Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:17]1[CH:16]=[C:15]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:19]=[N:18]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1csc(-c2cn[nH]c2)n1
Temperature: 70 °C
Yield: 57.3 %

Procedure:
To a solution of 2-bromothiazole (1 g, 6 mmol) in toluene (20 mL) and ethanol (10 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.41 g, 7.3 mmol), 2 M sodium carbonate solution (17.3 mL) and Pd(PPh3)4 (7 mg, 0.06 mmol). The reaction mixture was purged with argon for 15 min. The resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated and diluted with water (100 mL), extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), the organic solvent was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford racemic 2-(1H-pyrazol-4-yl)thiazole as brown liquid (520 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.22 (br s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.55 (d, 1H); LC-MS m/z calculated for [M+H]+152.02, found 152.1.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>ClCCl.CO>[ClH:23].[N:17]1([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[O:16])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCCNCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A solution of 1-(t-butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane (140.0 g, 0.44 mol) in dichloromethane:methanol (1:1, v/v, 600 ml) at 0° C. was saturated with hydrogen chloride gas and the reaction mixture was stirred at room temperature under nitrogen for 18 hours after which time the reaction mixture was evaporated under reduced pressure and slurried in ethyl acetate to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with diethyl ether and drying in vacuo at 60° C. to give the title compound as a colourless solid (99.0 g, 90%). Rf 0.41 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 214 (MH)+. Found: C,47.50; H,8.10; N,16.55; C10H19N3O2 HCl 0.2H2O requires C, 47.41; H, 8.12; N,16.59%.
Reaction SMILES: [Cl-].[C:2]([C:4]1([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>ClCCl>[CH2:21]([S:23]([N:7]1[CH2:8][CH2:9][C:4]([CH2:10][CH:11]([CH3:13])[CH3:12])([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:25])=[O:24])[CH3:22]
Reactant: CC(C)CC1(C#N)CC[NH2+]CC1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(C#N)(CC(C)C)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyano-4-isobutylpiperidinium chloride (3, 4.49 g, 44.4 mmol) dichloromethane (150 ml) and triethylamine (6.1 ml, 44.4 mmol). To this was added dropwise ethanesulfonyl chloride (2.1 ml, 22.2 mmol). This was stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)-4-isobutylpiperidine-4-carbonitrile (4) as a white solid. MS 259 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH3:24][S-:25].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([S:25][CH3:24])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: C[S-]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(SC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (200 mg, 0.60 mmol) and sodium thiomethoxide (126 mg, 1.80 mmol) in DMF (5 mL) is heated at 70° C. overnight. After cooling, water (20 mL) is added and the resulting mixture is extracted with EtOAc. The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-nicotinic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:13][C@@H:14]([C:16]([F:19])([F:18])[F:17])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Na+]>CO>[C:6]([NH:5][C@@H:4]([CH2:3][OH:2])[CH2:13][C@@H:14]([C:16]([F:19])([F:18])[F:17])[CH3:15])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)[C@@H](C[C@H](C)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](C[C@H](CO)NC(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 6a (420 mg, 1.4 mmol) in methanol (10 mL) was added NaBH4 (531 mg, 14.0 mmol) in small portions. The reaction mixture was stirred at room temperature for 1 h before removal of the solvent. The residue was partitioned between 100 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to yield 357 mg of the desired product as a white solid (94%). 1H NMR (300 MHz, CDCl3) δ 4.74 (m, 1H), 3.71 (m, 2H), 3.58 (m, 1H), 2.31 (m, 1H), 2.14 (m, 1H), 1.92 (m, 1H), 145 (s, 9H), 1.17 (d, 3H, J=7.0 Hz). 13C NMR (75.5 MHz, CDCl3) δ 156.26 (C═O), 128.41 (q, CF3, 1JCF=279.4 Hz), 80.14 (C), 64.78 (CH2), 50.73 (CH), 35.59 (q, CH, 2JCF=29.6 Hz), 31.74 (CH2), 28.52 (3×CH3), 13.71 (CH3); 19F NMR (282.6 MHz, CDCl3/CFCl3) δ −73.84 (br. s, 3F); GC-MS (CI, CH4): 272 (100, [M+1]+), 216 (68), 172 (26), 57 (11).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:9](=[O:11])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CC(CC(=O)O)c1ccccc1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)CC(C)c2ccccc2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 3-phenylbutanoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%. MS M+H calculated 339.6, found 339.5.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]=O)[CH:16]=[C:17]([F:20])[C:18]=1[F:19]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:15]3[CH:16]=[C:17]([F:20])[C:18]([F:19])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCCc1cc(F)c(F)c(F)c1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(F)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (7.394 mmol) and 3-(3,4,5-trifluoro-phenyl)-propionaldehyde (1.391 g; 7.394 mmol) afforded 3-ethyl-1-iodo-8-[2-(3,4,5-trifluoro-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.74 min.; [M+H]+=435.86 g/mol.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(B(O)O)c1O
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c(O)c1
Yield: 84 %

