Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:7]1[N:8]=[C:9]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:10][CH:11]=1)\[C:4]([OH:6])=[O:5].[C:32]1([C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N+]=[N-])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>ClCCl>[OH:1]/[N:2]=[C:3](/[C:7]1[N:8]=[C:9]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:10][CH:11]=1)\[C:4]([O:6][CH:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:5]
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Z)-2-Hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (4.2 g) as a suspension in dichloromethane (150 ml) was treated with a solution of diphenyldiazomethane (1.91 g) in dichloromethane (50 ml) in a dropwise fashion, over 5 min. After 2 h stirring at room temperature, acetic acid (1 ml) was added and stirred for a further 30 min. The solution was washed with saturated sodium bicarbonate and water, dried and filtered. Removal of solvent in vacuo gave a yellow crisp foam which was purified by chromatography on silica gel eluting with ethyl acetate/hexane. The title compound was obtained as a white solid; νmax (CH2Cl2) 1735, 1520 and 1490 cm-1 ; δH (CDCl3) 6.16 (1H, s), 7.17 (1H, s). 7.22-7.50 (25H, m). [Mass spectrum: +ve ion (thioglycerol) MNa+ (596)].
Reaction SMILES: CN1CCCCC1.[F:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:34]([C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=1)#[N:35]>C(Cl)Cl.O>[C:34]([C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][CH:42]([NH:44][C:21](=[O:23])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:25][CH:24]=2)=[O:15])[CH3:43])=[CH:38][CH:37]=1)#[N:35]
Reactant: CC(C)[C@H](NC(=O)Oc1ccc(F)cc1)C(=O)O
Reactant: CC(N)COc1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccc(F)cc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
1.2 g of N-methylpiperidine was added to a solution containing 3.0 g of N-(4-fluorophenoxycarbonyl)-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 1.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 2.3 g of (-)-2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white crystal (yield: 23% ).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OCCP(OCC)(OCC)=O)(=[O:19])[CH3:18].[H-].[Na+].C(N)CN.[H][H]>CN(C=O)C.C(O)C.[C].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:18][CH2:17][OH:19])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Solvent: CN(C)C=O
Product: OCCCc1cccc(OCc2ccccc2)c1
Yield: 59.2 %

