Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([NH:15][CH2:16][CH2:17][NH2:18])([CH3:14])[CH3:13]>ClCCl>[CH:12]([NH:15][CH2:16][CH2:17][NH:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCN
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCNC(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 65 grams of p-toluenesulfonyl chloride in 125 ml. of dichloromethane was added dropwise with stirring to a solution of 100 grams of N-isopropylethylenediamine in 150 ml. of dichloromethane. Following completion of addition the mixture was stirred one-half hour at room temperature, then heated in a steam bath for 45 minutes. The mixture was evaporated to dryness in vacuo. The residue was triturated with sodium carbonate solution then dissolved in a mixture of ethyl acetate and water. The ethyl acetate portion was extracted with saturated sodium carbonate solution and water. After drying the ethyl acetate portion over magnesium sulfate, the solvent was removed in vacuo. The solid residue was recrystallized from ethyl acetate-hexane to obtain N-[2-(isopropylamino)ethyl]-p-toluenesulfonamide, m.p. 76°-8°C.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>C1COCC1.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:10]1[C:5]2[N:6]([C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:3][N:4]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#C[Si](C)(C)C)cnc12
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A mixture of 3-iodo-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 3) (4.02 g, 10 mmol), trimethylsilylacetylene (2.8 mL, 20 mmol), Et3N (2.1 mL, 15 mmol), PdCl2(PPh3)2 (70 mg, 1 mol %) and PPh3 (26 mg, 1 mol %) in THF (20 mL) was stirred for 10 min at 23° C. while being purged with Argon. Then CuI (19 mg, 1 mol %) was added. Stirring was continued for 16 h at 80° C. The reaction mixture was purified by column chromatography (heptane/AcOEt) to give the title compound as a yellow foam (3.15 g, 85%). MS (ISP) 373.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)c4ccccc4)cc3c2c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(Cc4ccccc4)cc3c2c1C
Yield: 10.8 %

Procedure:
260 mg of 6-benzoyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester is hydrogenated in 36 ml of absolute ethanol with 2 ml of glacial acetic acid and 100 mg of palladium black for 2 hours at 10 bar hydrogen pressure at 40°-45° C. After separation of the catalyst, the reaction mixture is evaporated. The residue is chromatographed over silica gel, first with toluene:glacial acetic acid:water=10:10:1 and then with toluene:ethanol:water=80:20:1, thus obtaining 27 mg (11%) of 6-benzyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C>>[C:30]([O:14][CH:8]([C:3]1[S:4][C:5]([Br:7])=[CH:6][C:2]=1[Br:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(O)c1sc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)C(OC(C)(C)C)c1sc(Br)cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Ethyl 2-(3,5-dibromothiophen-2-yl)-2-hydroxyacetate (7b) (100 mg, 0.29 mmol) was dissolved in tert-butyl acetate (5.4 mL) at −20° C. and 70% perchloric acid (0.7 mL) was rapidly added. The mixture was stirred at 0° C. for 3 hours then poured in a saturated solution of potassium carbonate. Layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide ethyl 2-(tert-butoxy)-2-(3,5-dibromothiophen-2-yl)acetate (100 mg, 0.40 mmol, 86%).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([O-:9])=[O:8]>>[CH:2]1([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCC1
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1OC1CCCC1

Procedure:
In a similar manner as in Example 1, bromocyclopentane was reacted with o-nitrophenol to yield 2-cyclopentoxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-methylol-5-methylpyrrolidone to form the corresponding N-5-methyl-N-methylenepyrrolidonyl derivative; which was acylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1>CS(C)=O>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccnc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccnc1OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Potassium tert-butoxide (1.08 g, 8.62 mmol) was added to a solution of 1-benzyl-4-hydroxypiperidine (1.5 g, 7.84 mmol) in dimethylsulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. 2-Fluoro-3-methylpyridine (957 mg, 8.62 mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed with sodium hydrogen carbonate solution and brine. The organic solution was then dried over magnesium sulfate concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 70:30, to afford the title compound as a solid in 85% yield, 1.9 g. 1H NMR (CDCl3, 400 MHz) □: 1.79-1.94 (m, 2H), 1.98-2.09 (m, 2H), 2.17 (s, 3H), 2.37-2.47 (m, 2H), 2.68-2.77 (m, 2H), 3.61-3.51 (bs, 2H), 5.12-5.20 (m, 1H), 6.74 (m, 1H), 7.24-7.37 (m, 6H), 7.95 (m, 1H); LRMS APCI m/z 283 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:34])[CH2:21][O:22][C:23]1[CH:32]=[CH:31][C:30]([SH:33])=[C:29]2[C:24]=1[CH2:25][CH2:26][CH2:27][O:28]2>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:33][C:30]3[CH:31]=[CH:32][C:23]([O:22][CH2:21][C:20]([OH:34])=[O:19])=[C:24]4[C:29]=3[O:28][CH2:27][CH2:26][CH2:25]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 42C and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester. mp 112-113° C.; MS m/z 480 (M+1).
Reaction SMILES: CS(C)=O.[OH-:5].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:5][C:19]2[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:20]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1OCc1ccccc1
Temperature: 100 °C

