Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[C:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)S([Cl:45])(=O)=O.[ClH:48]>C(OCC)(=O)C.C1COCC1>[C:1]([C:3](=[C:25]1[C:29]([Cl:45])([Cl:48])[CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:23])[CH3:24])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:12])([F:11])[F:13])#[N:2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC(C)C
Reactant: Cl
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCC2(Cl)Cl)c1CC(C)C
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 24 %

Procedure:
A 100 mL round-bottomed flask was charged with 1.5 g (3.6 mmol) of the compound of Example 2 and 20 mL anhydrous THF. The solution was cooled to -70° C. and 3.6 mL sodium bis(trimethylsilyl)amide (1.0 M solution in THF) was added via syringe. After 5 minutes, 0.6 g (3.6 mmol) trifluoromethanesulfonyl chloride was added. After 15 minutes an additional 3.6 mL sodium bis(trimethylsilyl)amide was added followed by additional 0.6 g trifluoromethanesulfonyl chloride. After stirring one hour at -70° C., the reaction solution was poured into dilute HCl and extracted with ethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, an filtered to give 1.5 g of crude orange oil. Chromatography using 20% ethyl acetate in hexanes yielded 0.42 g of the desired product as a yellow oil, a 24% yield. nD25 1.4920.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2.N([O-])=O.[Na+].[ClH:20]>O.[Cu]Cl>[Cl:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(Cl)ccc2c1
Reaction time: 8 h

Procedure:
6-Amino-2-napthalenesulfonic acid (88.0 g, 0.4 mol) was suspended in 5 N HCl (200 mL) and water (150 mL) and cooled to 3° C. A solution of sodium nitrite (27.0 g, 0.4 mol) in water (50 mL) was added dropwise over two hours. After one additional hour, the mixture was poured in several portions into a stirred suspension of copper(I) chloride (39.6 g, 60.6 mmol) in 5 N HCl (200 mL). Considerable foaming occurred during this addition. After standing overnight at room temperature, the mixture was concentrated on a rotary evaporator to a brown solid that was then dried in a vacuum oven overnight at 100° C. to provide the acid (111.9 g)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][OH:13]>C1COCC1.O(C)[K]>[CH3:12][O:13][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CO[K]
Solvent: C1CCOC1
Product: COc1cc(O)ccc1[N+](=O)[O-]

Procedure:
To a solution of 3-Fluoro-4-nitro-phenol (15.7 g, 100 mmol) in THF (300 mL), 30% KOMe in Methanol (49 mL, 210 mmol) is added at 0° C. The mixture is heated to gentle reflux for 18 hours.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Cl:22][C:23]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:52]C([N-]C(C)C)C>>[Cl:22][C:23]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:52])=[CH:14][CH:13]=2
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc(/C=C/c2cc3cc(OC)ccc3[nH]2)c(Cl)c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-chloro-4-methoxybenzyl)(triphenyl)phosphonium bromide (574) prepared as described in example 162 using the procedure described in example 37, except that the LDA and aldehyde were sequentially added at 0° C., the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (575) as a pale yellow solid (the pure E isomer) (64%), mp 129–132° C. 1H NMR (CDCl3) δ 8.17 (br s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.19 (d, J=16.5 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.96 (d, J=17.3 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.86 (dd, J=8.7, 2.6 Hz, 1H), 6.85 (dd, J=8.7, 2.8 Hz, 1H), 6.54 (d, J=1.7 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H). Found: C, 69.05; H, 5.41; N, 4.68. C18H16ClNO2 requires C, 68.90; H, 5.14; N, 4.46.
Reaction SMILES: C([Li])CCC.C1C2CC3C(=CC=CC=3)C=2C=CC=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].[CH2:27]([CH:34]1[C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CCCCCC.O1CCCC1.O>[CH2:20]([C:34]1([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[C:41]2[C:46]1=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26]
Reactant: COCCOCCCl
Reactant: COCCOCCC1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Agent: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COCCOCCC1(CCOCCOC)c2ccccc2-c2ccccc21
Temperature: 22 °C
Reaction time: 1 h

