Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CN1CCCN(C)C1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: BrCc1ccccc1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Clc1ccc(C(=Cn2cncn2)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.2 %

Procedure:
670 mg (2.62 mmol) of 1-(2,4-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone in 12 ml of tetrahydrofuran and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone were added to a suspension of 171 mg (3.92 mmol) of sodium hydride (55% in mineral oil) in 15 ml of tetrahydrofuran and 5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and stirred at room temperature for 3 hours. Thereafter, 396 mg (5.24 mmol) of benzyl bromide were added and the mixture was stirred at room temperature for a further 16 hours. The tetrahydrofuran was removed under a vacuum, the residue was added to 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were dried over magnesium sulphate and the diethyl ether was removed in a vacuum. The crude product was purified by column chromatography on silica gel (diethyl ether/pentane 1:4). In addition to mixed fractions with the C-alkylation product there were obtained 65 mg (7%) of pure 1-[2-(2,4-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-[1,2,4]triazole as a colourless oil. [M+H]+ =345, 347.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)(C)(C)C.[H][H].[ClH:30]>C(OCC)(=O)C.O1CCOCC1.[Pd]>[ClH:30].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OCCCNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(C#N)cc1OCCCN
Reaction time: 8 h

Procedure:
3.8 g (10.2 mmol) of ethyl 3-[2-(3-(t-butoxycarbonylamino)propoxy)-4-cyanophenyl]acrylate was dissolved in 100 ml of ethyl acetate. 700 mg of 10% palladium/carbon (50% hydrous) was added to the obtained solution, and they were stirred in the presence of hydrogen for 3 hours. The reaction solution was filtered through Celite. The solvent was evaporated, and the obtained crude product was dissolved in 50 ml of 4 N solution of hydrogen chloride in dioxane. The obtained solution was stirred overnight. The solvent was evaporated to obtain hydrochloride of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 50.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-chlorophenyl)methyl](4-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.9 g) as starting materials, N-[(4-chlorophenyl)methyl]-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.9 g) was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([NH:15][S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:21][C:20]=1[CH3:46])(=[O:18])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>C(Cl)Cl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH2:8][CH2:9][C@H:10]([NH:15][S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[CH:21][C:20]=1[CH3:46])(=[O:17])=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C

Procedure:
Compound 22 was dissolved in CH2Cl2:Trifluoroacetic acid and stirred at room temperature for 30 min under nitrogen, after which it was concentrated, evaporated 6×CH2Cl2, and dried under high vacuum to afford 23 (pale yellow oil, 3.14 g). This was used as is in Step 17.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:16]([CH2:19]Cl)([CH3:18])[CH3:17])=[O:5])[CH3:2].[Na+].[I-:24]>C(#N)C.CCOCC>[CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:16]([CH2:19][I:24])([CH3:18])[CH3:17])=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1c([Si](C)(C)CCl)ccc2ccccc12
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCN(CC)C(=O)c1c([Si](C)(C)CI)ccc2ccccc12
Yield: 98 %

Procedure:
A solution of this naphthalenecarboxamide (1.0 g, 3.0 mmol) and NaI (13.5 g, 90 mmol) in acetonitrile (90 mL) was refluxed overnight, then was diluted with ether and filtered through celite to remove most of the salts. The filtrate was then concentrated and eluted through a plug of silica gel with ethyl acetate. Concentration of the ethyl acetate afforded 1.25 g of the desired compound as a yellow oil, a 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
A solution of mesylate 109 (2.89 g, 10.0 mmol) in anhydrous DMF (20 mL) was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (60 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The white precipitate was collected by filtration, washed with water (2×40 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione 110 (3.12 g, 91.8% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H13FN2O4, LCMS (EI) m/e 341 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:20]1[CH:21]=[C:22]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=1)[NH2:25]>C(OCC)(=O)C>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:22]1[C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=[C:20]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:21]=1)[NH2:25]
Reactant: Oc1cccnc1
Reactant: COc1ccccc1Oc1cc(F)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1.24 g of 3-hydroxypyridine and 5.42 g of potassium carbonate were added to a dimethylformamide (30 ml) solution of 3.03 g of 5-fluoro-3-(2-methoxyphenoxy)-2-nitroaniline, and the reaction liquid was stirred overnight at 90° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1 to 1/2) to obtain the entitled compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.C(O)(C)C>Cl>[ClH:1].[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCn1cncn1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
suspension of 4-chloro-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline (214 mg, 0.7 mmol), 4-bromo-2-fluoroaniline (160 mg, 0.84 mmol) in isopropanolic hydrogen chloride (1 ml of a 5M solution) and isopropanol (5 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, the precipitate was collected by filtration, washed with isopropanol and then ether and dried under vacuum at 70° C. to give 4-(4-bromo-2-fluoroanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (55 mg, 15%). 1H NMR Spectrum (DMSOd6) 3.99(s, 3H); 4.62(t, 2H); 4.75(t, 2H); 7.37(s, 1H); 7.5-7.7(m, 2H); 7.81(d, 1H); 8.04(s, 1H); 8.24(s, 1H); 8.63(s, 1H); 8.84(s, 1H); 11.52(s, 1H) MS-ESI: 459 [MH]+
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.Cl.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:38]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[O:45])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccncc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.5 %

