Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: OCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
15 g of tetraethyleneglycol and 23.4 g of triethylamine were dissolved in 200 mL of dichloromethane, to which 22.1 g of methanesulfonylchloride was added dropwise at 0° C., and then the solution was stirred for 1 hour. The reaction solution was filtrated to remove insolubles, and then the filtrate was concentrated under reduced pressure. The residue was separated with ethyl acetate-water, and the organic layer was concentrated under reduced pressure after washing with water. The residue was purified with silica gel column chromatography to obtain 27 g of the objective compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[C:23]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:19][CH2:20][CH2:21][CH3:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:25])[CH3:24]
Reactant: CCCCC(CC)CN(CCCCCCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccccc1
Yield: 93.8 %

Procedure:
6-((2-ethylhexyl)(phenyl)amino)hexan-1-ol (8.0 g, 0.023 mol) and dichloromethane (100 ml) were loaded into a three-neck flask, stirred, and added with acetic anhydride (2.8 g, 0.028 mol) and pyridine (3.0 g, 0.038 mol). The mixture was allowed to react at 40° C. for 12 hours with stirring. The reaction product was transferred into a separate funnel, and was then added with water and dichloromethane, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Subsequently, the obtained viscous liquid was separated through silica column chromatography, thus obtaining 7.5 g of a yellowish transparent liquid.
Reaction SMILES: [C:1]1([C:11]23[CH2:16][CH:15]2[C:14](=O)[CH2:13][CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:35]C(Cl)C>C(=O)(O)[O-].[Na+]>[ClH:35].[CH3:18][N:19]([CH3:20])[CH:14]1[CH2:13][CH2:12][C:11]2([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH:15]1[CH2:16]2.[ClH:35]
Reactant: O=C1CCC2(c3cccc4ccccc34)CC12
Reactant: CNC
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C1CCC2(c3cccc4ccccc34)CC12
Product: Cl
Reaction time: 19 h

Procedure:
5-Naphthalen-1-yl-bicyclo[3.1.0]hexan-2-one (0.25 g, 1.13 mmol) in dichloroethane (10 mL) and dimethylamine (2M solution in tetrahydrofuran, 5.62 mL, 11.25 mmol, 10 eq.) was treated with sodium triacetoxyborohydride (0.24 g, 1.13 mmol) at room temperature. The reaction mixture was stirred for 19 h and concentrated to afford an oily residue. The resulting residue was diluted with saturated aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (3×100 mL) and the combined organics were dried over potassium carbonate, filtered and concentrated in vacuo. The oil was dissolved in diethyl ether (10 mL) and the HCl salt was formed by slowly adding HCl (1M in diethyl ether, 1 mL). The slurry was stirred for 0.5 h before filtration. The solid pale brown solid was rinsed with diethyl ether and the compound was transferred to a vacuum oven for drying for 12 h to afford the desired compound as a brown solid. (0.074 g, 23%). 1H NMR (400 MHz, CD3OD) δ ppm. 1.17-1.44 (3H, m, 3×CH), 1.76-1.83 (2H, m, CH2), 1.94-2.06 (2H, m, CH2), 2.40 (3H, s, CH3), 2.42 (3H, s, CH3), 3.09-3.14 (1H, m, CH), 7.37-7.57 (4H, m, Ar), 7.71 (1H, d, J 8.0 Hz, ArH), 7.85 (1H, d, J 8.0 Hz, ArH), 8.26-8.28 (1H, d, J 7.6 Hz, ArH). 13C NMR (400 MHz, CD3OD); δ ppm 12.08 (s, 1C), 24.11 (s, 1C), 24.75 (s, 1C), 33.01 (s, 1C), 33.43 (s, 1C), 41.57 (s, 1C), 42.06 (s, 1C), 70.09 (s, 1C), 124.12 (s, 1C), 125.24 (s, 1C), 125.46 (s, 1C), 125.77 (s, 1C), 127.61 (s, 1C), 128.56 (s, 1C), 132.27 (s, 1C), 134.17 (s, 1C), 138.32 (s, 1C). LCMS (M+1) 252.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])(=O)=O)=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.[K]>CN(C)C=O>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([N:13]2[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][C@H:12]2[CH2:11][N:40]2[C:36](=[O:46])[C:37]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:38]3[C:39]2=[O:41])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 60 °C
Reaction time: 7 h
Yield: 78.8 %

