Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9]3[N:10]=[C:11]([O:21][CH:22]4[CH2:39][CH:38]5[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]6[C:35]([C:41](O)=[O:42])([NH:36][C:37]5=[O:40])[CH2:34]6)[CH2:23]4)[C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=4)[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]([C:9]3[N:10]=[C:11]([O:21][CH:22]4[CH2:39][CH:38]5[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]6[C:35]([C:41]([NH:64][S:61]([CH:58]7[CH2:60][CH2:59]7)(=[O:63])=[O:62])=[O:42])([NH:36][C:37]5=[O:40])[CH2:34]6)[CH2:23]4)[C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=4)[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 29 (91 mg, 0.14 mmol) and 1,1′-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) in dry THF (7 mL) was heated at reflux for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate (RT=5.37). Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) was added. Then, DBU (50 μL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. The solvent was evaporated, and the residue partitioned between AcOEt ethyl acetate and acidic water (pH=3). The crude material was purified by column chromatography (ethyl acetateAcOEt/CH2Cl2/pPetroleum ether, 1:1:1). The residue was crystallized in diethyl ether, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material was triturated in 3 mL of water, filtered, washed with water and dried overnight with the high vacuum pump to give 60 mg (57%) of the target compound 30 as a slightly yellow powder: m/z=734 (M+H)+, 1H-NMR (CDCl3): 10.94 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.12-7.15 (m, 2H), 6.91 (s, 1H), 6.35 (s, 1H), 5.74-5.77 (m, 1H), 5.63-5.69 (m, 1H), 5.06 (t, J=10.4 Hz, 1H), 4.60 (t, J=12.3 Hz, 1H), 3.93 (s, 3H), 3.35-3.42 (m, 2H), 3.04 (s, 3H), 2.89-2.96 (m, 2H), 2.52-2.52 (m, 2H), 2.37-2.45 (m, 2H), 2.10-2.32 (m, 2H), 1.61-1.93 (m, 4H), 1.3-1.51 (m, 4H), 0.90-1.30 (m, 8H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)[CH3:20])=[O:18])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH3:20])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:18])=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3ccccc23)cn1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
Acetic anhydride (0.12 mL, 1.24 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.10 g, 0.31 mmole) and sodium bicarbonate (0.13 g, 1.55 mmole) in THF (20 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the title compound (50 mg, 45%) as a white solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27](C3CCCCO3)[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccn[nH]1
Yield: 108.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (155 mg, 0.238 mmol) prepared in Example 138b, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (108 mg, 99%) as a colorless solid.
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH:6]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[NH:11][CH2:12][CH2:13][Cl:14])([CH3:8])[CH3:7]>ClC(Cl)C>[CH:6]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][Cl:14])[N:1]=[O:2])([CH3:7])[CH3:8]
Reactant: O=N[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)NCCCl)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CC(Cl)Cl
Product: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)N(CCCl)N=O)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Dinitrogen trioxide gas (1.3 g) was introduced into a solution of the thus prepared 3-isopropyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.58 g, 9.35 mmol) in dichloroethane (50 ml) with thorough stirring at 15°-20° C., and stirring was continued for further two hours at the same temperature. The reaction mixture was vacuum-concentrated concentrated at 25° C., and purified by column chromatography (packing: silica gel; eluent: hexane/ethyl acetate 4:1) to obtain 3-isopropyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea (2.78 g, 6.75 mmol); yield 72.2%, m.p. 70°-72° C., [α]D20 +69.7° (C 1.0, methanol).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH:25]([CH3:27])[CH3:26])=[C:11]([O:28]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH:25]([C:12]1[C:11](=[O:28])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:19]#[N:20])([CH3:27])[CH3:26]
Reactant: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3-(2,6-Bis-benzyloxy-5-isopropyl-pyrimidin-4-yloxy)-5-methyl-benzonitrile (372 mg, 65% pure, 0.52 mmol) was dissolved in 20 mL of EtOAc and 5 mL of EtOH. 10% Pd/C (75 mg) was added and a hydrogen balloon was applied. The reaction mixture was stirred at room temperature for 1 hour. The Pd/C was filtered through celite, and the filtrate was concentrated and purified using silica gel (EtOAc/hexane) to give a white solid (100 mg, 29%). LC-MS shows 286.0 (M+1).
Reaction SMILES: [Na].[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[C:17](=[C:18](Cl)[CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[N:15]([CH3:25])[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1.[CH2:26]([OH:28])[CH3:27]>>[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[C:17](=[C:18]([O:28][CH2:26][CH3:27])[CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[N:15]([CH3:25])[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: CCO
Agent: [Na]
Product: CCOc1cccc2c1c(=O)n(C)c1c(-c3noc(C4CC4)n3)ncn21

Procedure:
30 mg of sodium was dissolved in 10 ml of dry ethanol. Then 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6-chloro-imidazo(1,5-a)quinazoline (0.2 g, 0.5 mmol) was added and the resulting mixture was refluxed for 7 hours. The reaction mixture was evaporated. Glacial acetic acid and water was added to the residue whereupon the title compound was isolated by filtration. M.p. 195°-205° C.