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.06 ml TEA (0.44 mmol) were dissolved in 1.5 ml dichloromethane and treated with 36 mg isonicotinic acid chloride hydrochloride (0.2 mmol). After 22 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 86 mg yellow solid which was purified by column chromatography (9.5 g silicagel, dichloromethane/methanol 24:1). 46 mg product as a light yellow solid (48%) was obtained. MS (ISP) 606.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][S:9]1(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[S:9](=[O:14])(=[O:13])[N:10]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)S2(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 2-benzyl-1,2,5-thiadiazolidine-1,1-dioxide and 1-fluoro-4-nitrobenzene using a similar method to that described for Example 20 (step 1). The crude product was crystallised from ethyl acetate to give a yellow solid; mp 164°-165° C.; δH (360 MHz, DMSO-d6) 8.30 (2H, d, J=9.2 Hz, Ar--H), 7.40 (5H, m, Ph), 7.33 (2H, d, J=9.2 Hz, Ar--H), 4.31 (2H, s, PhCH2 --), 3.98 (2H, t, J=6.4 Hz, --CH2 --), 3.49 (2H, t, J=6.4 Hz, --CH2 --); m/z (EI) 333 (M+).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=3[OH:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1cccc(O)c1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3c(C)cccc3O)CC2)c(OC)nc1C
Yield: 57 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxy-6-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:30][CH2:29][CH2:28]1)[C:9]1[N:14]=[N:13][C:12]([CH:15]2[N:19]=[C:18]([OH:20])[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:30][CH2:29][CH2:28]1)[C:9]1[N:14]=[N:13][C:12]([CH:15]2[N:19]=[C:18]([O:20][CH3:38])[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1SC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)N=C1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1SC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)N=C1OC
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 53.7 %

