Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].Cl[C:20]1[C:25]2=[C:26]([CH2:29][N+](CC)(CC)CC)[CH:27]=[CH:28][N:24]2[N:23]=[CH:22][N:21]=1.C(OC(=O)[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(C)(C)C>C1COCC1.CN(C=O)C>[NH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:29][C:26]2[CH:27]=[CH:28][N:24]3[C:25]=2[C:20]([NH:43][C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[N:21][CH:22]=[N:23]3)[CH2:2][CH2:3]1
Reactant: Nc1ccncc1
Reactant: CC[N+](CC)(CC)Cc1ccn2ncnc(Cl)c12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC1CCN(Cc2ccn3ncnc(Nc4ccncc4)c23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a mixture of pyridin-4-ylamine (34 mg, 0.361 mmol) in THF (500 μl) was added 1N NaHMDS in THF (722 μl, 0.722 mmol). The mixture was cooled to 0° C. and a suspension of 1D (125 mg, 0.27 mmol) in DMF (800 μl) was added. The mixture was stirred at this temperature for 0.5 h. and piperidin-4-yl-carbamic acid tert-butyl ester (144 mg, 0.72 mmol) was added to the cold mixture. The reaction mixture was heated to 50° C. for 10 min and concentrated to remove THF. TFA (1 ml) was added, the mixture was stirred until the protecting group was removed (2 h) (progress was monitored by HPLC). TFA was removed in vacuo and saturated NaHCO3 was added. The mixture was extracted with EtOAc and the combined extracts were dried, concentrated and triturated first with Et2O to give the title compound (46 mg, 53%). Analytical HPLC retention time=0.51 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=324.
Reaction SMILES: [Cl:1][C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[CH:6]([C:11]3[C:19]4[O:18][CH2:17][CH2:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.CN(C)C=O.Cl.[CH3:30][N:31]([CH3:44])[CH2:32][CH2:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[CH:6]([C:11]3[C:19]4[O:18][CH2:17][CH2:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)[CH2:7][N:8]([C:39]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:31]([CH3:44])[CH3:30])=[CH:43][CH:42]=3)=[O:40])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Cl)CCNCC2c1cccc2c1OCC2
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)CCN(C(=O)c1ccc(OCCN(C)C)cc1)CC2c1cccc2c1OCC2

Procedure:
Similarly as described in example 22 using a solution of 7-chloro-1-(2,3-dihydrobenzofuran-7-yl)-8-methoxy-1,2,4,5-tetrahydrobenzo[d]azepine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 pi), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30]Br)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[OH:34][C@@H:35]([CH3:46])[CH2:36][NH:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30][N:37]([CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:36][C@@H:35]([OH:34])[CH3:46])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCBr
Reactant: C[C@H](O)CNCC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCN(CC(=O)OC(C)(C)C)C[C@H](C)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.25 ml of diisopropylethylamine are added to 650 mg of 4-[(3-bromo-phenyl)amino]-6-(2-bromoethoxy)-7-methoxy-quinazoline and 1.10 g of tert.butyl (S)-(2-hydroxy-propylamino)-acetate in 15 ml of acetonitrile. The reaction mixture is stirred overnight at 50° C. Since no reaction can be detected, the reaction mixture is concentrated by evaporation, combined with 20 ml of N,N-dimethylformamide and stirred for eight hours at 60° C. Then the temperature is increased to 80° C. After another eight hours the reaction is complete. The reaction mixture is concentrated by evaporation and chromatographed over a silica gel column with ethyl acetate as eluant. The desired product is obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:10]2[C:11]3[C@@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:26][CH:25]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 150 mg, 0.49 mmol), tetrabutylammonium iodide (181 mg, 0.49 mmol) and 4-chlorobenzyl bromide (400 mg, 1.95 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 60-70% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give an off-white solid. This was dissolved in ethanol and the solution was treated with charcoal, then filtered through Celite and evaporated. 1H NMR indicated that there was some tetrabutylammonium iodide present. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed with saturated aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and chromatographed, eluting with 75% ethyl acetate/petroleum ether, to give (4S,7R)-1-(4-chloro-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (100 mg, 48%). APCI(+)-MS (M+H) 429.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][C:14](=[O:16])[CH3:15])=[CH:6][C:5]=1[O:17][CH3:18].[CH3:20]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]([C:14](=[O:16])[CH3:15])[CH3:20])=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COS(C)(=O)=O
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetylamino-2-methoxy-5-nitro-benzoic acid methyl ester (4.0 g, 14.9 mmol), methanesulfonic acid methyl ester (1.3 mL, 15.4 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 40 mL DMF was stirred overnight at ambient temperature. The mixture was poured onto ice water and diluted with dichloromethane. The organic phase was separated, dried and concentrated i. vac.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>>[CH2:13]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 96.5 %

