxylate in 40 mL of THF was added 45 mg of lithium aluminum hydride at −78° C. The solution was warmed to 0° C., followed by stirring for 3 hours. Sodium sulfate decahydrate was added thereto, followed by stirring for 1 hour. After removing sodium sulfate by filtration, the organic layer was dried by adding anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 162 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[4-(hydroxymethyl)-2-thienyl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH2:20](O)[C:21]#C>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][C:20]#[CH:21])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: C#CCO
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Product: C#CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (3.0 g., 11.8 mmoles.) was stirred with 18 ml. of propargyl alcohol for 1.5 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ice-cold ether and washed twice with 20 ml. of ice-cold 10% aqueous acetic acid, 15 ml. of ice-cold water, and 10 ml. of ice-cold 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo. The resulting solid was recrystallized from hexane to give propargyl 9-xanthenyl ether, m.p. 74°-76°C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:6][C:5]1=[O:21].C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[F:23][C:2]([F:1])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:21]
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2N1CC(F)(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 45 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in 450 ml. of acetic acid was added dropwise at room temperature a solution of 13.2 g of chromium trioxide in 13.2 ml. of water. The mixture was stirred at room temperature overnight and then poured into 2 l of water. The resultant precipitate was collected by filtration, washed successively with diluted ammonia water and water, and dried to give 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone quantitatively.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:53])CC2)CC1>>[OH:53][CH:5]1[CH2:4][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:7][CH2:6]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (see example 36) and amine 21.