Procedure:
To a stirring solution of ethyl 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate (350 mg, 0.7 mmol) in DMF (4 mL) was added methyl iodide (200 μL, 3.3 mmol) and sodium hydride (60% dispersion in mineral oil, 40 mg, 1 mmol). The reaction was stirred at rt for 1 h and at 40° C. for 45 min. The reaction was then concentrated and quenched with water (5 mL), poured into ethyl acetate (150 mL), and washed with 0.1M HCl (50 mL, aq) and brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAC/hexanes) to afford 205 mg of ethyl 2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylate. This compound was dissolved in methanol (4 mL) and 1M KOH (aq, 2 mL). The reaction mixture was heated to 75° C. and stirred for 45 min. The reaction was cooled and the pH was adjusted to 4 using 1M HCl. The reaction was then poured into ethyl acetate (50 mL), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give 175 mg of 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylic acid as a white foam.
Reaction SMILES: C(O[C:14]1[CH:40]=[CH:39][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](OCCCCCCCCCCCC)=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1)CCCCCCCCCCC.O.[NH2:42][NH2:43]>C(O)CCCC>[C:17]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N+:42]=[N-:43])[CH:39]=[CH:40][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCC)cc2)cc1
Reactant: NN
Solvent: CCCCCO
Solvent: O
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4,4′-dihydroxybenzophenone (21.4 g, 100 mmol), 1-bromododecane (49.8 g, 200 mmol), K2CO3 (50 g) in 500 mL of DMF were heated with stirring at 120° C. for 60 hours. After the mixture was cooled to room temperature, 1 L of water was added. The solution was extracted with CH2Cl2 (4×500 mL). The combined organic layers were dried with MgSO4 and the most of the solvent removed under reduced pressure as a white solid formed. The solids were collected by filtration, washed with cold hexanes, and air dried to give 4,4′-didodecyloxybenzophenone (41.2 g, 75%). A mixture of 4,4′didodecyloxybenzophenone (20.6 g) and hydrazine monohydrate (20 mL) in 150 mL of pentanol were heated at reflux for 24 hours. After cooling to room temperature, a white solid precipitated which is collected by vacuum filtration, washed with 20 mL cold ethanol and air dried (19.4 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH3:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH3:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]2=[O:24])=[CH:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:32]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:13](=[O:24])[CH:14]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccccc23)C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
22.4 g of the product of Step C were dissolved in 225 ml of tetrahydrofuran and 14.3 ml of triethylamine and the mixture was cooled to 5° C. 7.9 ml of benzoyl chloride were slowly added and then stirring was maintained for 1 hour at ambient temperature. The insoluble part was separated and the filtrate was evaporated to dryness to obtain 28.4 g of the expected product melting at 144° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3[F:23])=[N+:2]=[N-:3].[CH2:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:26]#[CH:27]>C1C=CC=CC=1.CC1C([Ru+])(C)C(C)=C(C)C=1C.ClC1CCC=CCCC=1>[CH2:25]([C:26]1[N:1]([CH:4]2[CH2:24][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][C:10]=4[F:23])[N:2]=[N:3][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCc1ccccc1
Agent: CC1=C(C)C(C)([Ru+])C(C)=C1C
Agent: ClC1=CCCC=CCC1
Solvent: c1ccccc1
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(n1nncc1Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate (1 eq) and prop-2-yn-1-ylbenzene (1.5 eq) in benzene (0.3M) at room temperature was added chloro(1,5-cyclooctadiene) (pentamethylcyclopentadienyl)-ruthenium(II) (0.1 eq). The reaction mixture was flushed with nitrogen then aged at 80° C. for overnight, cooled to room temperature, filtered through silica gel, washed with EtOAc and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexane (0 to 50%) to give the desired material as a brown oil. The racemic mixture was resolved by HPLC using a 50×400 mm Chiralpak AD column eluting with 15% MeOH, 15% EtOH, 69.75% Hexanes and 0.25% Et3N at 50 mL/min and 254 nm to afford the desired chiral ester with retention time of 9.6 and 11.6 min respectively.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:7][C:6]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCBr
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCBr)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
A mixture of 4-(2-Bromoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (1.012 g, 3.417 mmole), 3-methoxy-benzoyl chloride (700 mg, 1.2 eq), and triethylamine (1.0 mL, 2 eq) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give title compound as white solid (957 mg, 52%). Exact mass calculated for C20H20BrN3O3429.1. found 430.3 (M+H 79Br, 100), 432.5 (M+H 18Br, 98).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][CH2:9][O:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>CC#N>[N:22]([CH:10]1[CH2:9][O:8][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:13][C:12](=[O:14])[CH2:11]1)=[N+:23]=[N-:24]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(=O)C=CCO1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC#N
Product: Cn1ncc([N+](=O)[O-])c1C1CC(=O)CC(N=[N+]=[N-])CO1
Temperature: 65 °C

Procedure:
To a solution of 2-(2-methyl-4-nitro-pyrazol-3-yl)-3,7-dihydro-2H-oxepin-4-one (440 mg, 0.42 mmol) in MeCN (3 mL) was added Amberlite IRA 900F resin (79 mg, 0.19 mmol) and trimethylsilylazide (1.2 mL, 9.35 mmol). The reaction mixture was heated at 65° C. behind a blast screen for 24 hr, cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave pure 6-azido-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one along with mixed fractions containing product and starting material. These were concentrated under reduced pressure and resubmitted to the same reaction conditions. Final purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 6-azido-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one as a colourless solid (449 mg). To this solid (449 mg, 1.60 mmol) was added deoxo-Fluor® (50% in THF, 5 mL) and the mixture was stirred at room temperature for 18 hr. DCM (50 mL) was added and the reaction mixture cooled to 0° C. Saturated aqueous NaHCO3 (30 mL) was then carefully added. The aqueous layer was extracted with DCM (3×30 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(6-azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole (Diastereomer 1-major) as a colourless solid (264 mg, 47% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.67-5.58 (m, 1H), 4.18-3.91 (m, 3H), 4.08 (s, 3H), 2.79-2.63 (m, 1H), 2.63-2.40 (m, 3H).