Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>C1C=CC=CC=1>[Cl:1][C:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][C:3]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)CC(C)(C)C1
Reaction time: 14 h
Yield: 36.4 %

Procedure:
The following two procedures were adapted from Organic Preparations and Procedures Int., 29(4):471-498. A 500-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehyde (38 g, 240 mmol) in benzene (240 mL). To the solution was added ethoxycarbonylmethylene triphenylphosphorane (84 g, 240 mmol). The mixture was stirred for 14 h. After that time, the solvent was evaporated and the residue was triturated with hexanes (2 L) to extract the product away from the PPh3 by-products. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using a 100% hexane—1:1 hexane/ethyl acetate gradient to afford a 37% yield (20 g) of (E)-ethyl 3-(2-chloro-4,4-dimethylcyclopent-1-enyl)acrylate 107a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[NH:17]([C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=2[N:23]=1)[NH2:18]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)[N:18]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc2nc(NN)sc2c1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc2nc(-n3nc(CCCO)cc3-c3ccc(Cl)cc3)sc2c1
Yield: 80.9 %

Procedure:
6-(4-Chlorophenyl)-4,6-diketohexanol (14.43 g, 60 mM) was treated with 2-hydrazino-6-methoxybenzothiazole (11.72 g, 60 mM) in pyridine (10 ml) and MeOH (300 ml) at reflux for 72 hr. Work-up as described in Example 1 followed by recrystallization from MeOH afforded the title compound 6 as a white solid (19.4 g), mp=123°-125° C.; NMR(CDCl3) δ 6.3 (s, 1H, C4 -H); MS, m/e 399 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH2:71][NH:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:69][CH:70]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].C(N(CC)CC)C>CN(C=O)C>[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH2:71][N:72]([CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:22]([F:25])([F:24])[F:23])=[CH:21][CH:20]=3)=[CH:69][CH:70]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (40 mg, 0.11 mmol) in DMF (1 mL) was added HATU (45 mg, 0.11 mmol). After stirring for 1 h at room temperature, 6-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)pyridin-3-yl 4-(heptyloxy)benzoate INT-20 (61.7 mg, 0.13 mmol) was added followed by triethylamine (22.8 mg, 0.22 mmol). The reaction mixture was allowed to stir at room temperature for overnight. The final product was isolated by HPLC purification to give 6-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)pyridin-3-yl 4-(heptyloxy)benzoate INT-21. LCMS-ESI (m/z) calculated for C43H48F3N3O8: 792; no m/z observed, tR=4.83 min (Method 1).
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Product: N#Cc1ccc(S(=O)(=O)CCn2cccn2)cc1

Procedure:
250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with pyrazole to yield 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.0 (M)+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>C(O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[OH:11])=[CH:19][CH:20]=1
Reactant: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(c1ccccc1)(c1ccc(F)cc1)C1CCNCC1
Temperature: 0 °C
Yield: 24.5 %

Procedure:
A mixture of 16.3 g (0.05 mole) of 1-acetyl-α-(4-fluorophenyl)-α-phenyl-4-piperidinemethanol and 5.6 g (0.1 mole) of potassium hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux for 18 hr. The mixture was poured into 1.5 liter of ice water and a solid precipitated. The solid was collected by filtration and dried. The gummy solid was dissolved in ethyl ethyl ether, the solution was filtered, and the filtrate slowly evaporated to 50 ml volume. The resulting solid was collected by filtration and recrystallized from 2-propanol-isopropyl ether to yield 3.5 g (25%) of white solid, m.p. 144.5°-146° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][C@@H:22]([OH:24])[C:21]4[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]=4[O:19]3)[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)#[N:2].[CH3:30][Si:31](C1NC=CN=1)([CH3:33])[CH3:32]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][C@@H:22]([O:24][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:21]4[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]=4[O:19]3)[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)#[N:2]
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: N#Cc1ccc2c(c1)CC[C@@H](N1CCC3(CC1)C[C@@H](O)c1cc(N)ccc1O3)C2
Solvent: CC#N
Product: C[Si](C)(C)O[C@@H]1CC2(CCN([C@@H]3CCc4cc(C#N)ccc4C3)CC2)Oc2ccc(N)cc21
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl]amine (50 mg, 0.128 mmole) in acetonitrile under argon was added trimethylsilylimidazole (0.36 gm, 2.5 mmole) and the reaction warmed to 60 C. for 1.5 hrs. The reaction was concentrated in vacuo and purified by flash chromatography using 95/5/0.1 dichloromethane/methanol/triethylamine to give N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-trimethylsilyloxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl]amine as a foam (58 mg, 98%). MS m/z 462 (M+), 1H NMR (CDCL3) δ 0.09 (9 H, s), 1.4-2.1 (8 H, m), 2.4-2.9 (9 H, m), 3.2 (2 H, br, s), 4.65 (1 H, t), 6.41(1 H, dd, J=9.2 and 3.3 Hz), 6.49 (1 H, d, J=3.3 Hz), 6.52 (1 H, d, J=9.2 Hz), 7.03 (1 H, d, J=9.2 Hz), 7.22 (2 H, m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:33])[C@H:18]([CH3:32])[NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:30])[C:21]=1[CH3:31]>C1(C)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:33])[C@H:18]([CH3:32])[N:19]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:30])[C:21]=1[CH3:31])[C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2]
Reactant: COC(=O)[C@H](C)Nc1c(C)c(C)cc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCC(=O)N(c1c(C)c(C)cc2ccccc12)[C@@H](C)C(=O)OC
Reaction time: 12 h