Procedure:
A mixture of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (25 g: 47.3 mmole) and potassium phthalimide (17.52 g: 2 eq.) in dimethylformamide (250 ml) is stirred at 60° C. for 7 hours. The reaction mixture is poured into ice water and filtrated. The resulting precipitate is dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from methanol to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (18.76 g). Yield: 79%. mp. 121° to 123° C.
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[CH:4][NH:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[Cl:19])#[N:2]>C(OCCO)C>[NH2:2][C:1]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: N#CC(C#N)=CNNc1c(Cl)cc(SC(F)(F)F)cc1Cl
Solvent: CCOCCO
Product: N#Cc1cnn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Yield: 69.4 %

Procedure:
14.1 g (0.04 mol) of 1-(2,2-dicyanoethen-1-yl)-2-(2,6-dichloro-4-trifluoromethylthio-phenyl)-hydrazine in 30 ml of ethylene glycol monoethyl ether are heated under reflux for 2 hours. Active carbon is added to the hot solution, the mixture is filtered and the filtrate is diluted with 60 ml of water. This precipitate which separtes out is filtered off under suction and dried. 9.8 g (70% of theory) of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthiophenyl)-pyrazole of melting point 185° C. to 187° C. are obtained. ##STR135##
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].I.[CH3:9][C:10]1[N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:12]([CH3:15])=[CH:13][CH:14]=1>[OH-].[Na+]>[C:1]([C:13]1[CH:14]=[C:10]([CH3:9])[N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:12]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(-n2c(C)ccc2C)cc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1
Temperature: 100 °C

Procedure:
Acetic anhydride (8.5 mL, 89 mmol) and hydriodic acid (0.48 mL, 6.3 mmol) were added to 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (8.0 g, 37 mmol) under nitrogen and the resulting mixture maintained at 100° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (200 mL), extracted with EtOAc (2×200 mL), and the combined extracts washed with brine (200 mL), dried (MgSO4), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (15% EtOAc/hexanes) to give 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a tan solid: 1H NM (CDCl3, 500 MHz) δ 7.08-7.04 (m, 2H), 6.99-6.96 (m, 2H), 6.30 (s, 1H), 4.08 (q, 2H), 2.41 (s, 3H), 2.29 (s, 3H), 1.97 (s, 3H), 1.45 (t, 3H); MS (ESI) 258 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].[C:27]([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:13]=[C:14]([CH:27]=[C:26]3[S:20][C:21](=[S:22])[NH:23][C:24]3=[O:25])[CH:15]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1ccc(Sc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Sc2cccc(C=C3SC(=S)NC3=O)c2)cc1
Yield: 66 %

Procedure:
The 4-[4-(t-butyl)phenylthio]benzaldehyde (1.5 g, 5.5 mmol) was condensed with rhodanine (0.865 g, 6.5 mmol) using sodium acetate (1.64 g, 20 mmol) and acetic acid (80 ml) essentially as previously described to yield 1.4 grams (66.7%) of the title compound. mp 188.5°-189.5° C. NMR. FDMS (M+) 385.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15]C.Br[C:31]1N=C(C)C(NC2C3C(=CC=CC=3)CCC2)=NC=1C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:28])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:31][CH2:19]2)=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(NC2CCCc3ccccc32)c(C)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1NC1CCCc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting Preparation of 5-bromo-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.95, 2.15, 2.28, 2.35, 2.90, 4.62, 5.52, 7.23, 7.34, 7.41, 7.51; MS (ESI+) for C22H21Cl3N3 m/z 399.1 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[Cl:29][C:30]1[N:31]=[CH:32][S:33][C:34]=1[CH:35]=O.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][CH2:35][C:34]2[S:33][CH:32]=[N:31][C:30]=2[Cl:29])[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1scnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2scnc2Cl)CC1
Yield: 74 %

Procedure:
Add sodium triacetoxyborohydride (30.50 g, 144 mmol) to a stirred solution of 4-amino-1-N-Boc-piperidine (18.00 g, 89.9 mmol), 4-chloro-thiazole-5-carbaldehyde (13.09 g, 88.7 mmol), acetic acid (5.5 mL, 96.1 mmol), and 1,2-dichloroethane (350 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (400 mL) and extract with ethyl acetate (3×150 mL). Wash the ethyl acetate with brine (2×150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 75% ethyl acetate/hexanes then with 100% ethyl acetate to yield 21.78 g (74%) of 4-{[(4-chloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=332.1 (M+1); 1H NMR (CDCl3): δ=8.67 (s, 1H), 4.10-4.02 (m, 4H), 2.88-2.82 (m, 2H), 2.74-2.67 (m, 1H), 1.92-1.89 (m, 2H), 1.49 (s, 9H), 1.37-1.28 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2ccccc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Reaction time: 10 h
Yield: 75.9 %

