Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[C:13]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].[NH2:27][N:28](C)[C:29](=O)OC(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.NN(C)C(=O)OCCCC.[ClH:59]>C(O)C>[ClH:59].[ClH:59].[CH3:29][N:28]1[C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][C:13]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:4]=2[C:1]([CH3:2])=[N:27]1
Reactant: CC(=O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: CCCCOC(=O)N(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c2c1C1(CCNCC1)Oc1ccccc1-2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (250 mg, 0.70 mmol), tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) and p-toluene sulfonic acid monohydrate (27 mg, 0.14 mmol) in ethanol (8 mL) was heated at 80° C. overnight. Additional tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 6.5 h, then another portion of ten-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 2 h. HCl (0.87 mL of 4.0 M in dioxane, 3.5 mmol) was added and the mixture was stirred at 80° C. for 1 h. After cooling, the precipitate was collected via filtration and washed with cold EtOH to provide 1,3-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (295 mg, >100%, may contain some methyl hydrazine HCl salt) as a solid. ESI-MS m/z calc. 269.2. found 270.5 (M+1)+; Retention time: 1.11 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J=7.8, 1.3 Hz, 1H), 7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.05 (m, 1H), 4.02 (s, 3H), 3.28-3.15 (m, 4H), 2.40-2.30 (m, 2H), 2.23 (s, 3H), 2.07-1.97 (m 2H).
Reaction SMILES: C1C=CC=C2C=1C=C1CCCCN12.C(=O)([O-])N.[C:18](Cl)(=O)[C:19](Cl)=[O:20].Cl.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][C:36](=[NH:41])[O:37]C(C)C)=[CH:27]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(OCC)(=O)C>[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]2[C:36](=[O:41])[NH:37][C:19](=[O:20])[CH:18]=2)=[CH:27]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: NC(=O)[O-]
Agent: c1ccc2c(c1)cc1n2CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C2=CC(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 770 mg (2.25 mmol) of tert.butyl [1(R or S)-[6,7,8,9-tetrahydropyrido[1,2-a]indol-8(R or S)-yl]-2-methylpropyl]carbamate (diastereomer A) in 30 ml of dichloromethane at 0° C. was treated dropwise with 287 mg (2.4 mmol) of oxalyl chloride. After 5 minutes, the solvent was removed under reduced pressure and the residue was dissolved in 30 ml of dichloromethane and treated with 686 mg (2.57 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 1.02 g (10 mmol) of triethylamine at 0° C. under nitrogen. After warming to room temperature, the solution was stirred for 18 hours, washed with 50 ml of water and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was dissolved in 10 ml of pyridine. The stirred solution was cooled to ice bath temperature and treated dropwise with 664 μl (4.8 mmol) of trifluoroacetic anhydride. After 15 minutes, 50 ml of ethyl acetate was added and the organic phase was washed with water and 2M hydrochloric acid, dried over magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 460 mg of 3-[8(R or S)-[1(R or S)-tert.butoxyformamido-2-methylpropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereomer A) as a red solid of melting point 223°-224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:27]([O:29][CH2:30][C:31](Cl)=O)[CH3:28].C(#N)C>ClCCl>[CH2:27]([O:29][CH2:30][C:31]1[N:12]([CH2:13][C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:28]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCCC1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopentanol (approximately 28.8 mmol) in dichloromethane (200 mL) at 0° C. was added triethylamine (4.41 mL, 31.6 mmol) and ethoxyacetyl chloride (88% purity, 3.96 g, 30.2 mmol). After 3 hours at room temperature, the solution was concentrated and ethanol (260 mL) and triethylamine (14 mL) were added. The resulting solution was heated at reflux for 18 hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was washed with brine twice, dried over MgSO4, filtered, and concentrated to yield an oil that formed a white solid when acetonitrile was added. The mixture was sonicated briefly and filtered. The white powder was dried under vacuum to provide 4.55 g of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].C([O-])(O)=O.[Na+].[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCCl>[Cl:22][CH2:23][C:24]1[N:1]=[C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[S:3][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115.1 %