Reaction SMILES: [Br:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[Br:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@@H]1CCCC[C@H]1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCC[C@H]1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution (1R*,2R*)-2-bromocyclohexanol (27 g, 0.151 mol) of and imidazole (24.9 g, 0.366 mol) in DMF (500 mL) was added TBSCl (24.9 g, 0.166 mol), the reaction mixture was stirred overnight at rt. Water was added and extracted by EtOAc three times. The combined organic layers were dried, filtered, and concentrated to give ((1R*,2R*)-2-bromocyclohexyloxy)(tert-butyl)dimethylsilane (32 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 0.05-1.05 (d, 6H), 0.90 (s, 9H), 1.20-1.40 (m, 3H), 1.60-1.85 (m, 3H), 1.98-2.10 (m, 1H), 2.25-2.40 (m, 1H), 3.63-3.73 (m, 1H), 3.85-3.97 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][CH2:14][CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C[O:17][C:18](=[O:48])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46]C)=[O:45]>>[C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:48])=[O:17])([OH:46])=[O:45]
Reactant: CCCc1c(O)ccc2c1CCCC2=O
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)O)ccc2c1CCCC2=O

Procedure:
Using the procedure of example 184, 6-hydroxy-5-propyl-1,2,3,4-tetrahydronaphthalene-1-one from example 9 was converted into the title compound by alkylation with 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from example 156, followed by saponification, in 68% overall yield. The diacid product was a colorless solid, mp 100°-101° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[N:23][CH:24]=2)=[CH:15][CH:14]=1>ClCCl>[Cl:3][CH2:25][C:21]1[CH:22]=[N:23][CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:11]([F:28])([F:27])[F:10])=[CH:14][CH:15]=2)[CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
136 mg (0.083 ml, 1.14 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.1 ml N,N-dimethylformamide (DMF) and 153 mg (0.57 mmol) [5-(4-Trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol in 10 ml dichloromethane and stirred for 2 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (156 mg, 89%) used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.[CH:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:36][O:35][C:31]1[CH:30]=[C:29]([CH:28]([OH:37])[CH:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[OH:20])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: COc1cccc(C=O)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(C(O)C(O)c2ccncc2)c1
Temperature: -20 °C

Procedure:
To a stirring solution of diisopropylamine (4.5 g, 5.8 mL, 44 mmol) in tetrahydrofuran (170 mL) at -78° C. was added n-butyllithium (17.7 mL of a 2.5M solution in tetrahydrofuran) dropwise. After ten minutes, a solution of 4-pyridylcarbinol t-butyldimethylsilyl ether (9.0 g, 40 mmol) in tetrahydrofuran (35 mL) was added dropwise, and the temperature allowed to rise to -15° C. The solution was recooled to -78° C. and to it was added a solution of 3-anisaldehyde (5.5 g, 4.9 mL, 40 mmol) in tetrahydrofuran (35 mL) dropwise. The solution was allowed to warm to -20° C. and poured into saturated aqueous sodium hydrogen carbonate (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was dissolved in tetrahydrofuran (120 mL) and to this solution was added tetrabutylammonium fluoride (48 mL of a 1.0M solution in tetrahydrofuran) dropwise. After ten minutes, the reaction mixture was concentrated at reduced pressure and the resulting oil was chromatographed on silica gel eluting with 97:3 ethyl acetate:methanol to give a mixture of diastereomeric diols as a foam (8.5 g) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13].Cl>C1COCC1.CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Glycine (8.26 g, 110 mmol) was dissolved in 2M NaOH (125 ml, 250 mmol). The resulting colorless solution was cooled to 0° C. and 3,4-difluorobenzoyl chloride (12 mL, 95 mmol) in 60 mL of THF was added dropwise over 10 minutes. The reaction was stirred for 1 hour at 0° C. and allowed to warm to room temperature over 2 hours. The reaction was acidified to pH 1 with concentrated HCl while cooling in an ice bath. 100 mL of EtOAc was added and the mixture was poured into a separatory funnel and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine (50 mL each), dried with sodium sulfate, filtered and concentrated in vacuo to about 30 mL whereupon a solid began to crystallize. The mixture was allowed to stand overnight. The solid residue was concentrated on a rotary evaporator to remove the remaining EtOAc and then dried in a vacuum oven at 40° C. to provide the desired product, 2-(3,4-difluorobenzamido)acetic acid as an off-white solid (20.73 grams, 96%). LCMS (+ESI) m/z 216.2 [M+H]+. 1H-NMR (CDCl3) δ 12.70 (br s, 1H), 9.00 (t, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 3.90 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([I:9])=[CH:7][N:8]=2)[CH2:3][CH2:2]1.I[CH3:11]>>[CH:1]1([C:4]2[N:8]([CH3:11])[CH:7]=[C:6]([I:9])[N:5]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: Ic1cnc(C2CC2)[nH]1
Product: Cn1cc(I)nc1C1CC1

Procedure:
The title compound, MS: m/e=249.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-cyclopropyl-5-iodo-1H-imidazole (example C) and iodomethane.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1SC(Cc2ccc(OCCN3CCc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCCN3CCc4ccccc43)cc2)S1
Yield: 60 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 470 mg of 5-{4-[2-(indolin-1-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 10) and 3 ml of trifluoroacetic acid were used, to give 170 mg of the title compound, melting at 132.8-135.6° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[C:33]([CH2:37][CH2:38][C:39](Cl)=[O:40])([O:35][CH3:36])=[O:34].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:39]([CH2:38][CH2:37][C:33]([O:35][CH3:36])=[O:34])=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COC(=O)CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 3-carbomethoxypropionyl chloride (14 mg) and N,N-diisopropylethylamine (40 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 6.