Procedure:
Three grams of said 3-fluoro-4-methoxybiphenyl was dissolved in 14 ml of carbon disulfide, and 1.17 g of acetyl chloride and 2.36 g of aluminum chloride were added, followed by stirring the mixture for 10 hours. Twenty milliliters of 10% hydrochloric acid and then 5 ml of water were added, and the precipitate was filtered and washed with water. The resulting crude crystals were recrystallized from ethanol to obtain 2.75 g of 3'-fluoro-4'-methoxy-4-acetylbiphenyl (yield 76%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]=3[OH:25])[C:11]=2[CH2:12]O)=[O:6])[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]3[C:14]4[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]=4[O:25][CH2:12][C:11]=23)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)c(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc2c(c1)OCc1c(C(=O)NC3CC3)nnn1-2
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.3 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (300 mg, 0.868 mmol) obtained in Example 317 was dissolved in THF (6.0 ml), tributylphosphine (0.300 ml, 1.13 mmol, 1.3 eq.) and ADDP (290 mg, 1.13 mmol, 1.3 eq.) were added, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was diluted with ethyl acetate (10 ml), and the precipitate was collected by filtration, washed with ethyl acetate and suspended in water. The insoluble component was collected by filtration, washed with water and methanol and dried to give the title compound as a white powder (228 mg, 0.697 mmol, 80.2%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]1[C:14]([O:16][C:17](=[O:18])[CH:8]21)=[O:15])[CH:5]=[CH2:6].[OH-].[Na+]>O>[OH:3][N:2]=[C:17]([CH:8]1[CH:9]([C:14]([OH:16])=[O:15])[CH:10]2[CH2:13][C:7]1([CH2:4][CH:5]=[CH2:6])[CH:12]=[CH:11]2)[OH:18]
Reactant: NO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NO

Procedure:
139 g (2 mols) of hydroxylamine hydrochloride are dissolved in 200 ml of water; there are then added 408 g (2 mols) of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (produced according to Example 1 of the U.S. Pat. No. 3,105,839), and 160 g of 50% aqueous sodium hydroxide solution are subsequently introduced dropwise with vigorous stirring. The mixture is afterwards refluxed for 1 hour; the water and traces of oily constituents are distilled off, the residue is taken up in toluene, the sodium chloride is filtered off, and the toluene is removed in a rotary evaporator at 150° C. and 2000 Pa. There remain 402.6 g of the product (91.5% of theory) in the form of a light-brown viscous liquid having a viscosity of 1.28 Pa.s at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8]2
Reactant: CCCN[C@@H]1CCc2cccc(OC)c2C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(C(=O)Cc1cccs1)[C@@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-1 when using 39 mg (0.18 mmol) enantiomerical pure (R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe) and 0.05 mL (0.41 mmol) 2-thienyl acetic acid chloride. Flash chromatography was done with hexane/ethyl acetate 20/1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.CN([CH:21]=[O:22])C.O>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:21]=[O:22])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COc2ccc(C=O)cc21
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 106.6 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (15.90 g, 70.01 mmol) in dry THF (100 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 105 mmol, 42 mL). The mixture was stirred for 5 minutes then DMF (16.3 mL, 210 mmol) was added and the mixture was quickly warmed up to −50° C. and then to 0° C. for 3 hrs. Water was added slowly and the solution extracted with ethyl acetate. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated to give 13.15 g of 3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde use as this in the next step. 1H NMR (300 MHz; CDCl3): 1.38 (s, 6H), 4.36 (s, 2H), 6.89 (d, J=7.8 Hz, 1H), 7.68 (m, 2H), 9.85 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 80 %

