Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]4OCCC[O:26]4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]=[O:26])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCCO4)CC3)CC2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC=O)CC3)CC2)CC1

Procedure:
To 140 g (333 mmol) of trans-4-(trans-4-(trans-4-(2-(1,3-dioxane-2-yl)ethyl)cyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester dissolved in 1.5 liters of toluene were added 153 g (3330 mmol) of formic acid and the mixture was heated under reflux for one hour. The reaction solution was washed three times with 500 ml of an aqueous saturated sodium carbonate and then with 750 ml of water, and dried over anhydorus magnesium sulfate. Distilling off the solvent under reduced pressure gave 90.0 g of crude trans-4-(trans-4-(trans-4-(2-formylethyl)cyclohexyl)-cyclohexyl)cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:29]([CH2:28][CH2:27][O:26][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reactant: COCCC(=O)Cl
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3cc(Br)ccc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(7-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152–156. 3-Methoxypropionyl chloride was used in Part C, and triethylamine (1.3 equivalents) was added to the reaction mixture. The crude product obtained in Part D was purified by flash chromatography on silica gel (eluting sequentially with 100:0 and 92.5:7.5 chloroform:methanol) followed by recrystallization from acetonitrile. The crystals were washed with acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26](Cl)=[O:27])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:26]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[N:16]=[CH:17][CH:18]=[N:19]5)=[O:27])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc2nccnc2c1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 6-quinoxalinecarbonyl chloride (96 mg; 0.50 mmol; 2.0 eq.) as a white powder (47.5 mg, 53%). HPLC, Rt: 2.73 min. (purity 62.3%). LC/MS, M+(ESI): 357.4, M−(ESI): 355.3.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1([CH3:34])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=O)[OH:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]>C(Cl)Cl>[CH3:5][C:6]1([CH3:34])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=[O:12])[Cl:3])[C@H:7]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reaction time: 1.75 h

Procedure:
10 ml of thionyl chloride were added all at once at 20° C. to a solution of 4.5 g of the product of Step C in 20 ml of methylene chloride and the mixture was stirred for 105 minutes and was evaporated to dryness under reduced pressure to obtain 4.7 g of (S)α-cyano-3-phenoxy-4-fluorobenzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-chloro-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:26](OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:26])[C:9]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CCc2ccccc2C1
Reaction time: 48 h

Procedure:
To 2-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (291 mg, 1.0 mmol) in DMF (2.0 mL) was added MeI (710 mg, 5.0 mmol) and NaH (50%, 250 mg, 5.0 mmol) at 0° C. Ethyl acetate (50 mL) was added after 3 days and the mixture was washed with water (3×15 mL). The material (380 mg) was taken up in methanol (5.0 mL) and water (3.0 mL) and NaOH (10 M, 3.0 mL) was added. After 2 days, 10% HCl was added to adjust the pH˜2 and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were concentrated in vacuo to provide the titled acid.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:3]=1[CH2:4][C:5]([OH:7])=O.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:20][C:5](=[O:7])[CH2:4][C:3]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:2]=1[F:1]
Reactant: COc1ccc(CC(=O)O)c(F)c1OC
Reactant: COC(CN)OC
Product: COc1ccc(CC(=O)NCC(OC)OC)c(F)c1OC

Procedure:
Following the procedures outlined in Examples 1 and 2, the 2-fluorohomoveratric acid is reacted with aminoacetaldehyde dimethylacetal to form N-(2,2-dimethoxyethyl)-3,4,-dimethoxy-2-fluorophenylacetamide which is ring closed with hydrochloric acid and glacial acetic acid to obtain 2,3-dihydro-7,8-dimethoxy-6-fluoro-2-oxo-1H-3-benzazepine. The dihydrobenzazepine is reduced first with hydrogen and palladium-on-carbon, then with diborane to give 7,8-dimethoxy-6-fluoro-2,3,4,5-tetrahydro-1H-3-benzazepine. The latter is treated with formaldehyde/formic acid to give the corresponding 3-methyl derivative which is demethylated with 48% hydrobromic acid. The resulting catechol is oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the dione is treated with a methanolic solution of thiophenol to furnish the product 7,8-dihydroxy-9-fluoro-3-methyl-6-phenyl-thio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C([O:8][C:9](=[O:36])[CH2:10][C@@H:11]([NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:12][N:13]([CH3:15])[CH3:14])C1C=CC=CC=1.CN(C)C[C@H](NC(=O)CCCCCCCCOC1C=CC=CC=1F)CC(O)=O>>[CH3:15][N:13]([CH3:14])[CH2:12][C@H:11]([NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:10][C:9]([OH:36])=[O:8]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOCCc1ccccc1
Agent: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCCOc1ccccc1F
Product: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCCOCCc1ccccc1