Procedure:
In an argon stream, 3-benzyloxybenzaldehyde (21.3 g) and diethylphosphonoethyl acetate (23.6 g) were suspended in dry DMF (250 ml). Under ice cooling and stirring, 65% oily sodium hydride (3.88 g) was added little by little; after completion of this addition, the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the residue was dissolved in ethyl acetate and washed with water and saturated saline, after which it was dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled off to yield 33.15 g of a crude product of ethyl (E)-3-[3-(benzyloxy)phenyl]-2-propenate as an oily substance. This product was dissolved in ethanol (406 ml); ethylenediamine-treated 5% palladium carbon [Pd—C (en), 2.7 g] was added, followed by vigorous stirring in a hydrogen atmosphere. Hydrogen (1.75 L) was consumed to complete hydrogenation, and the catalyst was filtered off. Under reduced pressure, the solvent was distilled off; the residue was dissolved in dehydrated THF (120 ml). This solution was added drop by drop to a mixture of lithium aluminum hydride (4.61 g) suspended in dehydrated THF (120 ml) under ice cooling. The reaction mixture was stirred under ice cooling for 1.5 hours and at room temperature for 1 hour. The reaction mixture was added to ice water and acidified, after which it was extracted with ethyl acetate, washed with water and saturated saline, after which it was dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled off; the residue was purified by silica gel column chromatography to yield the titled compound (14.39 g) as a colorless oily substance.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:18][C:19]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=1)C.[OH-].[Na+]>CO.Cl>[O:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][CH:9]=3)[S:14]([CH3:17])(=[O:15])=[O:16])[C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1cccc(CN(Cc2cccc3c2OCCO3)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)N(Cc1cccc(CC(=O)O)c1)Cc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of (3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid ethyl ester (210 mg, 0.5 mmol) in MeOH (3 mL) at 0° C. was added aqueous NaOH (2N, 0.5 mL). The reaction was stirred at room temperature for 16 h and was diluted with 1N HCl. The product was extracted into CH2Cl2 and the organic solution was washed with water followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (165 mg). 1H NMR (400 MHz, CDCl3) δ 7.19–7.32 (m, 4H), 6.73–6.81 (m, 3H), 4.29 (s, 2H), 4.22 (s, 4H), 4.18 (s, 2H), 3.63 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[C:44]([Br:45])=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([F:46])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.N1(S(N)(=O)=O)CCC1.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[C:24]12([CH2:34][O:35][C:36]3[C:44]([Br:45])=[CH:43][C:39]([C:40]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:41])=[C:38]([F:46])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoic acid and to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (1.00 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 7.90 (d, J=7.3 Hz, 1H), 7.17 (d, J=12.4 Hz, 1H), 3.71 (s, 2H), 3.35 (s, 3H), 1.98 (br s, 3H), 1.78-1.56 (m, 12H); MS (ES−) m/z 458.2, 460.1 (M−1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:19].Cl.[CH3:21][N:22]([CH:24]=O)C>>[CH:21]1[C:11]2[C:10](=[C:9]([NH:19][C:15](=[O:17])/[CH:14]=[C:13](/[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)\[CH3:18])[CH:8]=[CH:7][CH:12]=2)[CH:13]=[CH:24][N:22]=1
Reactant: N
Reactant: C/C(=C\C(=O)O)c1ccc(N2CCCCC2)cc1
Reactant: CN(C)C=O
Agent: Cl
Product: C/C(=C\C(=O)Nc1cccc2cnccc12)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound was prepared using the procedure described in 142D using the product from Example 147A instead of the product from Example 142C. 1H NMR (300 MHz, d6-DMSO) 10.50 (s, 1H), 9.82 (s, 1H), 8.71 (d, 1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.26 (d, 1H), 7.95 (m, 2H), 7.62 (m, 2H), 6.80 (s, 1H), 3.20 (m, 4H), 2.58 (s, 3H), 1.90-1.56 (m, 6H); MS (DCI/NH3) m/e 372 (M+H)+; Anal. Calcd. For C24H25N3O.2.0 HCl.2.0H2O.0.3 DMF: C, 59.24; H, 6.69; N, 9.27. Found: C, 59.44; H, 6.83; N, 9.24.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][CH2:16][O:17][CH3:18])[CH:6]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:7]1[C:8]([Br:19])=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCc1cc(OCOC)cc(OCOC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1cc(OCOC)cc(OCOC)c1Br
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(2-methoxyethyl)benzene (5.00 g, 19.5 mmol) obtained in Example 1, Step 3 was dissolved in N,N-dimethylformamide (40 mL). After the solution was cooled to 4° C., N-bromosuccinimide (3.47 g, 19.5 mmol) was added thereto, followed by stirring for 1 hour. To the reaction mixture was added water (0.10 L), and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (hexane/ethyl acetate=1/1, 0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)benzene (5.7 g, 87%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=1[F:28])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:27]1[CH:26]=[CH:25][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:8][C:7]=1[NH:6][C:2]([O:4][CH3:5])=[O:3]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(N)c3)c2cc1OC
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(Nc2ncnc3cc(OC)c(OC)cc23)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.4 %

Procedure:
Methyl chloroformate (0.048 ml) was added to a suspension of 4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline (161 mg) and triethylamine (0.14 ml) in dry methylene chloride (3.5 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Methylene chloride (100 ml) was added and the mixture washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by silica column chromatography, eluting with 3% methanol in methylene chloride to yield the title compound as a solid (16 mg, 8.4%); NMR: 3.66 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 7.16 (s, 1H), 7.22 (t, 1H), 7.57 (m, 1H), 7.82 (s, 1H), 8.01 (m, 1H), 8.42 (s, 1H), 9.34 (s, 1H), 9.47 (s, 1H); m/s: M+H+ 373.
Reaction SMILES: [C:1]1(=O)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:9].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH3:20][CH:21]([OH:23])[CH3:22]>O>[Br:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:23][CH:21]([CH3:22])[CH3:20])=[O:7]
Reactant: CC(C)O
Reactant: Br
Reactant: O=C1CCCCCO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)CCCCCBr

