Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(Cl)(=O)=O)=[CH:17][CH:16]=1>C(#N)C.Cl.CN(C)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](C)O
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Yield: 116 %

Procedure:
A solution of methyl (R)-(+)-lactate (6.66 g) in acetonitrile (33 ml) was cooled to 5° C. and triethylamine (9.8 ml) added followed by trimethylamine hydrochloride (0.62 g). A separate solution of p-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 mins maintaining the temperature below 5° C. The reaction mixture was filtered and concentrated. Diethyl ether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.71 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:8]2)[CH2:4][CH2:3]1.O1CCC[CH2:23]1.C([Li])CCC.COS(OC)(=O)=O>CCCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:8]2)[CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: CN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: CN1CCC2(CC1)OC(C)(c1ccccc1)c1ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 1.4 g. of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 2), in 20 ml. of tetrahydrofuran is cooled to -50° and treated dropwise with 4 ml. of butyllithium in hexane. Stirring is continued for 30 minutes under nitrogen. To the solution is slowly added 900 mg. of dimethylsulfate in 10 ml. of tetrahydrofuran. The mixture is stirred at -10° for 1 hour and overnight at ambient temperature. Ice is added, the mixture is extracted with ether, and the organic solution is concentrated to an oil. The oil is converted to the hydrobromide salt and recrystallized from ethyl acetate to give crystals, m.p. 122°-125°.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:12][C@:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][C@H:14]1[CH:16]=[CH2:17].[CH:23]1[N:27]=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1>C1COCC1>[N:25]1([C:28]([NH:12][C@:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][C@H:14]2[CH:16]=[CH2:17])=[O:29])[CH:24]=[CH:23][N:27]=[CH:26]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)n1ccnc1)C(=O)OCC
Yield: 70 %

Procedure:
Under nitrogen, (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate tosylate salt (5 g, 1 eq.) and CDI (2.7 g, 1.1 eq.) were dissolved in THF (50 mL) containing TEA (2.3 mL, 1.1 eq.). The reaction mixture was then refluxed overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM, and washed twice with water. The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel to yield compound 33 as pale yellow oil in 70% yield.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[OH-].[NH4+:7].[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH2:9]1[C:10]2[CH:9]=[CH:10][CH:11]=[C:12]([S:1]([NH2:7])(=[O:3])=[O:2])[C:11]=2[CH2:12][O:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: [NH4+]
Reactant: C1CCOC1
Agent: [OH-]
Product: NS(=O)(=O)c1cccc2c1COC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.8 g of the sulfonyl chloride, prepared in Part A, in 150 ml tetrahydrofuran was cooled to approximately 5°, and 6.6 ml of concentrated ammonium hydroxide was added dropwise. The resulting yellow suspension was allowed to warm to ambient temperature and stirred 0.5 hour; thin-layer chromatography showed the reaction was complete. The solvent was evaporated in vacuo and the resulting solid was slurried in 150 ml water, collected, washed with water and dried. The crude product was washed with 1-chlorobutane and dried to give 7.74 g of 1,3-dihydrobenzo[c]furan-4-sulfonamide, m.p. 153°-158°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:41])([F:40])[CH2:37][C@H:36]3[C:42]([OH:44])=[O:43])=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:40])([F:41])[CH2:37][C@H:36]3[C:42]([OH:44])=[O:43])=[O:34])[N:28]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 4-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml dichloromethane were added 300 μl TFA. After stirring for 12 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 63 mg MS (ES+): m/e=665.
Reaction SMILES: N1[CH:6]=[CH:5]C=CC=1.[CH3:7][C:8]([CH3:22])([CH:10]([OH:21])[CH:11]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9].C(=O)(O)[O-:24].[Na+]>C(OC(=O)C)(=O)C>[C:5]([O:21][CH:10]([CH:11]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH:12]=[C:13]([CH3:14])[CH3:15])[C:8]([CH3:22])([CH3:7])[CH3:9])(=[O:24])[CH3:6]
Reactant: O=C([O-])O
Reactant: CC(C)=CC(C(O)C(C)(C)C)n1cncn1
Reactant: c1ccncc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C(C=C(C)C)n1cncn1)C(C)(C)C
Temperature: 70 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
2 ml of pyridine were added to a solution of 11.0 g (0.05 mol) of 2,2,6-trimethyl-4-(1,2,4-triazol-1yl)-5hepten-3-ol (preparation analogous to Example 2) in 100 ml of acetic anhydride and the mixture was stirred at 70° C. for four hours. Thereafter, the reaction mixture was poured onto water and neutralized with sodium bicarbonate. The aqueous phase was extracted several times with ether and the ether phase was dried over sodium sulphate and concentrated. 9.7 g (74% of theory) of 3-acetoxy-2,2,6-trimethyl-4-(1,2,4-triazol-1-yl)-5-heptene were obtained as a colorless oil with a refractive index of nD20 =1.4809.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17](O)=[O:18])[CH:13]=[CH:14][CH:15]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:17](=[O:18])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1cccc(O)c1)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
A solution of resorcinol (3.56 g, 32.3 mmol), 2-(3-hydroxyphenyl)acetic acid (5.39 g, 35.4 mmol), and boron trifluoride etherate (12 mL) in toluene (10 mL) was heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature, and a solution of 12% sodium acetate in H2O (17 mL) was added. After stirring for 3 h, the resulting precipitate was collected by filtration to give 1-(2,4-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (4.47 g, 57%) as a yellow solid. 1H NMR (DMSO-d6): δ 12.57 (s, 1H), 10.67 (s, 1H), 9.34 (s, 1H), 7.92 (d, 1H), 7.09 (m, 2H), 6.65 (m, 2H), 6.40 (m, 1H), 6.25 (s, 1H), 4.14 (s, 2H).
Reaction SMILES: CN[CH2:3][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[C-:13]#[N:14].[Na+].C(O)(=O)C>CS(C)=O.O>[OH:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][C:13]#[N:14])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: [C-]#N
Reactant: CNCc1ccc(O)c(OC)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1cc(CC#N)ccc1O
Temperature: 125 °C
Reaction time: 2 h

