Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:33]([O:40][C:41]([C@H:43]1[CH2:48][CH2:47][C@@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([O:40][C:41]([C@H:43]1[CH2:48][CH2:47][C@@H:46]([C:49]([N:5]2[CH2:6][CH2:7][CH2:8][N:2]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[N:19]=[C:20]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[O:21][C:22]=4[C:23]([F:26])([F:24])[F:25])=[O:17])=[CH:11][CH:10]=3)[CH2:3][CH2:4]2)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCCN(C(=O)[C@H]3CC[C@@H](C(=O)OCc4ccccc4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (100 mg, 0.21 mmol), cis-cyclohexane-1,4-dicarboxylic acid monobenzyl ester (0.67 mg, 0.25 mmol), and triethyl amine (0.070 mL) in DMF (5 mL) was stirred for 5 minutes and PyBroP (116 mg, 0.25 mmol) was added. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. The residue was extracted with ethyl acetate and washed with saturated ammonium chloride (100 mL), water (50 mL), brine (100 mL) and dried with anhydrous sodium sulfate. The solvent was removed and the crude material was purified on a flash column chromatography eluted with ethyl acetate/hexanes to afford cis-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (100 mg, 71% yield) as a white solid. LCMS for C37H37F3N4O5 calcd. (m/e) 674, observed 675 (M+H).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O1COCO[CH2:23]1.C(O)(=O)C>O>[C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:23]2)([OH:17])=[O:16]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C

Procedure:
In a 3000-1 glass lined reactor, 550 Kg of oleum containing 25% of SO3 are charged under vacuum and good aspiration, then, consecutively, under stirring, 56 Kg of terephthalic acid at 20-23° C. and 26 Kg of 1,3,5-trioxane at 15-20° C. are added thereinto. The reactor is heated at 130-133° C. for 4 hours, then the mixture is cooled to 20-23° C. and 118 Kg of glacial acetic acid are couled portionwise thereinto at a temperature not higher than 25° C. At the end of this operation, 1000 Kg of water are added portionwise, whereby the temperature is maintained not higher than 43-45° C. by circulation of water in the jacket. The mixture is stirred for about 1 hour at 20-23° C., then the product is centrifugated, squeezed and abundantly washed with water in order to remove the larger amount of sulfuric acid from the mother liquors and to obtain 100-105 Kg of 5-carboxyphthalide as a well squeezed, wet raw-product. In a 3000-1 stainless steel reactor the product thus obtained is suspended in 680 Kg of deionized water and a solution of 60 Kg of sodium bicarbonate in 540 Kg of deionized water is then slowly added to said suspension to a pH of 7.0-7.2. To the solution thus obtained, lightly cloudy, 10 Kg of Celite® are added, the solid is filtered off and the solution, at a temperature of 22-25° C., is brought to pH=3 with 32% hydrochl 20-22° C. and centrifugated. The product is well squeezed, abundantly washed with deionized water and dried under vacuum to give 41-43.7 Kg of 5-carboxyphthalide.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.C(=O)(O)[O-].[Na+].C1COCC1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>O>[N+:30]([C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCC[C@@H](O)C1
Reaction time: 14 h

Procedure:
To a 100-mL round bottom flask (RBF) was added (R)-piperidin-3-ol hydrochloride (1.29 g, 9.37 mmol), sodium bicarbonate (2.76 g, 32.8 mmol), THF and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.31 ml, 9.37 mmol). The yellow mixture was heated to 75° C. with a water-cooled reflux condensor and allowed to stir 14 h. The reaction was filtered through a glass frit, rinsing with EtOAc, and concentrated in vacuo to give (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36].C(O)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:35]#[N:36])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:4][CH:3]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (2.33 g) is dissolved in N,N-dimethylformamide (16.8 ml) and thereto is added sodium hydride (60%) (273 mg) under ice-cooling. Twenty minutes thereafter, thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (2.08 g) and the mixture is stirred at room temperature for 1 hour and 15 minutes. To the reaction solution are added acetic acid to consume the excess sodium hydride, and thereto are added ethyl acetate and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-({(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile (2.81 g). MS (m/z): 626/628 [M+H]+
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:15]1([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:10](=[CH:11][CH:12]=2)[N:13]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:14]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Solvent: CCO
Product: c1ccc(-c2nc3ccc(Cn4ccnc4)cc3nc2-c2ccccc2)cc1
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 3.76 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 4.5 parts of diphenylethanedione and 80 parts of ethanol was stirred for 4 hours at reflux temperature. The reaction mixture was concentrated and the concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and ethanol. The product was filtered off and dried, yielding 4 parts (55%) of 6-(1H-imidazol-1-ylmethyl)-2,3-diphenylquinoxaline; mp. 159.3° C. (comp. 8).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=1.[OH-].[Li+].Cl>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]
Reactant: COC(=O)c1ccc(OC)c(NC(=O)Nc2cnccn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1NC(=O)Nc1cnccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a stirred solution of 4-methoxy-3-(3-pyrazin-2-yl-ureido)-benzoic acid methyl ester (1.0 g; 3.3 mmol) in methanol (25 mL) was added lithium hydroxide (5 mL of a 2M aqueous solution). The reaction was heated to 60° C. and stirred for 12 hours. The reaction was allowed to cool to room temperature and the pH was adjusted to 5.5 with hydrochloric acid (1N). A precipitate formed which was filtered and dried under reduced pressure to yield an off white solid (58% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH3:25])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: O=C(Cl)c1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 15, Step 7, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and benzoyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C(=O)(O)[O-].[Na+]>O.O1CCCC1.[Cl-].[Na+].O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21](=[O:22])[CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:24][CH:25]=1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C2CCN(CC(=O)c3ccc(F)cc3)CC2)cc1