Procedure:
As in the case of Reference Example 3 ,ethyl 4-hydroxybenzoate (2.50 g) was benzylated with benzyl bromide (2.57 g) followed by hydrolysis with potassium hydroxide, thereby yielding 3.31 g of 4-benzyloxybenzoic acid as a crystal. In tetrahydrofuran (50 ml), this compound (1.18 g) was suspended together with N,N'-dicyclohexylcarbodiimide (1.14 g) and 4-hydroxybenzotriazole (0.81 g) and then, with 1-isobutylpiperazine (0.71 g) added thereto, stirred at room temperature for 24 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) and the resulting solid was recrystallized (from n-hexane/ethyl acetate), thereby yielding 1.03 g of the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]([CH:34]=O)[CH2:27]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]([CH2:34][N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:9]1[C:8](=[O:17])[CH2:7][C:6]3[CH:18]=[C:19]([O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:11]=[CH:10]1)[CH2:27]2
Reactant: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1cc2c(cc1OC)C(C=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CC1Cc3cc(OC)c(OC)cc31)C=C2
Temperature: 0 °C
Yield: 96.4 %

Procedure:
Dissolve 1.1 g (3.78 mmol) of 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3-dihydro-2H-3-benzazepin-2-one in 50 ml of THF and 7 ml of dichloromethane. Add 0.69 g (4.53 mmol, 1.2 equivalent) of 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde and 0.22 ml of acetic acid. Cool the reaction mixture to 0° C. and add 1.2 g (5.67 mmol, 1.5 equivalent) of sodium triacetoxyborohydride. The reaction is instantaneous. Evaporate to dryness. The residue is taken up in water, and the aqueous phase is adjusted to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO4, filtered and evaporated to dryness. 1.7 g of an oil is obtained, which is purified by flash chromatography on 100 g of silica (eluant=dichloromethane/ethanol/NH4OH:95/5/0.5) to yield 1.4 g of title product in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:13][CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:19]([O:22][CH2:23]C)(=[O:21])C.C(N(CC)CC)C>CO>[CH3:23][O:22][C:19]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:13][CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[N:3]=1)=[O:21]
Reactant: CCOC(C)=O
Reactant: Brc1cnc(N2CCCC2)c(OCC2CCC2)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 50 mL bomb with a glass liner was charged with the 5-bromo-3-cyclobutylmethoxy-2-pyrrolidin-1-yl-pyrazine (2.27 g, 7.3 mmol), ethyl acetate (6 mL, degassed), methanol (7 mL, degassed) and triethylamine (2.0 mL, 14.5 mmol). PdCl2dppfCH2Cl2 (0.29 g, 0.36 mmol) was charged to the bomb; the bomb was sealed and degassed under vacuum. The reaction was purged with carbon monoxide (×5) then pressurized to 5 bar and heated to 100° C. for 1 hour. The reaction mixture was filtered through celite and washed with methanol then ethyl acetate and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester as an orange solid, 2.2 g (75% yield). LC@215 nm; Rt 2.39: 75%, m/z (ES+): 292 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[C:5]([NH:7][C@H:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6].CO>C(O)C.[Pd]>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([NH:7][C@H:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(C)c1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(C)c1)C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of diethyl N-(3-methyl-4-nitrobenzoyl)-(L)-glutamate (Cosulich, D. B. et al., J. Am. Chem. Soc., 1953, 75, 4675) (11.0 g, 30.0 mmoles) in 95% ethanol (250 mL) was mixed with 10% palladium on carbon (0.8 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 2 hours. The reaction mixture was filtered, spin evaporated, and dried to give a beige solid; yield, 10.1 g (100%); mp 79°-82° C.; 1H-NMR (DMSO-d6) δ 1.15 and 1.16 (2t overlapped, 6H), 2.00 (m, 2H), 2.06 (s, 3H), 2.39 (t, 2H), 4.03 and 4.06 (2q overlapped, 4H), 4.33 (m, 1H), 5.40 (s, 2H), 6.56 (d, Jo=8 Hz, 1H), 7.47 (d, Jo=8 Hz, 1H), 7.50 (s, 1H), 8.16 (d, 1H); uv (MeOH) 284 nm max (17000), 241 min (3020); mass spec (CI) m/e 337 (44%), 134 (100).
Reaction SMILES: [Br:1][CH2:2][Br:3].[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[CH:27]1[CH:32]([CH3:33])[CH:31]([CH3:34])[CH2:30][C:29](=[O:35])[CH2:28]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1([N-]C2CCCCC2)CCCCC1.[Li+]>O1CCCC1.O.CCOCC>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:25])([CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[CH:27]1[CH:32]([CH3:33])[CH:31]([CH3:34])[CH2:30][C:29]([CH:2]([Br:3])[Br:1])([OH:35])[CH2:28]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CC(C)C2C)c(OCc2ccccc2)c1
Reactant: BrCBr
Agent: C1CCC([N-]C2CCCCC2)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2CC(O)(C(Br)Br)CC(C)C2C)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a -78° C. solution of 17.4 g (0.10 mole) of dibromomethane and 21.7 g (0.050 mole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4,5-dimethylcyclohexanone in 100 ml of tetrahydrofuran is added dropwise over a period of 2 hours a solution of lithium dicyclohexylamide (0.10 mole) in 100 ml of tetrahydrofuran. The reaction is stirred one hour longer at -78° C. and quenched by addition of 2 ml (0.11 mole) of water. The reaction is added to 300 ml ether and 200 ml water. The ether extract is dried over magnesium sulfate and evaporated. The crude product is purified via column chromatography on 500 g of silica gel eluted with ether-pentane to give pure 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-dibromomethyl-4,5-dimethylcyclohexanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[S:21][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22]
Reactant: O=C([O-])[O-]
Reactant: COc1sc2[nH]c(=O)n(CCN3CCOCC3)c(=O)c2c1C
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1sc2c(c1C)c(=O)n(CCN1CCOCC1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A mixture of 6-methoxy-5-methyl-3-(2-morpholin-4-ylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.51 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.78 g), potassium carbonate (0.43 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 84%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:39]=2)/[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (190 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (250 mg, 2.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide (42 mg, 18%) as an amorphous white solid: EI-HRMS m/e calcd for C20H22N6O3S2 (M+) 458.1195, found 458.1192.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([O:4][C:5]([N:7](C(OC(C)(C)C)=O)[C:8]1[O:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1)=[O:6])[CH3:3].C([BH-](CC)CC)C.[Na+]>O1CCCC1>[C:2]([O:4][C:5](=[O:6])[NH:7][C:8]1[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)([CH3:25])([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1coc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: CC[BH-](CC)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(CO)co1