Procedure:
160.8 g of N-methylvanillylamine and 54 g of sodium cyanide are suspended in 1 liter of dimethylsulphoxide and dissolved by heating to 125°C. At this temperature, a solution of 100 ml of glacial acetic acid in 200 ml of water is added and the mixture is stirred for a further 2 hours under nitrogen at 125°C. It then cooled to 80°C and the dimethylsulphoxide is distilled off in a water-pump vacuum. 900 ml of water are added to the residue which is extracted with 350 ml of chloroform. The chloroform phase is extracted by shaking with water and dried with sodium sulphate. On distilling off the chloroform in vacuo, an oil is obtained, which is cooled and seeded. The crystals formed melt at 53°-54°C (boiling point0.1 :140°-144°C). The yield is 143 g (94% of theory).
Reaction SMILES: [F:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][C@H:5]1[C:9](=[O:10])[O:8][C@H:7]([C@@H:11]([NH:19][C:20]([C:22]2[CH:31]=[N:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.C(O)(=O)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCOCC1.O>[CH2:12]([C@H:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[C@@H:7]([OH:8])[CH2:6][C@H:5]([C:9](=[O:10])[NH:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:4][CH2:3][C:2]([F:1])([CH3:32])[CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(F)CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(F)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of the product from Method E (0.10 g, 0.22 mmol) in dioxane (2 mL) was added glacial acetic acid (0.038 mL, 0.66 mmol) and benzylamine (approx. 1 mL, excess). The resulting solution was warmed to reflux for 1 hour, cooled to ambient temperature and diluted with water. The solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate (MgSO4), filtered and concentrated. Chromatography on silica gel, followed by recrystallization from methylene chloride/hexanes gave the title compound (0.068 g, 56%). m.p. 183-184° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>>[CH3:19][S@:11](=[O:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[N:10][C:8](=[O:9])[C:7]1[CH:20]=[C:3]([C:1]#[C:2][C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[CH:4]=[N:5][CH:6]=1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Ic1cn[nH]c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cn[nH]c2)c1)c1ccccc1

Procedure:
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N—[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodopyrazole were reacted to give the title compound as a white film (15 mg, 17%).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)C(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: O=C(C(Cl)Cl)N1CCC2(CC1)OCCO2
Yield: 49.2 %

Procedure:
12.4 g (0.084 mol) of dichloroacetyl chloride were added dropwise to a mixture of 12 g (0.084 mol) of piperid-4-one ethylene ketal and 12.8 g (0.084 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of toluene, whilst stirring, at a rate such that the temperature of the reaction mixture did not exceed 40° C. Thereafter, the mixture was subsequently stirred at 20° C. for 2 hours. Working up was then effected by a procedure in which the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was recrystallized from a mixture of toluene and petroleum ether. 10.5 g (49% of theory) of N-dichloroacetyl-piperid-4-one ethylene ketal were obtained in this manner in the form of colorless crystals of melting point 102° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(COC)OC.[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[CH:4]=[N:3][C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cnc(-c2ccco2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: c1coc(-c2cnc(-c3ccncc3)cn2)c1
Yield: 57.9 %