Procedure:
6-(2-Hydroxy-3-methylphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 84% yield using method F; δH [2H6]-DMSO 13.38,(1H, b), 8.41-8.22,(4H, m), 8.13,(1H, d), 8.09-8.01,(2H, m), 7.96,(1H, d), 7.28,(1H, d), 6.90,(1H, t), 6.80,(2H, m), 2.33,(3H, s), 2.26,(3H, s); MS 369 (MH)+; HPLC retention time (system 1) 4.53 minutes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](O)(=[C:12]1[C:20](=[O:21])[CH2:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:13]1=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>CCO.C(O)(C(F)(F)F)=O>[NH:1]([C:7](=[C:12]1[C:13](=[O:14])[CH2:15][C:16]([CH3:17])([CH3:18])[CH2:19][C:20]1=[O:21])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)CC(O)=C1C(=O)CC(C)(C)CC1=O
Reactant: NCCC(=O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(NCCC(=O)O)=C1C(=O)CC(C)(C)CC1=O
Yield: 98 %

Procedure:
To a stirred suspension of H-β-Ala-OH (1.02 g, 11.4 mmol) and ivDde-OH (5 ml, 22.9 mmol) in EtOH was added TFA (88 μL, 1 mmol) at room temperature.1 The mixture was then refluxed for 24 hours. After the solvent was evaporated in vacuo, a crude product was purified by column chromatography with CH3OH/CH2Cl2 (0.1% TFA) gradient to afford ivDde-β-Ala-OH (3.3 g, 97.6%). NMR (CDCl3) δ 1.02 (m, 12H), 1.90-2.03 (m, 1H), 2.39 (s, 4H), 2.75 (t, J=6.0 Hz, 2H), 3.06 (br d, =6.0 Hz, 2H), 3.78 (q, J=6.0 Hz, 2H); 13C NMR (CDCl3) δ 22.8, 28.4, 29.4, 30.2, 34.1, 37.4, 39.6, 52.9, 107.4, 173.0, 177.2; MS (MALDI) m/z: calcd for C16H26NO4 296.2; found 296.5 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([F:12])([F:11])[F:10].C([O-])(=O)C.[Na+].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29].ClCCl>C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]([C:9]([F:12])([F:11])[F:10])=[N:29]1
Reactant: NNc1ccccc1Cl
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(2-furyl)-4,4,4-trifluorobutane-1,3-dione (105 g, 0.51 mole) in glacial acetic acid (220 mL) was added sodium acetate (42 g 0.51 mole). The temperature rose to about 34° C. 2-Chlorophenylhydrazine hydrochloride (90 g, 0.5 mole) was added portionwise over a period of 10 minutes to give a creamy suspension. The mixture was warmed to about 60° C. for about 45 minutes. The bulk of the acetic acid was removed by stripping on a rotary evaporator at a bath temperature of 65° C. The remaining oily residue was added to about 800 ml of water with vigorous stirring and a heterogeneous mixture resulted. After about 15 minutes, dichloromethane (500 mL) was added and the mixture was partitioned. The aqueous phase was extracted with 300 ml of dichloromethane. The combined organic phases were washed with water and saturated sodium bicarbonate solution and then dried with MgSO4 and filtered. Volatiles were removed on a rotary evaporator. The crude product consisted of 151 g of a dark red oil, which contained approximately 89% of the desired product and 11% of the regioisomeric pyrazole (determined by NMR analysis).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][C:9]1[C:10](=O)[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl.[CH3:16][O:17][NH2:18]>>[C:1]([CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[N:18][O:17][CH3:16])[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CON
Reactant: CCOC(=O)CCCC1=CCCC1=O
Agent: Cl
Product: CCOC(=O)CCCC1=CCCC1=NOC