Procedure:
7.05 g of butyllithium dissolved in 44 ml of hexane was slowly added in 5 minutes into 18.28 g of fluorene dissolved in 150 ml of anhydrous tetrahydrofuran at -50° C. under nitrogen protection. The mixture was stirred at -30~15° C. for 1 hour before it was cooled again to -40~-50° C. Then, 15.23 g of 1-chloro-2-(2-methoxyethoxy)-ethane was added in 5 minutes. The mixture was subsequently stirred for 2 hours while the temperature was gradually increased to 22° C. The main product in the solution was 9-(3,6-dioxaheptyl)-fluorene as detected by GC-MS. This solution was then cooled to -50° C., and 7.1 g of butyllithium dissolved in 44 ml of hexane was slowly added in 5 minutes under nitrogen protection. The mixture was stirred at -30 to -15° C. for 1 hour before it was cooled again to 40 to -50° C. Then, 15.30 g of 1-chloro-2-(2-methoxyethoxy)-ethane was added during 5 minutes. The mixture was subsequently stirred for 5 hours at 22° C., dispersed in water, and extracted with ether. The etheral solution was washed with water and brine, dried with magnesium sulfate, and evaporated. The residue was distilled to collect 37.1 g (91%) of colorless liquid at 160° C./0.08 mm Hg. MS (m/z): 370 (M+), 219, 191, 178, 89, 59.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([OH:21])=O)[O:10]1)C1C=CC=CC=1.[NH3:22].C(OCC)(=O)C>CO.CS(O)(=O)=O>[CH3:1][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([NH2:22])=[O:21])[O:10]1
Reactant: CC1(C)O[C@H]2[C@H](OCc3ccccc3)O[C@H](C(=O)O)[C@H]2O1
Reactant: N
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H](C(N)=O)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of (3aS, 4S, 6R, 6aR)-6-benzyloxy-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (588.6 mg, 2 mmol) in methanol (8.8 mL) was added methanesulfonic acid (0.007 mL, 0.1 mmol), and the mixture was stirred with heating to 60° C. for 24 hours. After the solution was dried under reduced pressure, ethyl acetate (2.9 mL) and 2,2-dimethoxypropane (0.17 mL, 1.4 mmoL) were added to the resulting oil, and the mixture was stirring at ambient temperature for 2 hours. Aqueous 7% sodium hydrogen carbonate solution (0.5 mL) was added for layer separation, and the resulting organic layer was concentrated under reduced pressure, to which was added aqueous 28% ammonia (1.2 mL, 20 mmol), and the mixture was stirred at ambient temperature for 14 hours. To the resulting solution was added ethyl acetate (3 mL) for layer separation, and the organic layer was concentrated under reduced pressure. To the resulting solid was added a hexane/ethyl acetate (3:1) solution (3 mL) for rinsing as a slurry at ambient temperature for 2 hours. Subsequently, the solid was filtered and rinsed in a hexane/ethyl acetate (3:1) solution (0.5 mL). The solid was dried under reduced pressure to recover (3aS, 4S, 6R, 6aR)-6-methoxy-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-carboxylic acid amide (278.7 mg; yield of 64.2%) as a white solid. Melting point: 136° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:12][CH2:13][CH2:14]Br.[OH2:16].Cl>CN(C=O)C>[C:1]([O:10][CH2:12][CH2:13][CH2:14][O:16][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: BrCCCBr
Reactant: O
Reactant: O=C(O)c1ccccc1O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OCCCOC(=O)c1ccccc1O)c1ccccc1O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
13.94 ml TEA (100 mmol) were added to a solution of 13.81 g salicylic acid (SA; 100 mmol) in 40 ml DMF at 60° C., the reaction mixture was stirred for 20 minutes at 60° C., and 12.2 g 1,3-dibromo propane (Compound 18d; 50 mmol) were added. The reaction mixture was stirred at 60° C. for 24 hours, cooled to room temperature, poured into 250 ml cold water, and acidified to about pH 4 with 1N HCl. A white precipitate separated. The precipitate was filtered, washed with water, and dried in a vacuum oven at 40° C. overnight. The thus obtained crude product was recrystallized from n-heptane to obtain a pure product.
Reaction SMILES: [S:1]1(=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12].C(OC(=O)C)(=[O:17])C>>[N+:11]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:17])[S:1][C:5]=2[CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=S1C=Nc2ccccc21
Reactant: CC(=O)OC(C)=O
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
0.1 mol of benzothiazolinone is dissolved in 100 ml of acetic anhydride and the solution is cooled to −10° C. 10 ml of nitric acid are then added dropwise, and the reaction is stirred for 2 hours. The resulting precipitate is filtered off and washed with water, and then purified by chromatography (eluant CH2Cl2 then AcOEt) to yield the title product, which is recrystallised from ethanol.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][CH:12]([O:16]C=O)[C:13](=O)[CH3:14])=[N:5][CH3:6])#[N:2].[CH:19]([O-:21])=O.[NH4+:22].C(=O)([O-])O.[Na+]>C(N)=O>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12](=[O:16])[CH:13]([NH:22][CH:19]=[O:21])[CH3:14])=[N:5][CH3:6])#[N:2]
Reactant: O=C[O-]
Reactant: CN=C(NC#N)NCCSCC(OC=O)C(C)=O
Reactant: [NH4+]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: NC=O
Product: CN=C(NC#N)NCCSCC(=O)C(C)NC=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
In 1.0 ml of formamide were dissolved 28 mg of N-cyano-N'-[2-(2-formyloxy-3-oxobutylthio)ethyl]-N"-methylguanidine and 25 mg of ammonium formate, and the solution was stirred at 50° C. for 2 hours. Then, 85 mg of sodium hydrogencarbonate was added to the solution and the solvent was removed under reduced pressure, and the obtained residue was refined by silica gel column chromatography (developing solvent: ethyl acetate/methanol=10/1) to obtain 11 mg of a colorless oily product (the yield was 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19](CN)=[N:20][CH:21]=1.C[CH2:25][N:26](CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([NH:26][CH3:25])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: NCc1ccc(Br)cn1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CNc1ccc(-c2cc3cc(OC)ccc3o2)cn1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 5-bromopyridine-2-methylamine (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (100 mg). 1H NMR δ ppm 8.53 (d, 1 H) 7.84 (dd, 1 H) 7.44 (d, 1 H) 7.08 (d, 1 H) 7.04 (s, 1 H) 6.91 (d, 1 H) 6.81 (dd, 1 H) 6.55 (d, 1 H) 3.78 (s, 3 H) 2.83 (d, 3 H); MS m/z 255 (M+H).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:6][CH:2]1[C:3](=[O:4])[C:18]2=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:21]=3[CH:20]=[C:19]2[CH2:7]1
Reactant: c1ccc2c(c1)CCCC2
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1=O)CCCC3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A total of 145 g (0.63 mol) of 2-bromo-2-methylpropanoyl bromide were added dropwise to a suspension of 223 g (1.67 mol) AlCl3 in 200 ml of CH2Cl2 with vigorous stirring for 15 min at 0° C. This mixture was stirred for 45 min at this temperature; then a solution of 83.4 g (0.63 mol) of tetraline in 200 ml of CH2Cl2 was added dropwise. The mixture was slowly warmed to ambient temperature, stirred additionally overnight, and, then, poured on 1000 cm3 of ice. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of CH2Cl2. The combined organic fractions were dried over MgSO4 and evaporated to dryness. Fractional distillation gave a yellowish mixture of the title indanones, b.p. 183-190° C./7 mm Hg. This mixture was recrystallized from 300 ml of n-hexane. Crystals of 2-methyl-1,2,6,7,8,9-hexahydro-3H-cyclopenta[a]naphthalen-3-one that precipitated at −30° C. were filtered off, washed with 2×25 ml of cold n-hexane, and dried in vacuum. Yield 56.5 g (45%). The filtrate was evaporated to dryness and dried in vacuum. This procedure gave 39.3 g (31%) of pure 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-1-one.
Reaction SMILES: C([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1)(=[O:8])C1C=CC=CC=1.[NH3:26]>CO.Cl>[OH2:8].[ClH:25].[OH:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:26])[C:15]=2[N:14]=[CH:13]1
Reactant: N
Reactant: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1
Agent: Cl
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2CCO
Product: O

