Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>ClCCl>[C:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: CN(CCCCCCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 23 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A stirred mixture of 4'-[(6-hydroxyhexyl)-methylamino]-4-methylsulfonylstilbene (App-Ex. 4, 20.0 g, 52 mmol), triethylamine (6.3 g, 62 mmol) and dry dichloromethane (DCM) was treated dropwise with acryloyl chloride (5.6 g, 62 mmol) in 50 mL of DCM at 23° C. under nitrogen. The resulting solution was stirred at 23° C. for 72 hours, and then filtered. The filtrate was washed successively with saturated NaCl, with saturated NHCO3, and with water. The organic layer was dried (MgSO4), and the solvent was removed at reduced pressure to deposit a yellow oil which gradually crystallized. The product was recrystallized from tetrahydrofuran (THF)/hexanes to yield 15.5 g (68%) of a yellow solid, mp 88°-90° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:37])[C:24]=2[CH:23]=1>>[CH:23]1[C:24]2[C:25](=[O:37])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32](=[O:36])[C:33]=2[CH:34]=[CH:35][C:22]=1[CH2:21][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c(=O)[nH]c1=O
Yield: 35.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (175 mg, yield: 35.1%).
Reaction SMILES: C[Al](C)C.[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@@H:22]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.CCOC(C)=O>[Si:14]([O:21][C@@H:22]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([S:6][CH3:5])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CSc1ccc(N)nc1
Reactant: COC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.8 %

Procedure:
Trimethylaluminium (2M in toluene) (10.40 mL, 20.80 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (2.54 g, 18.09 mmol) in toluene (100 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoate (Intermediate C7b) (5 g, 18.09 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was allowed to stir at room temperature for 1 hour. The temperature was increased to 60° C. and stirred for a further 24 hours. The reaction mixture was neutralised with citric acid (1M, aq) and then diluted with water and EtOAc (200 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% Et2O in isohexane to afford the product (3.95 g, 56.8%). 1H NMR (400 MHz, DMSO) δ 0.10-0.13 (6H, d), 0.90-0.92 (9H, m), 1.04-1.07 (6H, m), 2.40 (3H +DMSO, s), 3.54-3.63 (3H, m), 4.42-4.44 (1H, m), 7.77-7.80 (1H, dd), 8.03-8.06 (1H, d), 8.26 (1H, d), 9.49 (1H, s); m/z (ES+) (M+H)+=385; HPLC tR=3.66 min.
Reaction SMILES: [C:1](Cl)(=[O:11])[O:2][CH:3]([O:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:4].C(Cl)(Cl)(Cl)Cl.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.CCOCC>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:11])[O:2][CH:3]([O:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:4])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCCC(=O)OC(C)OC(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCC(=O)OC(C)OC(=O)Nc1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A solution of 1-butanoyloxyethyl carbonochloridate (5 mmol) in CHCl3 (10 mL) prepared as above but substituting CHCl3 for CCl4 is added to a solution of 4-chloroaniline (1.3 g, 10 mmol) in Et2O (40 mL) at -70° C. Following stirring for 2 h at -70° C. and 3 h at -40° C. the mixture is kept at -20° C. for 3d. After filtration, treatment of the filtrate with charcoal, and evaporation of the filtrate the residue is triturated with ice-cold pentane (15 mL) and recrystallized from pentane (70 mL) to yield 0.4 g (28%) of the title compound with mp 52°-54° C. C13H16ClNO4 calc. C 54.65 H 5.64 Cl 12.41 N 4.90 (285.7) found 54.72 5.64 12.31 4.83 IR (10% CHCl3): ν=1750 cm-1. 1H-NMR (CDCl3 /TMS)45 : δ=0.95 (t, 3H, J=7 Hz, CH3 (CH2)2CO); 1.50 (d, 3H, J=5.5 Hz, CH3CH); 1.7 (m, 2H, CH3CH2CH2CO); 2.31 (t, 2H, J=7 Hz, CH2CO); 6.8 (bs, 1H, NH); 6.91 (q, 1H, J=5.5 Hz, CHCH3); 7.28 (m, 4H arom.)
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[C:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:38][C@@H:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)=[C:22]([CH:37]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:24])#[N:17].C(N(CC)CC)C>ClCCCl>[CH2:1]([O:8][C:14]([NH:13][S:10]([N:41]1[CH2:42][CH2:43][C@@H:39]([NH:38][C:21]2[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:37][C:22]=2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[O:24])[CH2:40]1)(=[O:12])=[O:11])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCNC2)cc1OC
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCN(S(=O)(=O)NC(=O)OCc3ccccc3)C2)cc1OC
Temperature: 4 °C
Yield: 42.3 %

