Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:27](=[O:38])[NH:28][CH2:29][C:30]1[O:31][CH:32]=[C:33]([OH:37])[C:34](=[O:36])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(#N)C>[C:39]([O:37][C:33]1[C:34](=[O:36])[CH:35]=[C:30]([CH2:29][NH:28][C:27]([CH:9]2[CH2:10][N:11]([S:14]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=4)(=[O:16])=[O:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:38])[O:31][CH:32]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1C(=O)NCc1cc(=O)c(O)co1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2C(=O)OC(C)(C)C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In acetonitrile (10 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]piperazine (411 mg), followed by the addition of acetic anhydride (0.075 ml) and triethylamine (0.11 ml). The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. Methylene chloride was added to the residue. The resulting mixture was washed successively with 0.2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution. The organic layer was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (methylene chloride:methanol=50:5), whereby the title compound (256 mg) was obtained as a colorless foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].BrCC1(CC(OC)=O)CC1>ClCCl.O>[CH3:18][S:19]([O:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4]1)(=[O:21])=[O:20]
Reactant: COC(=O)CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)CC1(CBr)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
8.45 g of crude methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (compound 14a) was dissolved in 85 ml dry dichloromethane. The pale yellow solution was cooled to 0° C. Then, 7.71 g triethylamine was added and 8.05 g methanesulfonyl chloride was added dropwise over 8 minutes. The yellow suspension was stirred at 0° C. TLC showed that after 10 minutes the reaction was completed. To the reaction mixture, 35 ml water and 20 ml dichloromethane were added. The water layer was washed with 20 ml dichloromethane. The combined organic layers were washed with 30 ml water, dried (Na2SO4) and evaporated to dryness, resulting in a yellow oil. The product was immediately used in the next step (synthesis of methyl 1-(bromomethyl)-cyclopropaneacetate).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:12]([O:17]C)=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11].O.Cl>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:12]([OH:17])=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11]
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 0 °C
Yield: 89.1 %

Procedure:
In a three-necked flask, disperse 40.8 g of aluminium chloride in 200 ml of dichloromethane with stirring. Cool the solution to 0° C. Pour in dropwise a solution of 20 g (0.101 mol) of 3,4,6-trimethoxybenzaldehyde dissolved in 100 ml of dichloromethane. Allow the temperature to rise again to 19° C. and stir for 45 min. Hydrolyse the reaction mixture with 400 g of water and ice and then add 100 ml of 1N HCl and stir for 30 minutes. Allow to separate and then extract with 200 ml of dichloromethane. The organic phase is washed with 100 ml of 1N HCl, 100 ml of water and 100 ml of saturated aqueous NaCl solution, and then dried over MgSO4, filtered and evaporated to dryness. 16.4 g of title product are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:23])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-chloro-3-(trifluoromethyl)benzoic acid (CAS RN 1737-36-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (30%). MS (ESI): m/z=405.10 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](F)[C:25]=1[Cl:31].CCO>CN(C=O)C.Cl>[Cl:23][C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[O:20][C@@H:13]([CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)C2CCOCC2)C1
Reactant: Fc1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Clc1cccc(O[C@@H](C2CCOCC2)[C@@H]2CCNC2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-3-[(S)-Hydroxy(tetrahydropyran-4-yl)methyl]pyrrolidine-1-carboxylic acid t-butyl ester (30 mg, 0.1 mmol) was dissolved in DMF (380 μL). NaH (3.0 mg, 126 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (34.7 mg, 210 μmol) was added and the mixture was stirred at 100° C. overnight. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (510 μL, 610 μmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (10.8 mg, purity 100%). MS m/z: [M+H]+ calcd for C16H21Cl2NO2, 330.10. found 330.0.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][S:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[Cl:28].O>CN(C)C=O>[CH3:14][O:13][C:11]([C:7]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:29][C:24]2[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=2)=[CH:10][S:9][CH:8]=1)=[O:12]