Procedure:
1,1-Dimethylethyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.50 g, 6.14 mmol), NaHCO3 (0.570 g, 6.78 mmol) and 1,3-dichloroacetone (0.860 g, 6.77 mmol) were combined in 1,2-dichloroethane (4 mL) and the reaction mixture was stirred at room temperature for 12 h. The crude reaction mixture was filtered using CH2Cl2 and the filtrate was concentrated in vacuo until approximately 30 mL of solvent remained. To this solution was added pyridine (0.75 mL, 9.2 mmol), and the solution was cooled with an ice bath. Thionyl chloride (0.49 mL, 6.8 mmol) was added and the solution was allowed to warm slowly to room temperature. The solvent was removed in vacuo and the residue was taken up in 10% MeOH/ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo to yield 2.24 g (>100%) of crude 1,1-dimethylethyl 4-[4-(chloromethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, d6-DMSO): 7.62 (s, 1H), 4.60 (s, 2H), 3.98 (m, 1H), 3.63 (dd, 2H), 3.16 (m, 1H), 2.90 (broad s, 2H), 2.01 (dd, 1H), 1.51 (m, 2H), 1.40 (s, 9H). MS (EI) for C14H21N2O2SCl: 261 (M-tBu).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(Br)c1
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@H]1C[C@@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Dissolve 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 1 (preparation 2, 2.53 g, 11.75 mmol) in 1-methyl-2-pyrrolidinone (50 mL) and treat with 95% sodium hydride (0.33 g, 12.93 mmol), stir and heat at 70° C. After 1 hr., add 1-bromo-3-fluoro-benzene (1.44 mL, 12.93 mmol), stir and heat at 100° C. After 16 hr., cool to ambient temperature and quench with water (100 mL). Extract with 4:1 hexane:ethyl acetate (2×100 mL). Combine the organic layers and wash with aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 4:1 hexanes:ethyl acetate to obtain the title compound (2.47 g, 57%). 1H NMR (CDCl3): 7.15 (m, 1H), 7.05 (m, 2H), 6.8 (dd, 1H), 4.6 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 1.9 (m, 3H), 1.75 (m, 1H), 1.5 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:16][C:17]([O:19]CC)=[O:18])=[N-].C(=O)(O)[O-].[Na+]>ClCCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Yield: 38.9 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-2-methylpropanol (5.0 g, 26 mmol) and rhodium(II)acetate (90 mg) in 1,2-dichloroethane (500 ml) was heated to 80° C. Then ethyl diazoacetate (4.0 g, 35 mmol) was added over a period of 1 h, and the mixture was stirred at reflux for 3 h. Another portion of rhodium(II)acetate (90 mg) was added and the mixture was refluxed for another 5 h. The mixture was cooled overnight and saturated sodium bicarbonate (500 ml) was added, the phases were separated and the organic layer was washed with saturated sodium bicarbonate (2×200 ml), dried (magnesium sulfate) and concentrated in vacuo. The obtained product was dissolved in 1 M lithium hydroxide in methanol/water 3:1 (200 ml) and stirred overnight. The solvent was removed in vacuo, water was added (pH>9) and the Mixture was washed with ether (200 ml). Then 1 M hydrochloric acid was added until pH<4 and the mixture was extracted with ethyl acetate (200 ml), dried (magnesium sulfate) and concentrated in vacuo to give 2.5 g of (2-tert-butoxycarbonylamino-2-methylpropoxy)acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:13]([OH:15])[CH3:14]>C(O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:15][CH2:13][CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCO
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(C#N)cc1
Yield: 94.9 %