Procedure:
400 g of dimethyl sulfoxide and a solution of 37 g of potassium hydroxide (0.66 mol) in 400 ml:of water are warmed to 100° C. in a three-neck flask fitted with reflux condenser and stirrer. 163 g of the 5-fluoro-2-nitrophenyl benzyl ether prepared as described in Example 1 (0.66 mol) are then added in portions, and the mixture is then heated at 100° C. for 8 hours. After the mixture has been cooled to room temperature, a colorless reaction product precipitates; this is filtered off, washed with water and dried. The reaction product is then recrystallized from ethyl acetate.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH3:16]N(C)C=O.[OH-].[Na+].CI>O>[CH3:16][N:2]1[C:3](=[O:15])[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1]1
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: Cn1nc2n(c1=O)C=Cc1ccccc1C2

Procedure:
To a solution of 8 parts of 2,11-dihydro-3H-s-triazolo-[3,4-b][3]benzazepin-3-one in 80 volume parts of dimethylformamide is added 9 volume parts of 5N aqueous sodium hydroxide solution and then 3 volume parts of methyl iodide is added dropwise under stirring. After stirring for 1 hour, the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and the solvent is distilled off. The precipitate is collected by filtration to give 2,11-dihydro-2-methyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from isopropyl ether gives light-brown needles melting at 123° -124° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[CH:6][N:7]=1
Reactant: OCc1ccc(Br)nc1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc(Br)nc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
3.69 g (19.7 mmol) of the compound from Example 4A are initially introduced into the reaction vessel under argon and 25 ml thionyl chloride are added dropwise at −60° C. (bath temperature). The mixture is stirred at −60° C. for 1 h. It is concentrated at RT on a rotary evaporator, and 50 ml saturated sodium bicarbonate solution and 50 ml ethyl acetate are added to the residue. The aqueous phase is extracted with ethyl acetate (four times with 25 ml each time). The combined organic phases are dried over sodium sulfate and filtered, the solvent is removed on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2Br)cc1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-(4-methoxyphenyl)ethylamine in dioxane. ES-MS m/e (%): 391 (M{81Br}+H+, 100), 389 (M{79Br}+H+, 99).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=O)[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[NH:34][NH2:35].CCCCCC>C(O)CC>[CH2:1]([O:8][C:9]1[C:14]([C:15](=[N:35][NH:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Solvent: CCCO
Solvent: CCCCCC
Product: CCOC(=O)NN=C(C)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (1.50 g) in n-propanol (15 mL) was added ethyl carbazate (432 mg). The mixture was stirred under an argon atmosphere at 75° C. overnight and cooled to room temperature. Adding hexane (30 mL), the reaction mixture was stirred for 1 hour. The precipitate was filtrated to give ethyl N′-{1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethylidene}hydrazinecarboxate (1.16 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[CH3:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:21]1([C@@H:20]([NH:27][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]2[C:15]([O:17][CH3:18])=[O:16])[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[C@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (13.29 g, 51.6 mmol, 1 eq.), (S)-(−)-α-methylbenzylamine (6.66 mL, 51.6 mmol, 1 eq.), acetic acid (5.91 mL, 103.0 mmol, 2 eq.) and benzene (200 mL) were mixed at room temperature then refluxed using a Dean-Stark trap for 4 hours. Cooled to 0° C. Added acetic acid (23.66 mL, 412.8 mmol, 8 eq.) followed by the addition of sodium triacetoxyborohydride (21.90 g, 103.0 mmol, 2 eq.). Stirred for 20 minutes at 0° C. then allowed the reaction to warm to room temperature and stirred for 20 hours. Worked up by carefully (foaming) adding sodium carbonate until the pH=10. Extracted the aqueous 3 times with ethyl acetate. The ethyl acetate layers were combined, rinsed once with brine, then dried over sodium sulfate and stripped to give (3R,4S)-1-tert-butyl 3-methyl 4-((1S)-1-phenylethylamino)-piperidine-1,3-dicarboxylate (18.7 g) of an oil as product. Yield=100%. Mass Spec (ESI) detects (M+H)+=363.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22](C)[CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:28][CH:30]3[O:32][CH2:31]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3c2CCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(c2ccc(OCC3CO3)cc2)c2cccc3c2CCCC3)cc1
Temperature: 120 °C