Procedure:
A solution of benzyl alcohol (28 mg) in 1,2-dichloroethane (1 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (37 mg) in 1,2-dichloroethane (2 mL) under 5° C. on an ice-salt bath. The mixture was stirred for one and a half hours at 4° C. To the mixture was added dropwise a mixture of (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (100 mg) and triethylamine (40 mg) in 1,2-dichloroethane (3 mL) under 5° C. After addition, the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a thin layer chromatography developed with 5% methanol in chloroform. The obtained product was triturated with diethyl ether to give (R)-2-[1-(N-benzyloxycarbonylsulfamoyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (65 mg) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1F
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
59 mg of pale yellow solid 3-{4-[3-(2-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-fluorophenyl isocyanate.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]1[CH2:9][N:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7][CH2:6][O:5]1.O>CO>[CH3:3][C@@H:4]1[CH2:9][N:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7][CH2:6][O:5]1
Reactant: COC(=O)c1cc(C2CCCN2c2ccccc2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4ccccc4)c3o2)CCO1
Yield: 87.1 %

Procedure:
Sodium hydroxide (2N in water) (0.293 mL, 0.59 mmol) was added to a stirred suspension of methyl 2-((R)-2-methylmorpholino)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxylate (105 mg, 0.23 mmol) in MeOH (2 mL)/water (2 mL) as described in example 3.00 to afford 2-((R)-2-methylmorpholino)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxylic acid (87 mg, 86%) which was used without further purification. Mass Spectrum: m/z [M+H]+=435.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:5]=1[CH:6]=[O:7].[CH3:17]I>CN(C)C=O>[CH3:17][O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:5]=1[CH:6]=[O:7]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of NaH (16.0 g, 50% oily dispersion, 337 mM) in dimethylformamide (200 ml) was treated dropwise with a solution of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde (49.0 g, 248 mM) in DMF (300 ml) at such a rate that the temperature did not exceed 35° C. The mixture is aged at room temperature for 1 hour and then a large excess of methyl iodide (100 ml) is added dropwise. A slight exothermic reaction occurs. The mixture is then stirred vigorously for 19 hours at room temperature. After the removal of excess methyl iodide, the reaction mixture is poured into ice-water (1 l). The crude product, a brown solid, is filtered, washed with cold water, and then recrystallized from isopropyl alcohol (700 ml) to afford the product as a tan solid; yield 27.9 g (53.3%); m.p. 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc(N2C(=O)CCCC2c2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(N2C(=O)CCCC2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 2.42 g of 1-(4-aminophenyl)-6-(3,4-dichlorophenyl)-2-piperidone in 20 ml of chloroform were added 5 ml of acetic anhydride and 0.5 ml of pyridine, and the mixture was stirred at room temperature for 30 minutes and then at 80° C. for 30 minutes. The reaction mixture was cooled and diluted with isopropyl ether. The crystals precipitated were filtered and recrystallized from a mixture of ethanol and dimethylformamide to give 2.69 g of 1-(4-acetylaminophenyl)-6-(3,4-dichlorophenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C@@H:5]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:19]2=[O:34])[CH2:4][CH2:3]1.[CH:35]([N:38](C(C)C)CC)(C)[CH3:36].BrCC#N>C(#N)C>[CH2:27]([O:26][C:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:36][C:35]#[N:38])[CH2:7][C@H:6]2[NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:19]1=[O:34])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: N#CCBr
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](NCC#N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 30 h

Procedure:
A stirring solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-5-amino-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (400 mg, 0.82 mmol) in acetonitrile (3 mL) was charged sequentially with diisopropylethylamine (315.8 mg, 3 eq) and bromoacetonitrile (109.5 mg, 1.1 eq). The mixture was stirred at 40° C. for 30 h. The solvent was removed under reduce pressure. The residue was purified by silica gel column chromatography, using 1.5% of methanol in dichloromethane as the eluant. The desired 2-(trimethylsilyl)ethyl(1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(cyanomethylamino)cyclohexylcarbamate was obtained as a white solid (400 mg, 93%). LC/MS found [M+H]+=530.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.OC[C@@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C@@H:37]5[CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
1,1-Dimethylethyl (3R)-3-[{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl}methyl]pyrrolidine-1-carboxylate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1,1-dimethylethyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate following General Procedure J.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C[O:28][C:29](=O)[O:30]C>C1COCC1>[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH2:26][C:29]([OH:30])=[O:28])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(C(C)(C)C)ccc1C(=O)O
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a magnetically stirred solution of diisopropyl amine (0.75 g, 7.4 mmol) in THF (5 mL) at −30° C. is added BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol). The mixture is stirred for 10 minutes at this temperature and cooled to −78° C. A solution of 4-tert-Butyl-2-methyl-benzoic acid [J. Am. Chem. Soc. 1944, 66, 154] (250 mg, 1.3 mmol) and dimethylcarbonate (150 mg, 1.67 mmol) in THF (3 mL) is added dropwise at −78° C. The mixture is allowed to stir at this temperature for 2 hours before it is allowed to warm to room temperature. The mixture is quenched with MeOH and water once it reached room temperature. After removal of THF, the water layer is extracted with ether. The water layer is acidified with HCl and the product is extracted from ether. After chromatography, the title compound is isolated pure (125 mg, 41%). MS (ESI): 237.1 (M+1)+1.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3](N)[C@H:2]1O.[O:12]1CCNC1>>[CH:1](=[O:12])[C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:4]1([C:3]#[CH:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: C1COCN1
Product: C#Cc1ccccc1
Product: O=Cc1ccccc1