Procedure:
Hydrogenation of (R)-4-dimethylamino-3-(9-phenethyloxy-nonanoylamino)-butyric acid benzyl ester in analogy with example 1, step 4 produced (R)-4-dimethylamino-3-[9-(2-fluoro-phenoxy)-nonanoylamino]-butyric acid. White solid, m/e=405.6 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=[O:36]>[Cu]I.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=[O:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(C)NC(=O)CCl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NC(C)C)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-N-isopropylacetamide (76 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 7 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:22][CH2:23]O)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: OCCc1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Product: c1ccc(-c2cc3cc(CCN4CCCC4)cc(NC4CCCC4)c3[nH]2)cc1

Procedure:
2-[7-Cyclopentylamino-2-phenyl-1H-indol-5-yl]-ethanol prepared in Example 32 and pyrrolidine were reacted according to the same procedures as Steps A and B of Example 36 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.NS(O)(=O)=O.[C:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O>CO.NS(O)(=O)=O>[CH3:28][C:26]1[C:25]([C:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:1]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: NS(=O)(=O)O
Solvent: CO
Product: Cc1nc2ccc([N+](=O)[O-])cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A mixture of 2-amino-5-nitrobenzophenone (2 g, 8.26 mmol), H2NSO3H (0.09 g, 0.93 mmol) and tert-butyl acetoacetate (3 ml, 18 mmol) was stirred for 1 h at 120° C. under N2. To it, more of H2NSO3H (0.04 g, 0.41 mmol) was added and stirring was continued at 120° C. until all 2-amino-5-nitrobenzophenone was consumed (about 3 h). After cooling to room temperature the solid material formed was dispersed in MeOH (20 ml) and filtered off, washed with fresh MeOH and dried to give pure product as a creamy solid (1.6 g, 53%). 1H NMR (300 MHz, CDCl3) δ 8.41-8.5(m, 2H, 8.15 (d, J=9 Hz, 1H), 7.52-7.55(m, 3H), 7.3-7.4 (m, 2H), 2.82(s, 3H), 1.24(s, 9H).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[CH2:14][CH2:13]OCC1>>[C:1]1([C:14]([C:13]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: Cl[Mg]c1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylmagnesium chloride (2M, 6.8 mmol, 1.5 eq.) was slowly added to a stirred solution of the aldehyde from Part A (3.00 g, 4.5 mmol, 1.0 eq.) in dioxane (25 mL) at 0° C. After 1 h, the reaction was quenched with methanol (5 mL), followed by water (25 mL). Trifluoroacetic acid (25 mL) was then added, and the mixture stirred at room temperature for 1 h. 10N NaOH was added to adjust the pH to 10 and the organic solvents removed in vacuo leaving solid triphenylmethanol and an aqueous phase behind. The triphenylmethanol was filtered and the aqueous was acidified to pH=3 with conc. HCl producing a precipitate. The solids were filtered, dried, and recrystallized from hexane/ethyl acetate yielding 532 mg of a white solid; m.p. 137.0°-145.0° C. NMR (DMSO-d6): δ7.77-7.46 (m, 4H); 7.46-7.30 (m, 5H); 6.94 (d, 2H, J=9 Hz); 6.76 (d, 2H, J=9 Hz); 6.37 (d, 1H, J=5 Hz); 5.97 (d, 1H, J=5 Hz); 5.09 (s, 2H); 2.25 (t, 2H, J=7 Hz); 1.34 (t of t, 2H, J=7,7 Hz); 1.17 (t of q, 2H, J=7,7H); 0.74 (t, 3H, J=7 Hz). Anal. calcd. for C28H27ClN6O.(H2O)0.5 : C, 66.20; H, 5.56; Cl, 6.98. Found: 66.12; H, 5.51; Cl, 7.25.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#N.[OH-:25].[Na+].C1(C)C(C)=CC=CC=1>C(O)(=O)C.S(=O)(=O)(O)O.O>[F:23][C:21]([F:24])([F:22])[C:20]1[C:13]2[S:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[NH:1][C:15](=[O:25])[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: N#Cc1cccc(C(F)(F)F)c1Sc1ccc(C(F)(F)F)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2cc(C(F)(F)F)ccc2Sc2c1cccc2C(F)(F)F
Temperature: 0 °C