Procedure:
During 30 minutes 0.07 g-moles of ethoxyacetyl chloride, dissolved in 20 ml of toluene, and 0.07 g-moles of triethylamine, dissolved in 20 ml of toluene, are dropped at room temperature simultaneously to 0.06 g-moles of N-(2,3-dimethylnaphthyl)-alanine methyl ester, dissolved in 100 ml of toluene. Thereby the temperature rises to 43°. The reaction mixture is then stirred at about 40° during 12 hours. From the resulting yellow suspension the inorganic salt is filtered off and the filtrate is washed with water until neutral. Then the organic phase is dried over sodium sulfate and concentrated by evaporation. The crude oil is purified by column chromatography using silicagel 60 and diethylether as the eluant. After removal of the solvent 18.8 g (=91% of theory) of the final product are obtained in crystallised form, m.p. 96° to 108°.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C@@H:7]([OH:9])[CH3:8])[NH:4][N:3]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[OH:9][C@H:7]([C:5]1[NH:4][N:3]=[C:2]([O:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:6]=1)[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)c1cc(O)n[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc([C@H](C)O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a stirred solution of (S)-3-hydroxy-5-(1-hydroxyethyl)-1H-pyrazole (0.5056 g, 3.95 mmol) in anhydrous dichloromethane (20 ml) under nitrogen was added p-toluenesulfonyl chloride (0.8276 g, 4.34 mmol) then, dropwise, triethylamine (0.66 ml, 4.74 mmol). The mixture was stirred at room temperature for 3 h, then washed with saturated NaCl (15 ml). The aqueous layer was further extracted with dichloromethane (2×25 ml) and the combined organic extracts were dried (NaSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 0.8770 g (79%) of the title compound as an orange oil: 1H NMR (400 MHz, DMSO-d6) δ 1.31 (3H, d, J=6.5 Hz), 2.42 (3H, s), 4.67 (1H, m), 5.40 (1H, d, J=5.1 Hz), 5.79 (1H, d, J=2.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.77 (2H, d, J=8.4 Hz), 12.48 (1H, s); MS (ES+) m/e 283 [M+H]+, 265 [M−OH]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].O1CCC[CH2:34]1.S(C1C=CC(C)=CC=1)(OC)(=O)=O>O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@@H:27]([CH2:28][O:29][CH3:34])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3)CC2)c(C)c1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-hydroxymethylpyrrolidin-2-one (200 mg) described in Example 284 and sodium hydride (22 mg) was added tetrahydrofuran, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added methyl tosylate (74 μL), and the mixture was further stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methoxymethylpyrrolidin-2-one. The obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methoxymethylpyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (113 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14].Cl>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h

Procedure:
Commercially available 4-acetyl-benzenesulfonyl chloride (1.25 g, 5.7 mmol) was dissolved in THF (20 mL) and slowly added to a stirred solution of 25% NH3 in H2O (50 mL). The reaction mixture was stirred at it for 1 h. The reaction mixture was acidified using conc. HCl to pH=2. The white precipitation was collected by filtration, washed with H2O and dried in vacuo affording 975 mg of the title compound as off-white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1)[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[Pd].C([O-])(=O)C.C(#N)C>[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:19][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C=Cc1ccc(OCC)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc(C=Cc2cc(F)c(F)c(F)c2)cc1