Procedure:
Although mono-oxazolidines have been used for alkylation and alkynylation of aldehydes, the C2-symmetry of bisoxazolidine 1 provides superior results and appears to be crucial for both catalytic activity and asymmetric induction. For example, see: (a) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1997, 62, 3770-3771; (b) Kang, Y.; Wang, R.; Liu, L.; Da, C.; Yan, W.; Xu, Z. Tetrahedron Lett. 2005, 46, 863-865; and (c) Kang, Y. F.; Liu, L.; Wang, R.; Zhou, Y.-F. Yan, W. J. Adv. Synth. Catal. 2005, 347, 243-247. For comparison, we prepared a (1R,2S)-cis-1-amino-2-indanol-derived oxazolidine 2 using cyclohexanone instead of cyclohexanedione and tested its catalytic performance under the same reaction conditions. Alkynylation of benzaldehyde with phenylacetylene in the presence of 10 mol % of 2 gave the corresponding alcohol in only 76% yield and 17% ee (FIG. 3B).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1([CH2:31][OH:32])[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C1COCC1>[OH:32][CH2:31][C:18]1([N:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:1]2=[O:2])[CH2:19][CH2:20][N:21]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:22][CH2:23]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCNC1(CO)CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C1NCCCN1C1(CO)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
1,1′-Carbonylbis-1H-imidazole (0.0149 mol) was added to a mixture of intermediate (15) (0.0137 mol) in THF (40 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered off, crystallized from ACN, filtered off, washed with ACN and DIPE and then dried, yielding 2.05 g of tetrahydro-1-[4-(hydroxy-methyl)-1-(phenylmethyl)4-piperidinyl]-2(1H)-pyrimidinone (intermediate 16, mp. 210° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([S:32]([N:35](CC3C=CC(OC)=CC=3OC)[C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1.O1CCOCC1>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:22]1[C:31]2[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)nccc2c1
Temperature: 100 °C
Yield: 22.4 %

Procedure:
A pressure vessel was charged with (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (56.5 mg, 0.252 mmol), potassium carbonate (145 mg, 1.048 mmol), 1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.210 mmol), tetrakis(triphenylphosphine)palladium(0) (24.23 mg, 0.021 mmol), dioxane (1398 μl) and water (699 μl). The reaction vessel was swept with nitrogen, sealed with a cap and then heated in a microwave at 100° C. for 30 minutes. The mixture was cooled to room temperature. The organic layer was separated by pipet and then purified by reverse phase HPLC (Column: Gemini 150×30 mm, 5 μm, Phenomenex, Torrance, Calif., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing pure product were dried under a vacuum to provide 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (22 mg, 0.047 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.57 (br. s., 1H) 3.63-3.80 (m, 1H) 7.70 (d, J=8.82 Hz, 1H) 7.79 (d, J=7.90 Hz, 1H) 7.86-7.96 (m, 1H) 8.12 (s, 1H) 8.25 (d, J=5.61 Hz, 1H) 8.47 (s, 1H) 8.65 (d, J=1.49 Hz, 1H) 8.77 (d, J=5.73 Hz, 1H); m/z (ESI) 471.0 (M+H)+.
Reaction SMILES: [C:1]1(O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13].CC[O:18]CC>>[N+:12]([C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCOCC
Reactant: Oc1cccc2c1CCCC2
Product: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Reaction time: 1 h

Procedure:
To a solution of 25.9 g of 5, 6, 7, 8-tetrahydronaphthol in 210 ml of ether was dropwise added 60% nitric acid at 15°-20° C. with stirring in 1 hour, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water (6 times) and saturated saline and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:15) to give 10.12 g of 1-nitro-5, 6, 7, 8-tetrahydro-2-naphthol.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:12].[CH2:31](N(CC)CC)C.[OH2:38]>C(#N)C>[O:38]=[C:31]1[NH:2][CH:3]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=2[CH3:12])[C:13]2[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=2[N:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1
Reactant: CCN(CC)CC
Reactant: O
Reactant: Cc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Agent: Cl
Solvent: CC#N
Product: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 25 °C

Procedure:
A mixture of 4-(amino(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methyl)-3-methylbenzonitrile hydrochloride (intermediate 52, 1.06 g, 2.43 mmol), 1,1-carbonyl-diimidazole (495 mg, 3.05 mmol) and triethylamine (685 μL, 4.87 mmol) in acetonitrile (10 mL) is stirred at room temperature over night. Water ist added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic layer is concentrated under reduced pressure. The residue is by purified by preparative HPLC (Waters it) Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 364 mg; ESI mass spectrum [M+H]+=426; Retention time HPLC: 0.65 min (X012_S01).