Procedure:
At room temperature, 2-chloro-5-(furan-2-yl)pyrazine (N. Sato, J. Heterocyclic Chem., 19, 407(1982)) (1.00 g) and (pyridin-4-yl)boronic acid (1.09 g) were suspended in a mixed solvent of dimethoxyethane (50 ml) and methanol (50 ml), followed by the successive addition of tetrakis(triphenylphosphine)palladium (O) (640 mg) and cesium fluoride (5.55 g). The resulting mixture was heated under reflux for 16 hours. After cooling, the reaction mixture was concentrated. Dichloromethane and water were added to the concentrate to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, treated with activated carbon and filtered through Celite. After the filtrate was concentrated to about 5 ml, petroleum ether (50 ml) was added to the concentrate. Yellow crystalline powder thus precipitated was collected by filtration and dried, whereby the title compound (716 mg, 58%) was obtained.
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH2:9][NH2:10])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH:11][C:12]1[CH:27]=[CH:26][C:15]([C:16](=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)=[CH:14][CH:13]=1>C(O)(=O)C.O.Cl>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:8][CH2:9][N:10]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=2[CH:17]=[C:16]1[C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:27][CH:26]=1)([CH3:3])[CH3:2]
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Reactant: CC(C)N(CCN)C(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N(CCn1c(-c2ccc(O)cc2)cc2c1CCCC2)C(C)C
Temperature: 25 °C

Procedure:
A solution of 5.77 g (0.04 mole) of diisopropylaminoethylamine and 9.3 g (0.04 mole) of 2-(p-hydroxyphenacyl) cyclohexanone in glacial acetic acid is refluxed under nitrogen for 14 hours, then cooled to ambient temperature and diluted with water and dilute hydrochloric acid. The aqueous solution is washed with ether, basified with 10% sodium carbonate and extracted with ether. After drying the ether solution over magnesium sulfate, the ether is removed to give a pale yellow solid. The solid is recrystallized from an ether-petroleum ether mixture to give pale yellow crystals of 1-(2-diisopropylaminoethyl)-2-(p-hydroxyphenyl)-4,5,6,7-tetrahydroindole as pale yellow crystals, m.p. 112°-114.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14]Br.O>CC(O)=O>[Br:14][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: COc1cc(CC(=O)O)ccc1F
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CC(=O)O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-3-methoxyphenylacetic acid (5.0 g, 27.1 mmol) in AcOH (20 ml) was added bromine (1.5 ml, 29.8 mmol). The mixture was stirred at room temperature for three hours. Water was added and the precipitate was isolated by filtration. The white solid was washed with water and dried to give (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.21 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl-:15].[Al+3].[Cl-:17].[Cl-].ClCl>C(Cl)Cl>[Cl:15][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([Cl:17])[C:2]=1[CH3:1])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: [Cl-]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)CCC(=O)O)cc1Cl
Yield: 44.2 %