Procedure:
A mixture of 1.3 g (0.0037 mole) of 1-(2-benzoyloxyethyl)-4-chloro-1H-imidazo[4,5-c]quinoline (from Example 117) in 60 ml of methanol was saturated with about 10g of ammonia gas. The mixture was heated at 150° C. in a steel bomb for ten hours. The mixture was evaporated, and the residue was slurried in diethyl ether and filtered. The solid obtained was slurried in methanolic hydrochloric acid to provide off-white solid 1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride hydrate, m.p. >250° C. Analysis: Calculated for C12H12N4O·HCl·1.25H2O: C, 50.2; % H, 5.4; % N, 19.5; Found: % C, 50.2; % H, 5.2; % N, 19.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:20])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.053 g, 0.194 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.110 g, 0.386 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 31 mg of yellow solid (42%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.91 (br s, 2H), 4.05-4.00 (m, 2H), 2.89-2.85 (m, 2H), 2.70-2.64 (m, 8H), 2.02-1.97 (m, 2H), 1.90-1.82 (m, 4H). MS (ESI): 383.2 (M+1). ESI-HRMS calculated for C21H27N4SO2 (MH+): 383.1900, Observed: 383.1895.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.C1COCC1.[H-].[Na+].[C:50]1([S:56](Cl)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C.CCCCCC>[C:50]1([S:56]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:39])[CH:25]=3)[C:15]2=[O:23])(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(S(=O)(=O)c3ccccc3)c3ccccc32)cc(C)c1O
Reaction time: 0.5 h
Yield: 47 %