Procedure:
2-(2-Amino-4-trifluoromethylphenylthio)-3-trifluoromethylbenzonitrile (5.43 g, 15 mmol) was dissolved in a mixture of glacial acetic acid (60 ml), concentrated sulphuric acid (55 ml) and water (60 ml) and then heated under reflux for 8 hours. The cooled mixture was added to ice water (500 ml) and brought to pH 4 by addition of 10N aqueous sodium hydroxide. Extraction with dichloromethane followed by filtration, drying (sodium sulphate) and evaporation of the organic layer afforded a residue which was put into xylene (500 ml) and refluxed for 72 hours with azeotropic removal of water. The resulting solution was evaporated and the residue was recrystallised twice from ethanol to give the product as colourless needles (4.30 g, m/s, M+ =363).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([N:9]([CH2:12][CH2:13][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][CH3:29])[CH:10]=[O:11])[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:30](Br)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([N:9]([CH:8]1[CH:3]([CH2:2][O:1][C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:4][CH:5]=[CH:6][CH2:7]1)[CH:10]=[O:11])[CH2:13][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][CH3:29]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)C1CC=CCC1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(C=O)C1CC=CCC1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
[6-(Hydroxymethyl)-3-cyclohexenyl]-N-octadecylformamide obtained in Example 1 (2) is reacted with trityl bromide in acetone in the presence of potassium carbonate to obtain N-octadecyl-[6-(trityloxymethyl)-3-cyclohexenyl]formamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:27])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)c1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(C(=O)Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a suspension of 4-({[(benzyloxy)carbonyl]amino}-sulfonyl)benzoic acid (2.90 g) in dichloromethane (30 mL) was added N,N-dimethylformamide (19.0 mg) and followed by oxalyl chloride (1.15 g) under an ice-bath. The mixture was stirred for 0.5 hour at room temperature and refluxed for 1 hour. The resulting mixture was refluxed further for 5 minutes after adding oxalyl chloride (439 mg). The volatile was evaporated off to give a white solid. The solid was triturated in diisopropyl ether to give benzyl[4-(chlorocarbonyl)phenyl]sulfonylcarbamate as a white powder (2.40 g), which was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.CCN(C(C)C)C(C)C>C(O)(C)(C)C.CCO>[F:22][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13](=[O:21])[N:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]([C@@H:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH2:3][CH3:4])=[N:6]2
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A suspension of compound 111 (65.6 mmol, 1 eq), 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq), and DIEA (24.3 mL, 140 mmol, 2 eq) in tert-butanol (40 mL) was stirred for 24 h at 80° C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the obtained solid crude product was dissolved in MeOH (600 mL), concentrated onto silica gel (300 mL dry), and purified by flash chromatography (7.5×36 cm, eluted with 10 L of 4% MeOH/CH2Cl2) to yield a solid product. The solid product was then dissolved in EtOH (250 mL) and concentrated in vacuo to compound 107 as a light yellow solid (7.2 g, 50%). 1H NMR (300 MHz, 80° C., DMSO-d6) δ 12.66 (broad s, 1H), 8.11 (s, 1H), 8.02 (broad s, 1H), 7.81-7.73 (m, 1H), 7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, 1H), 2.02-1.73 (m, 2H), 0.79 (t, J=7.3 Hz, 3H). ESI-MS m/z 416.2 (MH+). C, H, N elemental analysis (C22H18N7OF.EtOH.0.4H2O). Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6×250 mm Chiralpak ODH column, 20° C., 85:15 hexanes:EtOH, 1 mL/min, sample loaded at a concentration of 1 mg/mL in EtOH). The reaction described above and compound 107 are shown below.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using 2-benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzo[b]thiophene (5.50 g, 15.3 mmol) and 1M boron tribromide/CH2Cl2(49.1 mL) in CH2Cl2. Purification on silica gel eluting with a 5 & 10% EtOAc/pet. ether step gradient gave the tide compound as an oil. 1H NMR; consistent. mass spectrum (EI) m/z 344 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6](C2CCCCO2)[C:5](=[O:15])[CH:4]=1.Cl.[OH-].[Na+]>CO>[OH:15][C:5]1[N:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cnn(C2CCCCO2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnnc(O)c1
Temperature: 35 °C
Yield: 65.3 %

Procedure:
5-Methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (2035 g, 9.69 moles) and 2 L of methanol were added to a 22 L round bottomed flask equipped with a heating mantle, reflux condenser and mechanical stirrer. The mixture was warmed to 35° C. and 8 L of 6N HCl was added and then the mixture was heated to reflux for 2 h. The reaction mixture was then cooled slightly and transferred to a glycol cooled 22 L flask where the mixture was cooled further to 30° C. The mixture was made basic (pH 13-14) by cautious addition of 50% NaOH in small portions. The basic mixture was extracted with CH2Cl2 (4×3 L). The aqueous phase was then acidified with concentrated HCl (pH 1-2) to precipitate the product. The product was collected by vacuum filtration on a Buchner funnel. The product was dried to constant weight on a fluid bed dryer at 70° C. This afforded 798 g (65% yield) of 3-hydroxy-5-methoxypyridazine as a white solid which was recrystallized from methanol, mp=253°-255° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[N:26](S(C3C=CC=CC=3)(=O)=O)[CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[NH:26][CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2c[nH]c3ncc(Cl)cc23)cn1
Yield: 85.7 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (583, 60.0 mg, 0.097 mmol) in tetrahydrofuran (1.0 mL) was added aqueous potassium carbonate (1.0 M, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 100° C. for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (584, 0.040 g, 64%) that was used in the next step without further purification.