Procedure:
Prepared by the method of Example 120 using 2-{bis[(1,1-dimethylethoxy)carbonyl]amino}-4-oxazolcarboxylic acid, ethyl ester (0.65 g) and sodium triethylborohydride (5.5 mL of a 1M solution in tetrahydrofuran). Yield 0.24 g. Used directly.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.[Cl-].[Na+]>CN(C=O)C>[CH:21]1([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCC1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(NC2CCC2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2 g, 10.8 mmol) in DMF (10 mL) was added DIEA (4.2 g, 32.4 mmol) and cyclobutanamine (2.3 g, 32.4 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into saturated sodium chloride, and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified via silica gel column chromatography (10% ethyl acetate in petroleum ether) to get the desired product as a white solid (1.7 g, 7.7 mmol, 71% yield). MS (ESI) m/z=221.2[M+H]+.
Reaction SMILES: O=[C:2]([NH:15]/[N:16]=[C:17]1\[NH:18][C:19](=[O:31])[C:20]2[NH:21][CH:22]=[N:23][C:24]=2[N:25]\1[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:5](=[O:14])[NH:4][CH2:3][C:2]1[N:18]2[C:19](=[O:31])[C:20]3[NH:21][CH:22]=[N:23][C:24]=3[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:17]2=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCn1/c(=N/NC(=O)CNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)OCc3ccccc3)nnc12
Yield: 87.2 %

Procedure:
The solution of benzyl 2-oxo-2-[(2E)-2-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazino]ethylcarbamate (0.60 g, 0.84 mmol) in toluene (30 mL) was refluxed overnight. M+H=410.1. The product was precipitated from the reaction mixture and filtered to give the desired product (300 mg, 87%). LCMS calculated for C20H24N7O3 (M+H): 410.2. Found: 410.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:34](=[O:36])[CH3:35])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [6-methoxy-2′-(phenethylamino-methyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.