Procedure:
In a 40-mL vial, combine 0.15 g (1.0 mmol) of 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one with 15 mL of dry THF under nitrogen. Add 1.0 equivalent of sodium hydride and stir the resulting mixture 30 minutes under nitrogen. Add 2.0 equivalence of benzenesulfonyl chloride and stir an additional 30 minutes. Remove solvent in vacuuo and chromatograph the crude intermediate (1-Benzenesulfonyl-3,3-bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one) using 1:4 ethyl acetate/hexane to elute. Dissolve the intermediate in refluxing 1:1 THF/methanol and add excess cesium fluoride. Stir for 10 minutes, remove solvent in vacuuo, and add 10 mL of water. Extract with ethyl acetate to obtain 0.06 g (47%) of the titled compound as an off-white solid: LCMS (system 2) tR=4.05 min (100%), ESMS (M+1) m/z=514.2; 1H NMR (DMSO-d6); 8.28 (s, 1H), 7.98 (d, 2H), 7.90 (d, 1H), 7.81 (t, 1H), 7.65 (t, 2H), 7.39 (m, 1H), 7.20 (m, 2H), 6.30 (s, 4H), 1.93 (s, 12H).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2CCCN(Cc3ccccc3)C2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc(C2CCCNC2)c1

Procedure:
(-)-N-benzyl-3-(3-methoxyphenyl)piperidine hydrochloride (3.8 g, 0.0120 mol) was dissolved in ethanol (80 m), 10% Pd/C was added and the mixture was hydrogenated at room temperature and atmospheric pressure (28 h). The catalyst was removed (Celite) by filtration, the solvent was evaporated off and the crystalline residue was recrystallized from methanol-ether giving the desired (+)-3-(3-methoxyphenyl)-piperidine hydrochloride (2.54 g, 30% total yield of the maximal theoretical) m.p. 175.5°-177° C.; [α]22D +10.1° (C 2.1, CH3OH).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26](Br)[N:25]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](Cl)Cl>[CH2:14]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:25]=1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Br)nc(C(=O)NCc2ccccc2)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
1.04 g (0.0029×2.2 mol) of 3-(trifluoromethyl) phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.24 g (ca. 60% in mineral oil; 0.0029×2.0 mol) of NaH and then with 0.94 g (0.0029 mol) of N-benzyl-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.15 g (0.0029×0.5 mol) of copper chloride (I), the solution was stirred at about 120° C. for about 5 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.N1C=CC=CC=1.[C:19]([Cl:29])(=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:29].[C:19](=[O:28])([O:1][CH2:2][CH2:3][NH:4][CH3:5])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), and benzyl chlorocarbonate (1.57 mL) was dropwise added. After stirring at room temperature for 2 hrs., pyridine (0.65 mL) and benzyl chlorocarbonate (1.28 mL) were added. After stirring at room temperature for 5 days, pyridine (0.81 mL) was added under ice-cooling and a solution (5 mL) of benzyl chlorocarbonate (1.43 mL) in ethyl acetate was dropwise added slowly. After stirring at room temperature for 2 hrs., ethyl acetate (50 mL) was added to the mixture, washed with water (50 mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (1.99 g) as a white solid.