Procedure:
To a mixture of 3-(4-methylbenzoyl)propionic acid (7.5 g) and methylene chloride (250 ml) was added slowly portionwise aluminum chloride (15 g) at 0° C. After the addition was completed chlorine gas was bubbled in slowly at 0° C. After 6 hours the reaction mixture was poured into a mixture of hydrochloric acid and ice and extracted with methylene chloride (3×150 ml), the combined organic layers were washed with water, dried and evaporated under vacuum yielding 3-(3,5-dichloro-4-methylbenzoyl)propionic acid as a yellow solid (4.5 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:23][CH2:22][C@H:21]2[C@@H:16]([C:17](=[O:30])[C:18]3[C:26]4[CH2:27][CH2:28][CH2:29][C:25]=4[NH:24][C:19]=3[CH2:20]2)[CH2:15]1.[CH3:31][C:32]([CH3:50])([CH2:36][CH2:37][O:38][C:39](=[O:49])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:33](Cl)=[O:34]>O1CCCC1.CCCCCC>[CH3:50][C:32]([CH3:31])([CH2:36][CH2:37][O:38][C:39](=[O:49])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:33]([N:24]1[C:19]2[CH2:20][C@@H:21]3[C@@H:16]([C:17](=[O:30])[C:18]=2[C:26]2[CH2:27][CH2:28][CH2:29][C:25]1=2)[CH2:15][N:14]([CH3:13])[CH2:23][CH2:22]3)=[O:34]
Reactant: CCCCCCCCCC(=O)OCCC(C)(C)C(=O)Cl
Reactant: CN1CC[C@@H]2Cc3[nH]c4c(c3C(=O)[C@H]2C1)CCC4
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCC(=O)OCCC(C)(C)C(=O)n1c2c(c3c1C[C@H]1CCN(C)C[C@@H]1C3=O)CCC2
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
To a solution of diisopropylamine (0.15 g) in tetrahydrofuran (15 mL) was added n-butyllithium in hexane (0.75 mL, 2M solution) at -20° to -30° and the solution was stirred at -20° to -30° C. for 30 minutes. To the solution was added at -20° to -30° C. (in one portion) trans-1,3,4,4a,5,7,8,9,10,10a-decahydro-2-methyl-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(2H)-one (0.244 g) and the mixture was stirred at -20° C. for 2 hours. To the solution was added the crude 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoyl chloride (0.45 g) in tetrahydrofuran at -20° to -30° and the mixture was stirred at this temperature for an additional 1 hour. The mixture was poured onto ice water and extracted in the dichloromethane. The combined dichloromethane extracts were washed with brine dried sodium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give 0.24 g of oily material (47%), trans-1,3,4,4a,5,6,7,8,9,10a-Decahydro-6-[2,2-dimethyl-1-oxo-4-[(1-oxodecyl)oxy]butyl]-2-methylcyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(2H)-one IR (CHCl3), 1778 (C=O) and 1657 (C=O); NMR (CDCl3), δ0.88 (t, 3, CH3); 1.2-1.4 (m, 20, CH2 and CH3) 2.41 (5, 3, CH3); 3.04 (br.d, 1, CH); 3.56 (br.d, 1, CH); 4.14 (t, 2, CH2); MS m/e 512 (M+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:36][C:37]([CH3:39])=[O:38].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[OH:38][C:37]([CH3:39])([CH3:36])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:15][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CCN3CCOCC3)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccc(CCN2CCOCC2)cc1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-C-[4-(2-morpholin-4-ylethyl)phenyl]methanesulfonamide (50 mg) in THF (1 ml) was initially charged and then, at −78° C., 1.6 N butyllithium solution in hexane (0.3 ml) was added dropwise. The reaction mixture was stirred for 10 minutes, and then acetone (50 μl) was added dropwise. The mixture was stirred at constant temperature for 30 minutes, trifluoroacetic acid (40 μl) was added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 2 ml of dichloromethane, and 250 μl of trifluoroacetic acid were added. After stirring at room temperature for 2 h, the mixture was diluted with dichloromethane and extracted with 1 M hydrochloric acid. The aqueous phase was concentrated and the residue was coevaporated with toluene. This gave the crude product with a molecular weight of 378.9 g/mol (C16H26N2O4S), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].P(Cl)(Cl)(Cl)=O.[C:22]1([CH3:31])[C:23]([C:28](O)=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:31]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[N:16][N:15]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a suspension of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) in phosphorus oxychloride (1.68 mL, 18.4 mmol) was added o-toluic acid (188 mg, 1.38 mmol) and was stirred for 30 min at ambient temperature. The suspension was heated for 2 h at 90° C. whereupon it became homogeneous. After cooling to ambient temperature it was then poured onto a mixture of ethyl acetate (20 mL) and aqueous sodium carbonate (saturated, 20 mL). The aqueous phase was then separated and extracted with ethyl acetate (20 mL). The combined organic extracts were then washed with aqueous sodium carbonate and brine. Concentration and trituration in tert-butylmethylether (3 mL) afforded the title compound (99 mg, 34%) as a white solid. MS: m/e=318.1 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H+].[B-:13]([F:17])([F:16])([F:15])[F:14].CC(C)CCO[N:23]=O.C(OCC)C>O1CCCC1>[F:14][B-:13]([F:17])([F:16])[F:15].[N:1]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]#[N:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(C)CCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#[N+]c1ccc2ncccc2c1
Reaction time: 1 h

Procedure:
To a solution of quinolin-6-yl amine (2.88 g, 20 mmol) and HBF4 aqueous solution (48% W/W, 11 mL) in tetrahydrofuran (100 mL) was added 3-methyl-1-nitrosooxy-butane (10.7 mL, 60 mmol) dropwise under nitrogen atmosphere at from −10° C. to −15° C., then, the mixture was stirred for 1 hour. At from −10° C. to −15° C., diethyl ether (200 mL) was added dropwise, the precipitated solid was collected by filtration, washed with diethyl ether, dried, and quinolin-6-diazonium tetrafluoroborate (6.85 g) was obtained as a yellow-red solid.