Reaction SMILES: C([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20](O)=[O:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:38][CH2:37][N:36]1[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([CH:35]2[CH2:38][CH2:37][N:36]2[C:39]([O:41][CH2:42][C:43]([Cl:45])([Cl:46])[Cl:44])=[O:40])=[C:28]([CH2:27][NH:26][C:20](=[O:21])[C@@H:19]2[CH2:23][CH2:24][CH2:25][NH:18]2)[CH:33]=1
Reactant: NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl)[C@@H]1CCCN1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-Fmoc-L-proline (0.249 g, 0.739 mmol) was added to a stirred mixture of 2,2,2-trichloroethyl 2-[2-(aminomethyl)-4-chlorophenyl]azetidine-1-carboxylate (0.275 g, 0.739 mmol), EDC (0.213 g, 1.11 mmol) and HOAT (50 mg, 0.37 mmol) in DMF (2 mL). After 16 h the reaction mixture was partitioned between ethyl acetate and dilute HCl solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to a foam. This material was dissolved in DMF (2 mL) and piperidine (0.5 mL) and stirred for 30 min. The solution was poured into water (50 mL) and the precipitated solids were removed by filtration, washing with water (5×10 mL, which was collected and set aside) and methanol. The methanol was evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with ethyl acetate followed by chloroform/methanol/ammonium hydroxide, 90:9:1) to give 2,2,2-trichloroethyl 2-{4-chloro-2-[(L-prolylamino)methyl]phenyl}azetidine-1-carboxylate (66 mg) as a gum. The milky aqueous washings were extracted into ethyl acetate (adding brine to dispel the emulsion) and the organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give more of the desired compound (0.206 g) as a gum: MS 468.5 (M+1) with an isotope distribution consistent with four chlorines.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2c(COC)nnc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The mixture of 9-butyl-3-(methoxymethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (6 mg, 21.7 mmol), N-bromosuccinimide (4.64 mg, 26.0 mmol) in tetrahydrofuran (10 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by prep LCMS to yield the desired product. LCMS calculated for C13H18BrN6O2 (M+H): 369.1. found 371.1.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.OO.NC(N)=[O:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([CH:6]2[CH:7]([CH2:8][CH2:9][CH3:10])[O:16]2)=[O:11])[CH2:3][CH2:2]1
Reactant: CCC/C=C/C(=O)NC1CC1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCC1OC1C(=O)NC1CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a three-neck 250 mL round bottom flask equipped with mechanical stirrer and containing compound 37 (10.0 g, 65.3 mmol) and urea hydrogen peroxide (UHP) (25.0 g, 4.0 eq.) in CH2Cl2 (100 mL, 10 vol) at 0° C., was added trifluoroacetic anhydride (41.1 g, 27.2 mL, 3.0 eq.). The reaction mixture was heated to 35±5° C. and stirred for 2 hours. After cooling the reaction mixture down to room temperature, another aliquot of trifluoroacetic anhydride (13.7 g, 9.0 mL, 1.0 eq.) was added. The reaction mixture was heated again to 35±5° C. and stirred for another 3 hours. The reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO3 (5 vol.) slowly and stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol). The combined organic layer was dried and evaporated to afford the crude product, N-cyclopropyl-3-propyloxirane-2-carboxamide (38), as a pale yellow oil. The crude product was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:21](OS(C(F)(F)F)(=O)=O)([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To methyl 2-(4-hydroxyphenyl)acetate (E1) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stirred. After 4 h the solution was poured into NH4Cl(sat) and CH2Cl2 and the organic layer was further extracted with NH4Cl(sat). The organics were dried (Na2SO4) filtered and evaporated. Column chromatography (0-15% EtOAc/Hexanes) gave pure methyl-2-(4-(triisopropylsilyloxy)phenyl)acetate (E2).