Reactant: COC(=O)c1cscc1NC(=O)CCl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of methyl 4-(2-chloroacetamido)-3-thiophenecarboxylate ([51486-30-7], 100 mg, 0.428 mmol) in dimethylformamide (1.5 mL) was added potassium carbonate (88.7 mg, 0.642 mmol) and 3,4-dichlorophenol (83.7 mg, 0.514 mmol) and the reaction mixture was stirred at 90° C. overnight. After such time water was added. The precipitate was isolated by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (108.1 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH:6][C:5]2=[O:15].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:19]=3)(=[O:26])=[O:25])=[CH:10][CH:9]=2)[C:5](=[O:15])[NH:6]1)[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)Cn1[nH]c(=O)c2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(C)Cn1[nH]c(=O)c2cc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)ccc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
To a solution of 5-amino-1-isobutyl-1,2-dihydro-indazol-3-one (0.04 g) in pyridine (1 mL) was added 3-trifluoromethylbenzenesulfonylchoride (0.041 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired N-(1-isobutyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-3-trifluoromethyl-benzenesulfonamide (0.015 g) as a pale yellow powder. MS (ESI+): 414.4[M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[N:8][OH:9].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1.C(=O)([O-])O.[K+]>COCCOC.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2([C:30]([F:33])([F:31])[F:32])[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][C:3]([Cl:11])=[C:2]([Cl:1])[CH:10]=3)[CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2cnc(Cl)c(Cl)c2)=NO1
Temperature: 70 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
In a solution of 2.1 g of 5,6-dichloronicotine aldehyde oxime in 30 mL of 1,2-dimethoxyethane, 2.3 g of N-chlorosuccinimide was added, and stirred at 70° C. for 4 hours. Then, the reaction mixture was left and cooled to room temperature, 2.5 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 1, 1.4 g of potassium hydrogen carbonate and 2.0 mL of water were added and continued to stir at room temperature further for 20 hours. After the completion of the reaction, the reaction mixture was diluted with 70 mL of ethyl acetate, washed with water (50 mL×1), and the organic was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:10 to 1:5) to obtain 1.7 g of the aimed products as white crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.Cl>ClCCCl.O>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: Cc1ccc2c(Br)c(F)ccc2n1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A solution of 12.1 kg (75 mole) of 6-fluoro-2-methylquinoline in 33 liters of 1,2-dichloroethane was chilled to 5° C., and 15.0 kg (113 mole) of aluminum chloride was added thereto in portions over 15 minutes. The mixture was purged with nitrogen and then heated to 75° C. A solution of 13.2 kg (82.6 mole) of bromine in 2 liters of 1,2-dichloroethane was added over a period of 5.5 hours. The reaction was maintained at 75° C. during the addition and for an additional 15 minutes after the addition was completed. The reaction was stirred at 70° C. for 23 hours and was then cooled to 10° C. and slowly added to a mixture of 8 kg of 30% hydrochloric acid, 41 liters of water and 31.75 kg of ice. The mixture warmed to 50° C. during the addition. The mixture was heated in reflux and the 1,2-dichloroethane was removed by azeotropic distillation. The remaining aqueous solution was cooled to 60° C. and 12 kg of 10% hydrochloric acid was added. The solution was treated with Celite® (available from Johns-Manville Corp.) and filtered. The filtrate was cooled to 25° C. and 18 kg of 30% hydrochloric acid and 10.22 kg of zinc chloride were added. The resulting slurry was chilled to 5° C. and allowed to stir for several days. The solid was collected and then reslurried with 10 gallons of water. The slurry was chilled to 5° C. and 22 kg of chilled ammonium hydroxide was added. The resulting slurry (pH 10-11) was diluted with 25 gallons of water and the solid was collected, rinsed with water and dried in vacuo at 60° C. to give crude 5-bromo-6-fluoro-2-methylquinoline (84.5% pure by gas chromatography analysis). The material was recrystallized from hexane to give 99.2% pure 5-bromo-6-fluoro-2-methylquinoline.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[NH2:15][O:16][CH2:17][CH2:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:15][O:16][CH2:17][CH2:18][CH2:19][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:27])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(CCCON)OCC