Procedure:
p-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and ethanol (460.3 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 78° C. for 12 hours while a 20% hydrochloric acid/ethanol solution (162.4 g) prepared in advance was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 83.1 g of ethyl p-cyanobenzoate (yield 95%). Subsequently, the reaction mixture was concentrated under reduced pressure, and water was added thereto. The resultant mixture was dissolved through heating, and cooled for crystallization, to thereby obtain 74.7 g of ethyl p-cyanobenzoate having a purity of 99.5% (yield 85%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.N1C=CN=C1.C(OCC)C>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
tert-Butyldimethylsilyl chloride (1.8 g) was added over 30 minutes to a stirred solution of 4-bromo-4'-hydroxybiphenyl (2.49 g) and imidazole (1.63 g) in dimethylformamide (15 ml) whilst keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (225 ml) was added, the ether washed with saturated sodium hydrogen carbonate solution (3×60 ml) and brine (100 ml), dried (MgSO4) and evaporated to yield, as a colourless oil, 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (3.2 g); NMR (CDCl3): 0.2(6H, s), 1.0(9H, s), 6.8-6.9(2H, d), 7.3-7. 4(4H, m) and 7.45-7.55(2H, d).
Reaction SMILES: Cl.C([O:6][C:7](=[O:28])[CH2:8][N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:10]1=[O:27])(C)(C)C>C(OCC)(=O)C>[CH3:15][C:14]1[N:9]([CH2:8][C:7]([OH:28])=[O:6])[C:10](=[O:27])[C:11]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
HCl gas was bubbled through a stirred suspension of 2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1-yl]acetic acid t-butyl ester (16-3; 12.3 g, 33 mmol) in ethyl acetate (250 ml) at −15° C. for 20 min. The resulting solution was allowed to warm to room temperature and was then stirred there for 3 h. After purging with argon, the bulk of the solvent was rotavapped off and ether added to the residue. The solid which precipitated was filtered off and washed with ether. The title compound 16-4 was thus obtained as a white fluffy powder: 1H NMR (CD3OD) δ 2.32 (s, 3H), 4.86 (s, 2H), 5.18 (s, 2H), 6.24 (d, J=7.9 Hz, 1H), 7.31-7.41 (m, 6H), 7.94 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 80.1 %

Procedure:
A solution of 4-trifluoromethylphenylacetic acid (784 mg, 3.84 mmol) in tetrahydrofuran (3 mL) was cooled to 0° C. and treated dropwise with a solution of borane in tetrahydrofuran (1.0 M, 5.4 mL, 5.4 mmol). The mixture was stirred at room temperature for 2.75 hours, then was treated slowly with 50% water in tetrahydrofuran (2 mL), followed by water (2 mL). The mixture was stirred for 5 minutes, and solid potassium carbonate was added to saturate the aqueous phase. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide a colorless liquid (585 mg, 80%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.59 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 2H), 3.92 (t, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 1.53 (s, 1H).
Reaction SMILES: C(N1C2C(=CC=CC=2)CC1=O)C1C=CC=CC=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23](=[O:35])[C:22]2=O.CCOCC>CCCCCC>[CH2:28]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([F:18])=[CH:27][CH:26]=2)[CH2:22][C:23]1=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(F)cc21
Agent: O=C1Cc2ccccc2N1Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Yield: 75.2 %

Procedure:
The title compound was prepared in a manner similar to the method of N-Benzyl-oxindole using 5-fluoro-N-benzylisatin (14.5 g, 56.8 mmol). Trituration using Et2O: hexane yielded the title compound as a pale yellow solid (10.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 5H), 7.00 (d, J=7.6 Hz, 1H), 6.87 (t, 1H), 6.63 (m, 1H), 4.91 (s, 2H), 3.63 (s, 2H); MS ESI 241.9 [M+H]+, calcd for [C15H10FNO2+H]+ 241.09.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].B.CO>O1CCCC1>[OH:6][CH2:5][C:4]1[C:3]([CH3:11])=[C:2]([OH:1])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(O)cccc1CO
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A solution of 3-hydroxy-2-methylbenzoic acid (44.4 g, 285 mmol) (prepared as described in Preparation 1A) dissolved in dry tetrahydrofuran (200 mL) was added to 1 M borane in tetrahydrofuran (800 mL) while stirring at a temperature of 0° C. The resulting semisolid mixture was heated in a mantle to just short of reflux and heating was maintained for about 15 hours. Methanol (200 mL) was added to the reaction mixture. The resultant clear solution was evaporated in vacuo and then evaporated with further portions of methanol to give 3-hydroxymethyl-2-methylphenol (30.3 g, 99%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: O=C(O)Cc1cccs1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-thiopheneacetic acid (1.50 g, 10.6 mmol) in MeOH (20 mL) was added thionyl chloride (3.80 mL, 53 mmol) dropwise at 0° C. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give the title compound as a dark brown oil (1.65 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: [I-].I[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC1C=CC=CC=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>ClC1C=CC=CC=1>[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH:18][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Ic1ccccc1
Agent: [I-]
Solvent: Clc1ccccc1
Solvent: Brc1ccccc1
Product: CCOC(=O)C=Cc1ccccc1