Procedure:
Methyl 2-chloroisonicotinate (427 mg), 4-(trifluoromethyl)phenylboronic acid (474 mg), potassium phosphate (800 mg), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (102 mg), in PhMe (5 ml) were placed in a microwave tube and the contents were heated in the microwave oven for 20 min at 150° C. The cooled mixture was filtered through Hyflo® to remove inorganic material, the Hyflo® was washed with EtOAc and the combined organic extracts were dispersed between H2O and EtOAc. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography on silica using 10-25% EtOAc in hexane to yield the product as a crystalline solid (560 mg, 85%). 1H NMR (400 MHz, CDCl3) δ: 4.01 (3H, s), 7.76 (2H, d, J 8.3), 7.84 (1H, dd, J 1.4, 4.9), 8.18 (2H, d, J 8.2), 8.33 (1H, t, J 1.1), 8.87 (1H, dd, J 0.6, 4.8).
Reaction SMILES: [Si](OC(=C)[CH2:10][C@@:11]([C@@H:14]1[C@:22]2([CH3:23])[C@H:17]([C@@H:18]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15]1)([OH:13])[CH3:12])(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)[CH2:34][CH2:35][CH2:36]C.[F-].C([O-])(O)=[O:52].[Na+]>C1COCC1>[Si:25]([O:24][C@@H:18]1[C@H:17]2[C@@:22]([CH3:23])([C@@H:14]([C@:11]([OH:13])([CH3:12])[CH2:10][C:35](=[CH2:36])[CH2:34][OH:52])[CH2:15][CH2:16]2)[CH2:21][CH2:20][CH2:19]1)([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27]
Reactant: O=C([O-])O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C=C(C[C@](C)(O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]21C)O[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(CO)C[C@](C)(O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]21C
Reaction time: 1 h

Procedure:
A solution of 7 (1.3 g, 2.6 mmol) in dry THF (6 mL) was treated with a nBu4NF (1.6 g, 5 mmol). After 1 h, a saturated solution of NaHCO3 (30 mL) was added. The mixture was extracted with EtOAc (3×30 mL). The organic phase was dried, filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 3×10 cm, 25% Et2O-hexanes) to give 8 (0.86 g, 86%, white solid, mp: 95° C.), Elementary analysis: C=68.12%, H=11.18%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[NH4+].[Cl-].[N-:27]=[N+]=[N-].[Na+]>CO>[NH2:27][C:16]1[C:17](=[O:18])[C:10]2[O:9][C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=3)=[C:12]([CH3:13])[C:11]=2[C:14](=[O:22])[C:15]=1[CH2:19][CH2:20][CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC1=CC(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC1=C(N)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O

Procedure:
To a solution of 2-(4-methoxybenzyl)-3-methyl-5-propyl-4,7-benzofurandione (from Example 28) (295 mg, 0.91 mmol) in MeOH (3 mL) were added NH4Cl (109 mg) and NaN3 (130 mg). The mixture was heated to reflux for 4 hours and the solvent was then removed in vacuo. Water was added and the product was extracted into CH2Cl2 and chromatographed on silica gel (15% EtOAc/hexane) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:9][CH:10]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44]F)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:18][N:15]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([O:1][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][S:33]([C:30]4[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][CH:31]=4)(=[O:35])=[O:34])=[CH:14][CH:13]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]=2[CH:7]=1)[CH:16]=[O:17]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: CN(C=O)c1ccc2c3ccc(O)cc3n(C(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc3c4ccc(N(C)C=O)cc4n(C(=O)OC(C)(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
To tert-butyl 2-hydroxy-7-(N-methylformamido)-9H-carbazole-9-carboxylate (65 mg, 0.19 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (174 mg, 0.38 mmol) in 0.5 mL NMP was added Cs2CO3 (68 mg, 0.21 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (80 mL). It was washed with water (3×50 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified with silica chromatography (hexane/EtOAc) to afford tert-butyl 2-(N-methylformamido)-7-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)-9H-carbazole-9-carboxylate (AD-CB-004Pb-WZ01191) as a clear oil (75 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.79 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.15 (dd, J=8.4, 2.0 Hz, 1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 3.89 (m, 2H), 3.88 (m, 2H), 3.73-3.68 (m, 4H), 3.66-3.63 (m, 2H), 3.41 (s, 3H), 2.42 (s, 3H), 1.76 (s, 9H); MS (ESI) m/z 527 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CNC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cccc(Oc2ccc(F)cc2)c1
Yield: 91.2 %

Procedure:
Alternatively, 3-(4-fluoro-phenoxy)-phenylamine was prepared by a two-step procedure by heating a suspension of m-fluoronitrobenzene (4.06 g, 28.7 mmol), p-fluorophenol (3.21 g, 28.6 mmol) and K2CO3 (8.13 g, 58.8 mmol) in DMA (dimethylamine) (60 mL) at 150° C. for 3 hours. The brown reaction mixture was concentrated to one-quarter original volume, diluted with ethyl acetate (220 mL) and washed successively with water (220 mL), 1N NaOH (220 mL) and brine (220 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford the diphenylether (5.30 g, 80%) as a brown oil.