Procedure:
A solution of ε-caprolactone (30 g) in 2-propanol (250 ml) at 0° C. was saturated with hydrogen bromide gas. Sulphuric acid (18M, 5 ml) was then added and the solution was heated under reflux for 16 hours. The reaction mixture was poured into water (200 ml), basified with sodium hydrogen carbonate, and extracted with diethyl ether. The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (alumina, dichloromethane) to give isopropyl 6-bromohexanoate as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:24][O:23][C:21]([CH2:20][CH2:19][C:12]1[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:15]=[CH:14][C:13]=1[NH2:16])=[O:22]
Reactant: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 116.1 %

Procedure:
A solution of methyl 3-(3-tert-butoxycarbonylaminomethyl-6-nitrophenyl)propionate (3.2 g, 9.5 mmol) in ethyl acetate (35 mL) in the presence of 10% Pd/C was hydrogenated under atmospheric pressure of hydrogen at room temperature. The catalyst was removed by filtration by using celite and the filtrate was concentrated to give 3.4 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1.O.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: O
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution (80 mL) of [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7.1 g) in acetonitrile were added tetra-n-propylammonium perruthenate (0.63 g), N-methylmorpholine N-oxide hydrate (4.2 g) and molecular sieves 4A powder (3.5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 4.6 g, 71%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@H:8]2[CH2:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:3]1=[O:28].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35].C(N(C(C)C)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:25]([S:22]([CH2:21][C@H:8]1[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=3)[C:3]2=[O:28])[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:9]1)(=[O:24])=[O:23])([CH3:26])[CH3:27]
Reactant: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A sample of tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(isopropylsulfonylmethyl)cyclohexylcarbamate (200 mg, 0.47 mmol) in DMF (10 mL) was charged with 3-(trifluoromethyl)benzoic acid (109 mg, 0.57 mmol), N,N-diethylisopropylamine (0.1 mL, 0.57 mmol), and HATU (216 mg, 0.57 mmol). The reaction was stirred for 48 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,3R,4S)-3-(isopropylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate. MS found: (M+H)+=590.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][C:6]1([CH3:14])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7]1=[O:13].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][C:8]([CH3:12])([C:9](=[O:10])[CH:6]([CH3:14])[CH3:5])[C:7]([O:3][CH2:2][CH2:1][OH:4])=[O:13]
Reactant: OCCO
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(=O)C(C)(C)C(=O)OCCO
Reaction time: 1 h

Procedure:
To a 2-liter round bottom flask was charged ethylene glycol (800 mL) and 2,2,4,4-tetramethyl-1,3-cyclobutanedione (185.8 g, 1.33 moles). While using good mixing, potassium carbonate (91.4 grams, 0.663 moles) was added. An exothermic reaction resulted and the batch temperature rose to approximately 65° C. The reaction was held for 1 hour between 50-60° C. The batch was then drowned into 1300 mL demineralized water and extracted with 800 mL ethyl acetate. The ethyl acetate layer was washed several times with water and dried with anhydrous sodium sulfate. The ethyl acetate was removed at 75° C. under 5 mmHg vacuum and the resulting crude product distilled through a 0.5×6 inch Penn-State packed column to provide 153 g of distilled product. The vapor boiling point was recorded as 113° C. at a pot temperature of 135° C. at <1 mmHg vacuum. The GC assay of the resulting product was 97.2%.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].[Al+3].[Cl-:7].[Cl-].[Cl-].[CH2:10]([SiH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].COC1C=CC=CC=1OC>>[CH3:1][SiH:2]([CH3:5])[Cl:3].[CH2:10]([Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[Cl:7])[CH3:11]
Reactant: CC[SiH](CC)CC
Reactant: C[Si](C)(Cl)Cl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: COc1ccccc1OC
Product: CC[Si](Cl)(CC)CC
Product: C[SiH](C)Cl
Reaction time: 1 h