Procedure:
More specifically, we have found that chlorobenzene reacts with ethyl acrylate to form ethyl cinnamate in relatively high yield by reacting the chlorobenzene with iodide and/or bromide ion to form a mixture of chlorobenzene, iodobenzene and/or bromobenzene, then reacting the mixture with ethyl acrylate in the presence of a catalyst to form ethyl cinnamate.
Reaction SMILES: [Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCCCC.[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31].ClC1C=CC=CC=1C.[F-:43].[K+]>>[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[F:43].[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Solvent: Cc1ccccc1Cl
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Temperature: 180 °C
Yield: 79 %

Procedure:
100 g of octadecyltrimethylammonium chloride are dissolved at 60° C. in 2900 g (15.1 mol) of 3,4-dichloronitrobenzene. 100 g of 2-chlorotoluene are added to the solution. After addition of 825 g (14.2 mol) of potassium fluoride, the resulting suspension is heated for 11 hours at 180° C. During this time, some of the 2-chlorotoluene is continuously distilled off. The reaction suspension is then quickly filtered off using suction, the filter cake is washed with 2-chlorotoluene and the combined filtrates are fractionated in vacuo. In this manner 1966 g (79% of theory) of 3-chloro-4-fluoronitrobenzene and 340 g of unreacted 3,4-dichloronitrobenzene are obtained.
Reaction SMILES: C1([C@H](NCC2C=CC=C(C(C)(C)C)C=2O)[C@@H](NCC2C=CC=C(C(C)(C)C)C=2[OH:27])C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:27])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: CC(C)(C)c1cccc(CN[C@@H](c2ccccc2)[C@@H](NCc2cccc(C(C)(C)C)c2O)c2ccccc2)c1O
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: CC(C)(C)OO
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
A chiral zirconium complex was prepared by rapidly stirring (forming a vortex) a mixture of zirconium(I) acetylacetonate (43.5 mg, 0.089 mmol) and 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]bis(iminomethylene)]bis[6-(1,1-dimethylethyl)-phenol] (Formula IIIb wherein R6 is H, 0.096 g, 0.18 mmol) in toluene (1.00 mL) at 50° C. for one hour. The resulting solution was evaporated to dryness in vacuo, then a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) in toluene (2.00 mL) was added. The reaction mixture was heated to 65° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 0.340 mL, 2.46 mmol) was added. After 3.5 hours at 65° C., the reaction was quenched by adding an acetonitrile solution (7.00 mL) containing biphenyl (0.125 g) as an HPLC internal standard and cooling to ambient temperature. Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 85% yield (85% chemoselectivity) and 94% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18]CC)=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>O>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Yield: 68.6 %

Procedure:
Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (2.8 g.) and a solution of sodium hydroxide (0.54 g.) in water (20 ml.) were treated according to a similar manner to that of Preparation 6-5) to give brown powder of 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4yl)glyoxylic acid (1.75 g.).
Reaction SMILES: [CH2:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH2:4][CH2:3][CH2:2]1.C1C2C(=CC=CC=2)C=CC=1>>[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2ccccc21
Solvent: c1ccc2ccccc2c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
In the process according to U.S. Pat. No. 2,938,913, the mixture which is present after the Diels-Alder reaction and which contains tetrahydroanthraquinone, solvent and naphthalene is first treated with aqueous alkali, an aqueous alkaline solution of salts of tetrahydroanthraquinone and a mixture of solvent and naphthalene being obtained. Crude solid anthraquinone is isolated from the solution containing the salts of tetrahydroanthraquinone by passing air through this solution and filtering off the anthraquinone which precipitates out. The mixture of naphthalene and the solvent is separated, by distillation, into the components, which can then be re-used in the anthraquinone synthesis.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Temperature: 175 °C
Yield: 66.8 %

Procedure:
2,6-Dichloro-3-nitropyridine (0.222 g, 1.15 mmol), 4-aminotetrahydropyran (0.109 g, 1.08 mmol) and DIEA (0.300 mL, 1.72 mmol) were taken up in ethanol (3.0 mL) and heated to 175° C. for 15 minutes in a heavy walled sealed tube under microwave irradiation. The solvent was removed under reduced pressure and the residual solid was purified by preparative HPLC to give the title compound (0.186 g). LCMS m/z=258.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.60-1.75 (m, 2H), 2.8 (d, J=12.4 Hz, 2H), 3.60 (t, J=11.4 Hz, 2H), 4.02 (d, J=11.8 Hz, 2H), 4.30-4.45 (m, 1H), 6.63 (d, J=8.6 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H).