Procedure:
To a solution of 3.0g (12.2 mmol) of N-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide in 10 ml of water and 100 ml of tetrahydrofuran was added 2.3 g (13.4 mmol) of 2-chloro-4'-fluoro-acetophenone followed by 2.0g (24.4 mmol) of sodium bicarbonate. This mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 500 ml of brine and extracted with chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield a solid which was recrystallized from 2-butanone/cyclohexane. 1-(4-Fluorophenyl)-2-[4-[(4-acetamidophenyl)carbonyl]-1-piperidinyl]-ethanone was obtained as an off-white solid having a mp of 168°-170° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:15][C:14]([C:16]([OH:18])=[O:17])=[C:13]([N:19]([C@H:29]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]4)[C:20]([C@H:22]4[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]4)=[O:21])[CH:12]=3)=[CH:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.C(Cl)Cl>[OH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:19]([C:20]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)=[O:21])[C:13]2[CH:12]=[C:11]([C:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=3)[S:15][C:14]=2[C:16]([OH:18])=[O:17])[CH2:30][CH2:31]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC4(CC3)OCCO4)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=O)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 40 °C

Procedure:
To a solution of 5-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (428 mg, 0.85 mmol) in THF (5 mL) was added 3N HCl (2.5 mL), and the mixture was heated at 40° C. for 5 h. Then it was diluted with CH2Cl2 (70 mL) and washed with brine and water. Organic fraction was dried over Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 0-10% MeOH in CH2Cl2 to give 278 mg (71%) of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxo-cyclohex-1-enyl)-thiophene-2-carboxylic acid.
Reaction SMILES: [F:1]/[C:2](/[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=[CH:3]/[F:4].[Li]C(C)(C)C.[I:19]I.O>C1COCC1>[F:1]/[C:2](/[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=[C:3](/[F:4])\[I:19]
Reactant: II
Reactant: CCCC1CCC(/C(F)=C\F)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(/C(F)=C(\F)I)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.0 g (26.3 mmol) of 1-((E)-1,2-difluorovinyl)-4-propylcyclohexane are initially introduced in 150 ml of THF at −55° C., and 20.5 ml (30.2 mmol, 15% soln. in n-pentane) of t-BuLi are metered in. After 2 h at this temperature, a solution of 7.67 g (30.0 mmol) of iodine in 50 ml of THF is added dropwise. The mixture is slowly warmed to 0° C., and water is added. The batch is extracted with MTBE, and the organic phase is washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, pentane), giving 1-((Z)-1,2-difluoro-2-iodovinyl)-4-propylcyclohexane as a pale-violet oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[NH:8][C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1.IC.[CH3:20]C([O-])(C)C>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[N:8]([CH3:20])[C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2c(Cl)nc(Cl)nc2N2CCOCC12
Reactant: CC(C)(C)[O-]
Solvent: CS(C)=O
Solvent: CI
Product: CN1C(=O)C2COCCN2c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
2,4-Dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (500 mg, 1.818 mmol) and iodomethane (1.134 mL, 18.18 mmol) were mixed in DMSO (3 mL). 2-Methylpropan-2-olate (699 mg, 7.27 mmol) was added and the suspension was stirred overnight at room temperature. Ten more equivalents of iodomethane were added and the solution was heated at 50° C. for about 18 hours. The reaction was purified by mass-triggered preparative HPLC 20-60% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column)) to give 20 mg of 2,4-dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a tan solid. MS [M+H] Found 289.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a solution of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (8.2 g, 21 mmol) in dichloromethane (150 mL), which was cooled to −10° C. under a nitrogen atmosphere, was added triethylsilane (7.08 g, 60.9 mmol) and trifluoroacetic acid (9.82 g, 86.1 mmol). The resulting reaction mixture was stirred overnight at room temperature. The mixture was neutralized with 20 g of Sodium bicarbonate. The solid was filtered and the filtrate was evaporated to remove the solvent. The residue was dissolved in methanol, and insoluble solid was the crude product (3.0 g). The filtrate was purified on silica gel to afford 170 mg of methyl 2-(4-chloro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[CH:12][C:4]=2[CH:3]=1.C([O:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)(=O)C.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:10]1[C:5]2[N:6]([CH3:9])[C:7](=[O:8])[C:2]([C:35]3[CH:34]=[C:29]([CH:28]=[CH:27][C:26]=3[CH2:25][OH:24])[C:30]([OH:32])=[O:31])=[CH:3][C:4]=2[CH:12]=[N:11]1
Reactant: COC(=O)c1ccc(COC(C)=O)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2cc(C(=O)O)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 130 °C
Yield: 41.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 μmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (373 mg, 1096 μmol), methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (403 mg, 1206 μmol) were treated with 1,4-dioxane (5.4 mL) and 1 M aqueous Na2CO3 (2.74 mL, 2741 μmol) under argon and heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with EtOAc (20 mL) and extracted with 1N NaOH (2×15 mL). The pH was adjusted to ca. pH 6 with 5N HCl and extracted with DCM (3×20 mL), dried over MgSO4, filtered and concentrated affording the title compound (186 mg) as a yellow tar. The crude residue was used in the next step without further purification. MS (ESI, pos.ion) m/z: 412.1 (M+1).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[CH2:9]1[O:11][C@@H:10]1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:11][C@H:10]([CH2:12][OH:13])[CH2:9][N:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3]
Reactant: OC[C@@H]1CO1
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccn(C[C@H](O)CO)c(=O)n1
Yield: 43.1 %