Procedure:
In the manner described for the preparation of the compound of Example 20, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 18) and methoxyamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:46][C:47]1[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](Cl)=[O:50]>ClCCl>[Cl:56][C:55]1[C:47]([F:46])=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49]([N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15])=[O:50]
Reactant: O=C(Cl)c1cccc(Cl)c1F
Reactant: C#CC[C@@H](NCCCNC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCNC(=O)OCc1ccccc1)C(=O)c1cccc(Cl)c1F
Yield: 84.9 %

Procedure:
(R)-Benzyl 3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propylcarbamate (0.28 g, 0.53 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (0.22 mL, 1.60 mmol) was added followed by the addition of 2-fluoro-3-chlorobenzoyl chloride (0.112 g, 0.58 mmol). The reaction was stirred under a nitrogen atmosphere until the reaction was complete (LC/MS) (total of 5 min). The mixture was stirred for an additional 10 min, diluted with dichloromethane (50 mL) and washed with aqueous sodium bicarbonate (5 mL), water (5 ml×2) and brine solution and dried over anhydrous sodium sulfate. The solid was removed by filtration and the solvent removed under vacuum to provide (R)-benzyl 3-(3-chloro-N-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynyl)-2-fluorobenzamido)propyl-carbamate as an orange solid (0.31 g, 0.45 mmol, 84%). mp 103-105° C. 1H-NMR (DMSO-d6): δ 9.41-8.94 (m, 1H), 8.21-5.62 (m, 16H), 5.35-4.80 (m, 2H), 3.46-1.15 (m, 11H). LC/MS: 686 [M+H].
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:24](=[O:26])[CH3:25])(=O)C>C([O-])(=O)C.[Na+].C(OCC)(=O)C>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:7][O:8][C:24](=[O:26])[CH3:25])[O:9][C@H:1]1[N:10]1[CH:11]=[N:12][C:13]2[C:19]1=[N:18][CH:17]=[N:16][C:14]=2[OH:15])(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 181.6 %

Procedure:
A suspension of 0.367 Kg (1.36 moles) of Inosine, 0.52 Kg (5.51 moles) of acetic anhydride and 5.6 g (0.068 mole) of sodium acetate is heated between 90° C. and 140° C. for about 4 hours. At the end of the reaction, the solids are dissolved. The reaction mixture is then cooled to about 45° C. and 0.75 L of ethyl acetate are added. The resulting suspension is stirred for about 1 hour at room temperature. The solid is filtered, washed with ethyl acetate and dried under reduced pressure at about 60° C. to afford 0.487 Kg of crude product. The crude product is used in the next reaction.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:29][CH2:30][O:31][CH3:32]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][CH2:30][O:31][CH3:32])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COCCI
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in tetrahydrofuran (9.1 mL, 9.1 mmol) under N2 at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (1.0 g, 4.1 mmol) in tetrahydrofuran (2.0 mL). The resulted light brown solution was stirred at −78° C. for 30 min before adding a solution of 1-iodo-2-methoxyethane (0.93 g, 5.0 mmol) in tetrahydrofuran (2.0 mL). The mixture was stirred for an hour at −78° C. then kept in a freezer reading at −20° C. overnight. The reaction was quenched with saturated ammonium chloride. The layers were separated and the aqueous extracted with ether three times. The combined organics were then washed with brine, dried (magnesium sulfate), filtered and purified by flash chromatography (EtOAc/Hexane) to provide the desired product (0.28 g, 23%). LCMS calculated for C15H26NO5: (M+H) 300.2; found 300.2.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([OH:24])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]([O:24][CH3:3])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(O)C(Nc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1Nc1ccccc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To 10 ml of anhydrous tetrahydrofuran was added 0.34 g (0.0085 mole) of a 60% sodium hydride-mineral oil, and while stirring the mixture at 45° to 50° C., 1.21 g (0.0085 mole) of methyl iodide was added thereto. To the mixture was added dropwise a solution of 2.37 g of 1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained in Reference example 17 (1) dissolved in 10 ml of anhydrous tetrahydrofuran, and the mixture was further stirred at the same temperature for 1 hour. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was spplied to silica gel column chromatography (the eluent used was a mixture of methyl acetate:toluene=1:4) to obtain 1.98 g of 1-t-butoxycarbonyl-3-methoxy-4-phenylaminopyrrolidine as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)=O)[S:9][CH:10]=1.FC(F)(F)C([O-])=O.[NH4+:28].O>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2[NH:28][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=2)[S:9][CH:10]=1
Reactant: O=C(NC1CCCCC1=O)c1nc(-c2ccco2)cs1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: c1coc(-c2csc(-c3nc4c([nH]3)CCCC4)n2)c1
Yield: 28.2 %