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (410 mg, 0.001 mol), epichlorohydrin (25 ml) and anhydrous K2CO3 (2.0 gm, 0.014 mol) was refluxed at 120° C. for 6 hrs, K2CO3 was filtered off and the filtrate was concentrated. The residue obtained was dissolved in ethyl acetate and washed with water, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel using hexane:chloroform as the eluent to give the title compound. Yield 388 mg (82.37%).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>>[CH3:13][O:12][C:11]1[C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH3:20])=[O:18])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4]2
Reactant: C=CC(=O)OC
Reactant: COc1ccc2nc(C)ccc2c1Br
Product: COC(=O)/C=C/c1c(OC)ccc2nc(C)ccc12
Yield: 71 %

Procedure:
The title compound was prepared from 5-bromo-6-methoxy-2-methylquinoline (6b) and methyl acrylate using methods as described in the literature for similar compounds (Frank et al., 1978) in 71% yield. 1H NMR (DMSO-d6, HMDSO), δ: 2.63 (3H, s); 3.76 (3H, s); 4.01 (3H, s); 6.71 (1H, d, J=15.5 Hz); 7.43 (1H, d, J=8.5 Hz); 7.64 (1H, d, J=8.8 Hz); 8.02 (1H, d, J=8.8 Hz); 8.16 (1H, d, J=15.5 Hz); 8.42 (1H, d, J=8.5 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH2:19]([C@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:19]([C@H:21]1[CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH2:24][CH2:23][N:22]1[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:20]
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 60.3 %

Procedure:
Heat a mixture of 1-chloro-4-(4-fluorophenyl)phthalazine (5.02 g, 19.4 mmol), (S)-tert-butyl 2-ethylpiperazine-1-carboxylate (5.00 g, 23.3 mmol) and K2CO3 (5.38 g, 38.9 mmol) in DMSO (75 mL) at 120° C. for 1 d. Pour the reaction mixture into water, rinsing with EtOAc. Extract with EtOAc. Wash the organic layer with water (2×), then brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 20 to 80% EtOAc in hexanes) to provide the title compound (5.11 g, 60%). ES/MS m/z 437.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][Br:18])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1ncn2C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Yield: 60 %

Procedure:
To a stirred solution of 4-methyl-benzimidazole-1-carboxylic acid tert-butyl ester (800 mg, 3.4 mmol) in CCl4 (7 mL) was added N-bromosuccinimide (730 mg, 4.1 mmol) and 2,2′-azobis(2-methylpropionitrile) (84 mg, 0.51 mmol). The resultant mixture was heated at reflux for 18 h after which it was filtered and concentrated to a yellow/orange syrup and crystals (1.4 g). Purification by column chromatography on silica gel (200:15—Hexanes:EtOAc) gave the desired title compound as a yellow syrup (635 mg, 60%). 1H NMR (300 MHz, CDCl3) δ8.48 (s, 1H), 7.95 (dd, 1H, J=7.8, 1.5 Hz), 7.42-7.34 (m, 2H), 4.96 (s, 2H), 1.71 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]=[C:29]=[O:30]>O1CCCC1>[CH3:27][NH:28][C:29](=[O:30])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NC)ccc21

Procedure:
To 2.5 g of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol in 30 ml of tetrahydrofuran was added potassium carbonate (milled, 1.3 g) followed by methyl isocyanate (0.56 ml). The reaction was allowed to proceed for half an hour. The reaction mixture was then filtered and the filtrate concentrated to yield a solid (2.9 g) which was eluted with 5% methanol in dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid (2.7 g) which was recrystallized from isopropyl ether to yield a solid 1.8 g, m.p. 158°-159° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][CH2:40][CH2:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH2:41][CH2:40][O:39][CH3:38])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 63.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (600 mg, 1.1 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (678 mg, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (77 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (400 mg, 63%) as a white solid: LC/MS m/e calcd for C29H29FN2O5S2 [M+H]+ 569.69, observed 569.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CN(C)CCN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Product: CN(C)CCNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
8-(Bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with N1,N1-dimethylethane-1,2-diamine using the procedure of Example 153 to give 197.