Procedure:
A four-necked flask was equipped with a condenser, thermometer, dropping funnel, and stirrer was charged with 12.9 g (0.10 mol) of dimethyldichlorosilane and 0.27 g (0.002 mol) of AlCl3, which were agitated with the stirrer. To the flask at room temperature, 5.8 g (0.05 mol) of triethylsilane was added dropwise over 30 minutes. Thereafter, agitation was continued for one hour while the flask was kept at 30° C. 0.28 g (0,002 mol) of o-dimethoxy-benzene was added to the reaction solution which was agitated for a further one hour. Dimethylchlorosilane and triethylchlorosilane were isolated from reaction solution by distillation. There were obtained 3.78 g of dimethylchlorosilane and 7.37 g of triethylchlorosilane in a yield of 80% and 98%, respectively.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].Cl[CH2:19][C:20]1[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=1.O>C(O)(C)(C)C>[CH2:28]([O:27][C:25]([C:23]1[O:24][C:20]([CH2:19][CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][CH:22]=1)=[O:26])[CH3:29]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc(CC(C(C)=O)C(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A solution of 1.78 g of potassium tert-butoxide in 60 ml of tert-butyl alcohol was stirred together with 3.00 g of tert-butyl acetoacetate at 60° C. for 30 minutes under heating and then cooled to room temperature. 3.40 g of ethyl 5-(chloromethyl)-2-furancarboxylate was added dropwise, and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=9/1→5/1] to give 2.26 g of the title compound as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH2:23]([O:30][C:31]1[C:32]([F:41])=[C:33](B(O)O)[C:34]([F:37])=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(O)O>>[CH2:23]([O:30][C:31]1[C:32]([F:41])=[C:33]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[C:34]([F:37])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1c(F)ccc(OCc2ccccc2)c1F
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: Fc1ccc(OCc2ccccc2)c(F)c1-c1nc(N2CCOCC2)nc2c1CCN2c1ccncc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-benzyloxy-2,6-difluorophenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C1CCN2C(=NCCC2)CC1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COC(=O)CCCBr
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CCCN1C(=O)C(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Into a solution of 5-iodo-1H-indole-2,3-dione (1.0 g, 3.66 mmol) in anhydrous THF (18 ml) were added DBU (0.82 mL, 5.49 mmol) and methyl 4-bromobutanoate (0.6 mL, 5.49 mmol). After stirring at rt for 2 hrs, the reaction mixture was quenched with water (60 mL) and HCl (IN, 10 mL). Extraction with EtOAc (3×50 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Purification by flash chromatography (chexanes/Et2O (1/3)) gave the title compound as an orange powder (1.10 g, 71%) in 90.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14](Cl)=[CH:15][CH:16]=1.Cl>CS(C)=O.O>[CH2:3]([S:9][C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14]([S:9][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCS
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCSc1ccc(SCCCCCC)c(C(=O)O)n1
Temperature: 135 °C
Yield: 75.4 %

Procedure:
To 300 ml of DMSO was added 84.5 g of powdered NaOH with vigorous stirring followed by the addition of 150 g of n-hexyl mercaptan. The anion of the mercaptan was allowed to form and then 111 g of 3,6-dichloro-2-pyridinecarboxylic acid in 110 ml of DMSO was added through a dropping funnel. The temperature was increased during addition to 135° C. and maintained at that temperature for 21/2 hours. Upon cooling the brown solution was poured into three volumes of water. The resulting solution was acidified with HCl and extracted with 1,1,1-trichloroethane. The organic layer was dried over MgSO4 and the solvent removed on a rotary evaporator. The reaction yielded 155 g (68% yield) of 3,6-bis(n-hexylthio)-2-pyridinecarboxylic acid as a dark oil which solidified on standing; m.p. 40°-42° C.