Procedure:
4-(2-Furyl)-N-(2-oxocyclohexyl)thiazole-2-carboxamide (239 mg, 0.823 mmol) obtained in Step 2 and ammonium trifluoroacetate (1.00 g, 7.63 mmol) were stirred at 140° C. for 2 hours, and water and ethyl acetate were added thereto, then the mixture was extracted. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a title compound (63.0 mg, 28%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:29][C:28](=[O:30])[NH:27][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[CH:33]=[CH:34][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:39])[N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:31]=[C:32]([C:35]([F:37])([F:36])[F:38])[CH:33]=[CH:34][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)oc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-1,3,4-oxadiazol-2(3H)-one (Example 441, 10 mg, 0.0183 mmol) in DMF (0.10 mL) was added cesium carbonate (6 mg, 0.0183 mmol) and iodomethane (0.0011 mL, 0.0183 mmol). After stirring at rt for 1.5 h, the reaction mixture was quenched with water, and the product was extracted with EtOAc (3×). The combined extracts were washed with water and brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 chromatography, to provide the title compound. LC/MS: m/e 560.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.09 (1H, d, J=2.0 Hz), 7,69 (1H, dd, J=8.5, 2.1 Hz), 7.61 (1H, d, J=7.5 Hz), 7.10-7.20 (3H, m), 6.94-6.98 (3H, m), 6.83 (1H, d, J=8.7 Hz), 4.65-4.95 (2H, br), 3.53 (3H, s), 1.25 (9H, s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:26]=[C:18]3[C:19]4[C:24]([CH2:25][N:17]3[N:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(Cl)Cl>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:26]=[C:18]3[C:19]4[C:24]([CH2:25][N:17]3[N:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(COc2cccc(-c3nc4n(n3)Cc3ccccc3-4)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Oc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1

Procedure:
2-(3-Benzyloxyphenyl)-5H-s-triazolo[5,1-a] isoindole (17 g) is suspended in 500 ml of ethanol and hydrogenated at atmospheric pressure and room temperature in the presence of 3 g of 10% Pd on charcoal. After addition of 500 ml of methylene chloride, the catalyst is filtered off and the solution is concentrated to dryness. The title product is purified by crystallization from dioxane. Yield 10.68 g (85.7%); m.p. 251-2°C.
Reaction SMILES: CC(C)([O-])C.[K+].CN(C=O)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C@H:21]([CH2:24][OH:25])[O:20][C:19]=2[CH:26]=1)([O-:14])=[O:13].ClC1C=CC(O[CH2:33][C:34]#[N:35])=CC=1>CC(OC)(C)C>[OH:25][CH2:24][C@H:21]1[CH2:22][O:23][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[C:26]([CH2:33][C:34]#[N:35])[C:19]=2[O:20]1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: N#CCc1c([N+](=O)[O-])ccc2c1O[C@@H](CO)CO2
Yield: 60 %

Procedure:
A 5 L 3-necked flask equipped with a mechanical stirrer is charged with solid potassium t-butoxide (103.00 g, 0.918 mol) and DMF (1900 mL). The stirred solution is cooled until the internal temperature is 0° C., and a DMF (1100 mL) solution containing [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (47.33 g, 0.224 mol) and (4-chlorophenoxy)acetonitrile (39.05 g, 0.233 mol) is added over 45 min. The reaction is quenched with 1 N HCl (1 L) and the volatiles are removed by rotary evaporation (˜3 L removed). The residue is dissolved in water (2 L) and extracted with EtOAc (3×600 mL). The combined extracts are washed with water (2×300 mL), 1 N NaOH (3×400 mL) and brine (300 mL), and evaporated to give an orange/brown solid. The solid is suspended with stirring in MTBE (300 mL) for 30 min. The solid is collected by vacuum filtration, washed with MTBE (50 mL) and then suction dried giving the title compound (33.60 g, 60%) as a tan solid. LCMS (Standard Method): 2.14 min, 251 (M+H)+. 1H NMR (300 MHz, CDCl2) δ 7.77 (d, J=9.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 4.48-4.37 (m, 2H). 4.28-3.91 (series of m, 5H), 2.32 (br s, 1H).