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.48 g, 6.3 mmol), diethyl 3-(aminooxy)propylphosphonate (1.33 g, 6.3 mmol), diisopropylethylamine (2.19 ml, 12.6 mmol) in diglyme (20 ml) was heated at 100° C. for 11/2 hours. After cooling, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (dichloromethane-methanol (97:3) as eluant) to give the title compound as a yellow foam (1.15 g, 58% based on recovered pyrimidine). 1H NMR: δH ((CD3)2SO+D2O) 1.21 (6H, t, J=7Hz, (OCH2CH3)2), 1.65-2.00 (4H, m, CH2CH2P), 3.85-4.05 (6H, m, N--OCH2, (OCH2CH3)2), 7.90+8.15 (1H, 5-NHCHO), 9.25 (2-NHCHO) Found: C, 38.12; H, 5.15; N, 16.25%. C13H21N5O6PCl requires: C, 38.10; H, 5.17; N, 17.09%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:26](OC1C=CC=CC=1)=[O:27].[C@H:35]12[CH2:41][C@H:38]([NH:39][CH2:40]1)[CH2:37][O:36]2.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([N:39]3[CH2:40][C@@H:35]4[CH2:41][C@H:38]3[CH2:37][O:36]4)=[O:27])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3C[C@@H]4C[C@H]3CO4)nc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34.6 %

Procedure:
To a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (265 mg, 1.0 mmol) in dichloromethane (15 ml) is subsequently added pyridine (0.24 ml, 3.0 mmol) and phenyl chloroformate (0.15 ml, 1.2 mmol) and the resulting solution stirred for 45 min at ambient temperature. Then (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane (490 mg, 3.6 mmol) is added and the mixture stirred at ambient temperature for 15 min and at 40° C. for 2.5 h. After cooling to ambient temperature, saturated aqueous sodium carbonate (15 ml) is added, the organic phase is separated, dryed and the solvent evaporated in vacuo. Flash chromatography (silica, eluent: dichloromethane containing methanol (gradient from 0 to 5%)) afforded the title compound as white crystals (135 mg, 35% yield). MS: m/e=391(M+H+).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14](Br)[CH:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.O.ClCl.[Cu]I>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:29]#[N:30])=[C:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(CCC)C1CC2CN(C(=O)c3ccccc3)C3=C2C(C1)C(Br)C=C3
Reactant: N#C[Cu]
Agent: [Cu]I
Agent: ClCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of (±)-1-benzoyl-6-bromo-4-(di-n-propylamino) hexahydrobenz[cd]indole (5.5 g, 12.5 mmol) in DMF (100 mL) under a N2 atmosphere was added 3.4 g (37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The reaction mixture was then stirred at 140° C. for 6 hr. The reaction mixture was poured onto ice, diluted with water, CH2 Cl2 added and stirred for 30 minutes. The mixture was filtered through a Celite pad and the filtrate was extracted twice with CH2 Cl2. The organic solution was washed twice with saturated NaCl solution. The CH2Cl2 solution was dried over MgSO4 and then evaporated to provide 4 g of a solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2Cl2 as eluent gave 3 g (62%) of product.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH3:13])[CH:10]([OH:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:15]>CN(C=O)C>[CH3:15][O:12][CH:10]([CH3:11])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:13]
Reactant: CC(O)C(C)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)C(C)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A 2 L reaction flask was charged with NaH (32 g, 0.79 mol) in oil dispersion (60%) and DMF (500 mL) under N2. The mixture was heated to 40° C. 3-Phenyl-butan-2-ol (100 g, 0.66 mol) was fed to the mixture over 1 hour. The reaction mixture was aged for 1 hour at 40° C. Iodomethane (113 g, 0.79 mol) was then fed into the reaction mixture over 2 hours. The reaction mixture was further aged for 8 hours, and quenched subsequently with saturated NH4Cl solution (300 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (300 mL) and brine (300 mL) to provide a crude product, which was purified by distillation to afford (2-methoxy-1-methylpropyl)-benzene (101 g, 61% yield).