Procedure:
Reaction of cytosine (2.2 g, 19.8 mmol) with (R)-glycidol (88% ee, 1.51 ml, 22.8 mmol) in the presence of anhydrous potassium carbonate (40 mg, 0.289 mmol) in dry DMF (20 ml) at 72° C. for 5 hours, as described in Example 1, furnished the title compound (88% ee) in 43.1% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][Si:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:39]1([CH2:45][S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:16][C:6]1[CH:5]=[C:4]([C:17]2[O:19][C:48](=[O:49])[C:47]([S:46][CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:51]([OH:52])[CH:18]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][Si:9]([CH3:14])([CH3:15])[C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared by Method A using 3',5'-dimethyl-4'-[[dimethyl(l,l-dimethylethyl)silyl]oxy] acetophenone (1.50 g, 5.39 mmol), trimethylsilyltriflate (1.24 mL, 6.47 mmol), triethylamine (1.50 mL, 10.78 mmol), methylene chloride (13 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 137-139° C.; 1H NMR (400 MHz, DMSO-d6) δ0.21 (s, 6 H), 0.99 (s, 9H), 2.22 (s, 6 H), 3.96 (s, 2 H), 6.54 (s, 1 H), 6.99 (d, 1 H), 7.21 (m, 5 H), 7.44 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[C:19]([CH3:26])=[C:20]([OH:25])[C:21]([CH3:24])=[C:22]([CH3:23])[C:4]=2[O:3]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:25][C:20]2[C:21]([CH3:24])=[C:22]([CH3:23])[C:4]3[O:3][C:2]([CH3:27])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[CH:11][CH:12]=4)[C:5]=3[C:19]=2[CH3:26])=[CH:32][CH:31]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N3CCOCC3)cc1)C(C)(C)O2
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(N4CCOCC4)cc2)C(C)(C)O3)cc1
Yield: 38 %

Procedure:
Using 2,2,4,6,7-pentamethyl-3-[4-(4-morpholinyl)phenyl]-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In a similar manner to Example 2, 1.28 g (9 mmol) of anisaldehyde, 1.89 g (9 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of chlorobenzene and under nitrogen were heated for 4.5 hours to yield 2.86 g (96%) of SULF-8 as a white powder: IR (Nujol) 3300-2700 (br), 1693, 1601, 1584, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 8.91 (s, 1), 8.4-7.7 (m, 8), 3.92 (s, 3).