Procedure:
A mixture of 10.5 g of 1-bromo-3,4,5-trifluorobenzene, 7.4 g of p-ethoxystyrene, 0.25 g of Pd acetate, 0.6 g of tri-o-tolylphosphine, 7 g of triethylamine and 125 ml of acetonitrile is heated at reflux until completion of the reaction. Customary working-up gives 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethene (C 76 I), which is hydrogenated on Pd-C (5%) in THF to give 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethane, C 45 I.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General procedure for the syntheses of carbamates, pyridinamides, and sulfonamides. In a 16 mL reaction vessel was placed (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (42 mg, 0.1 mmol), triethylamine (90 μl) and DMF (1.5 mL) was added to completely dissolve the solid material. Isopropyl chloroformate (0.15 mL, 1.0M in toluene) was added to the solution and the mixture was stirred 30 min under N2 at room temperature. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to give Compound A22, 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 1.89 (m, 2H), 1.93 (m, 2H), 3.07 (s, 3H), 3.63 (m, 2H), 3.67 (m, 2H), 4.94 (m, 1H), 5.61 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.40 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C20H25N5O7S 479.15, found 480.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[C:11]([CH2:13][OH:14])[CH:12]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[OH-].[Na+].[Cl:32][C:33]([Cl:40])([Cl:39])[CH2:34][O:35][C:36](Cl)=[O:37]>CCOC(C)=O.O>[Cl:32][C:33]([Cl:40])([Cl:39])[CH2:34][O:35][C:36](=[O:37])[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][Si:16]([CH:20]([CH3:21])[CH3:22])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])=[C:11]([CH2:13][OH:14])[CH:12]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1CO)(C(C)C)C(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1CO)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of Intermediate 61c (0.15 g, 0.36 mmol) in EtOAc (1.8 mL) was added 1N aqueous NaOH solution (0.6 mL, 0.60 mmol) followed by 2,2,2-trichloroethylchloroformate (54.0 μL, 0.40 mmol). The reaction was stirred at RT overnight then treated with another portion of 1N aqueous NaOH solution (0.3 mL, 0.30 mmol) followed by 2,2,2-trichloroethylchloroformate (27.0 μL, 0.20 mmol). After stirring for another 4 h, the mixture was diluted with EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-25% EtOAc in cyclohexane, to give the title compound (176 mg, 84%). LCMS (Method 3): Rt 5.35 min, m/z 592, 594 [MH+].
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
p-Toluenesulfonic anhydride (326 mg, 1 mμol) and N,N-diisopropylethylamine (1.92 μl, 1.1 mμol) are added to an ice-cold, stirring solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 mμol) in anhydrous methylene chloride (10 ml). The resulting solution is stirred in the cold and under a nitrogen atmosphere for 2.5 hours. The solution is diluted with methylene chloride (20 ml), washed with water (10 ml). 1 M pH 3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10 ml) dried with magnesium sulfate, filtered, and evaporated under vacuum to a semi-solid. This material is triturated with ice-cold ethyl acetate (2×2 ml) and diethyl ether (2×5 ml) to provide benzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (276 mg. 67%) as a white powder. Recrystallization from methylene chloridediethyl ether gives analytically pure product as small white needles: mp 103°-105°; IR (CH2Cl2) 1786, 1723, 1382, and 1190 cm-1 ; NMR (CDCl3) 8 2.44 (s,3,ArCh3) 3.03 (dd,1,J=3.0 and 17.0,HGβ), 3.16 (dd,1,J=8.5 and 18.7,H4a), 3.32 (dd,1,J=10.0 and 18.7,H46), 3.55 (dd,1,J=5.5 and 17.0, HG), 4.21 (m,1,H5), 5.14 (ABq,2,J=12,CH2Ar), 7.35 (S,5,ArH0, 7.26 and 7.75 (two d's,4,J=9,ArH); UV (dioxane) 283 (E6600) and 277 (E6500) nm.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>CC#N.O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(N)cn1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Solvent: O
Product: CCCCN1C(=O)C(Nc2ccc(OC)nc2)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 4.4 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (58 mg, 0.20 mmol) and 6-methoxypyridin-3-amine (49 mg, 0.40 mmol) was dissolved in MeCN (11.0 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 5 mins. The reaction mixture was diluted with MeCN and water and purified by preparative HPLC using MeCN/0.1M NH4OAc as eluant giving the title compound (3.4 mg, 4.3%). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, 1H), 7.25-7.1 (m, 4H), 7.0 (bs, 1H), 6.85 (dd, 1H), 6.3 (d, 1H), 3.78 (t, 2H), 1.9-1.8 (m, 2H), 1.5-1.4 (m, 2H), 1.0 (t, 3H); Mass Spectrum: M−H+ 386.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[C:20]([F:31])[C:19]=2[CH3:32])=[C:14]([F:33])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)C)=[O:7].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[C:20]([F:31])[C:19]=2[CH3:32])=[C:14]([F:33])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
To a solution of isopropyl 2-[2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenoxy]acetate (300 mg, 0.65 mmol, 1.0 eq) in a mixture of THF (10 mL) and MeOH (10 mL) was added NaOH (2M aqueous solution, 10 mL). The reaction mixture was stirred at room temperature for 3 h. The THF was evaporated in vacuo and the pH of the aqueous phase adjusted pH 3 with diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (104 mg, 38%).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[H][H]>CO>[CH2:1]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C@H:9]([OH:10])[CH2:11]1
Reactant: [H][H]
Reactant: O=C1CCCc2ccccc21
Solvent: CO
Product: O[C@@H]1CCCc2ccccc21
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl((R,R)—O-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.73 g (5.0 mmol) of α-tetralone and 4.4 ml of methanol were added thereto, then hydrogen gas was charged to 3.0 MPa. Subsequently, the mixture was stirred for 20 hours at 60° C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-1-tetralol was obtained at a conversion rate of 52.0% with an optical purity of 99.3% ee.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:21][CH2:20][CH2:19][O:18][CH3:17])[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: COCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-methoxyethanol and DBU in THF. ES-MS m/e (%): 362 (M+H+, 100).