Reaction SMILES: [K+].[C:2]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[CH:5][C:6]([O-:8])=[O:7])#N.S(=O)(=O)(O)[OH:19]>C(O)=O.O>[N+:15]([C:11]1[CH:10]=[C:9]([C:4]2[C:2](=[O:19])[O:7][C:6](=[O:8])[CH:5]=2)[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: N#CC(=CC(=O)[O-])c1cccc([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=C1C=C(c2cccc([N+](=O)[O-])c2)C(=O)O1

Procedure:
To a suspension of.3-cyano-3-(3-nitro-phenyl)-acrylic acid potassium salt (1.28 g) in formic acid (10 ml) and water (1 ml) was added sulfuric acid (1 ml), and the mixture was refluxed for 3 hours. After cooling, the mixte was poured into water. The resulting precipitate was collected by filtration and dried to give 3-(3-nitrophenyl)-furan-2,5-dione(0.69 g).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=2)=[CH:3]1
Reactant: Nc1ccc2c(ccn2O)n1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2cn(O)c3ccc(N)nc23)CC1

Procedure:
condensing 1-hydroxy-5-aminopyrrolo[3,2-b]pyridine (G) with 1-methyl-4-piperidinone in the presence of a base to provide 1-hydroxy-5-amino-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)pyrrolo[3,2-b]pyridine (H); and
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1.Br[C:13]1[CH:20]=C(C)C(C=O)=C(C)[CH:14]=1>>[CH3:10][C:8]1[CH:9]=[C:2]([CH:13]([CH3:20])[CH3:14])[CH:3]=[C:4]([CH3:11])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(Br)cc(C)c1CO
Reactant: Cc1cc(Br)cc(C)c1C=O
Product: Cc1cc(C(C)C)cc(C)c1CO
Yield: 95 %

Procedure:
4-Bromo-2,6-di methylbenzyl alcohol, from 4-bromo-2,6-dimethylbenzaldehyde (Hjed, H. et al. Acta Chem. Scand. 1965, 19:2166); 95% yield, mp 1 17-119° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.[H][H]>[Pd].C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([C:20]#[N:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 90.1 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile (5.1 g, 17.2 mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel, and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. The reaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parr vessel was purged with nitrogen and the reaction mixture was filtered. The filtrate was added to 500 mL water, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were dried (MgSO4) and evaporated to yield 4.6 g (15.5 mmol, 90%) of 6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile as an oil. MS: 298 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH3:29].CC(C)(C)CNC[C@@H]1OC2C=C(S(C)(=O)=O)C=CC=2OC1>C(#N)C>[CH3:27][N:28]([CH3:29])[CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CNC
Agent: CC(C)(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Solvent: CC#N
Product: CN(C)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylmethanamine (2.0 M in MeOH, 0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 269 (M+, 2), 131 (4), 77 (4), 63 (2), 59 (4), 58 (bp).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16].[I-].[Na+]>C(#N)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([O:16][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH:14][CH3:13])=[CH:22][CH:21]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC=C(O[Si](C)(C)C)c1ccc(Cl)cc1
Reaction time: 15 h
Yield: 94.3 %

Procedure:
13.47 g of chlorotrimethylsilane are slowly added to 12.55 g of triethylamine, under a nitrogen atmosphere, at 20°±3° C. 16.86 g of 4-chloropropiophenone (endothermic mixture) and then a solution of 18.58 g of sodium iodide in 125 ml of acetonitrile are further added while maintaining the temperature at 18°±2° C. The mixture is then heated for 3 hours at 40°±5° C., the acetonitrile is removed under reduced pressure and 150 ml of toluene are added to the solid residue. 50 ml of solvent are distilled under reduced pressure to drive the residual acetonitrile off. The inorganic materials are extracted with 100 ml of iced water, the organic phase is washed with 100 ml of iced water and dried over magnesium sulfate. The toluene is removed under reduced pressure and complete removal of the solvents is performed for 15 hours at 60° C. under a pressure of 1 mbar to give 22.7 g of an oil. NMR run at 200 MHz (CDCl3) 0.13 ppm:s:9H 1.7 ppm:d:3H 5.28 ppm:q:1H 7.21-7.39 ppm:m:4H.