Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)=O.[BrH:5].Br.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.Br>FC(Cl)(F)C(Cl)(Cl)F.ClCCl>[Br:5][C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[N:13][CH:14]=1
Reactant: Cc1cccnc1CCCCN
Reactant: Br
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCN
Yield: 51.5 %

Procedure:
A solution of sulphur trioxide (150 ml) in 1,1,2-tri-fluorotrichloroethane (350 ml) was added over ca 30 min. to a suspension of 2-(4-aminobutyl)-3-methyl-pyridine dihydrobromide (17 g) [prepared by passing hydrogen bromide gas through a solution of the amine in dichloromethane] in 1,1,2-trifluorotrichloroethane (100 ml) and the mixture was heated under reflux for ca 16 hr. The solvent was removed by distillation and unbrominated starting material was removed by acetylation as described in Example 1(h) to yield 5-bromo-2-(4-aminobutyl)-3-methylpyridine (6.53 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH3:30]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: CCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 85.8 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.391 ml (5.181 mmol) of ethyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 184 mg (0.4444 mmol, 86%) of 2-ethoxy-2'-hydroxy-5, 5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.36 (3H, t, CH3), 1.7-2.2 (4H, m, 2CH2), 2.36 (4H, t, 2CH2), 2.64 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.10 (2H, q, CH2), 6.66 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 413 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.[CH:31](CS([O-])(=O)=O)([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH:31]([CH3:33])[CH3:32])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)CS(=O)(=O)[O-]
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(C(C)C)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 3, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and isopropylmethanesulfonate. The desired product was obtained in a yield of 69% as light yellow solid. MS (m/e): 540.3 (M+H, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)=[CH2:2].C1CCCCC1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C([Li])CCC.CO>[CH2:17]([N:19]([CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: CCNCC
Reactant: C=Cc1ccc(C=C)cc1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCCCC1
Product: C=Cc1ccc(CCN(CC)CC)cc1
Temperature: 50 °C
Yield: 71.4 %

Procedure:
In a 200 ml three necked flask were placed 26 g of p-divinylbenzene and 40 ml of cyclohexane, and to the mixture were further added 40 ml of a cyclohexane solution of an amide-amine complex prepared from 14.8 g of diethylamine and 0.512 g of n-butyllithium. The mixture thus obtained was heated at 50° C. for 3 hours with stirring. Then the reaction solution was added with 10 ml of methanol and subjected to distillation to give 29.0 g of p-diethylaminoethylstyrene having a boiling point of about 84° C./1 mmHg.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=1.[I-].ClC1C=CC=C[N+]=1C>O.C(#N)C>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@H:11]([NH:10][C:27](=[O:28])[C:24]1[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:22][CH:23]=1)[CH2:12]2
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
1.5 ml of Acetonitrile and Triethylamine (700 uL, 5.0 mmol) was added to a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (199 mg, 1.0 mmol) and α,α,α-Trifluoro-p-toluic acid (209 mg, 1.1 mmol), followed by addition of 2-Chloro-1-methyl pyridinium iodide (383 mg, 1.5 mmol) at room temperature. After stirring overnight, about 2 ml of water was added to reaction mixture to resolve a clear solution that was subsequently injected into a Preparative HPLC instrument for purification. Desired fractions were combined, concentrated under vacuum, and then recrystallized from 4 mL of Methanol/water (3:2) to isolate white crystalline solid of (S)—N-(quinuclidin-3-yl)-4-(trifluoromethyl)benzamide (278 mg, 93% yield). 1H NMR (400 MHz, Methanol-D4) δ (ppm): 8.05 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 4.47 (m, 1H), 3.87 (t, J=11.8, 11.8 Hz, 1H), 3.38 (m, 4H), 2.39 (m, 1H), 2.27 (m, 2H), 2.13 (t, J=8.2 Hz, 1H). LCMS (ESI): m/z 299.1 (M+H [C15H17F3N2O]=299.13).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([Cl:12])=[N:7]2.[Li+].[CH3:14]C([N-]C(C)C)C.IC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6]([Cl:12])=[N:7]2
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)cccc2nc1Cl
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloroquinoline (1.0 g, 4.1 mmol) in anhydrous THF (20 mL) at −78° C. was added LDA (2.0 M in heptane/THF/ethylbenzene, 3.1 mL, 6.2 mmol) dropwise. After stirring for one hour, iodomethane (1.28 mL, 20.6 mmol) was added, and the mixture was stirred at −78° C. for another hour. The mixture was poured into saturated NH4Cl (aq) then extracted twice with EtOAc. The organic extracts were concentrated and the residue was purified by reverse-phase HPLC to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.34 (s, 1H); 7.96 (d, J=8.3 Hz, 1H); 7.80 (d, J=7.5 Hz, 1H); 7.53 (d, J=7.8 Hz, 1H); 2.60 (s, 3H) LC3: 1.41 min. (M+H) 258.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:46][CH2:45]C1>>[Si:1]([O:8][CH2:9][C@@H:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([O:46][CH3:45])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a 100 mL flask was charged 4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.0 equiv) and Tetrabutylammonium flouride monohydrate (1.3 equiv) and dissolved in 40 mL dry THF. The reaction was stirred in rt under an inert atmosphere for 20-24 hours. The reaction mixture was concentrated and purified by CC (Heptane/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[CH3:10].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Cl)nn1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1ccccc1-c1ccc(N)nn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of 700 mg of 3-amino-6-chloropyridazine, 1.42 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 148 mg of tris(dibenzylideneacetone)dipalladiuim(0), 603 mg of tricyclohexylphosphine (18% toluene solution), 3.43 g of tripotassium phosphate, 4.5 ml of 1,4-dioxane and 1.5 ml of water was stirred at 100° C. for 3 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 3-amino-6-(2-ethylsulfanylphenyl)pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH2:17][CH3:18])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]([OH:16])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]([CH2:17][CH3:18])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: CCOc1cccc(-n2cc(C=O)c(CC)n2)c1
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(O)CC(C)C)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution (20 mL) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized in Example 83(2) in tetrahydrofuran was added dropwise under ice-cooling, isobutylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.4 g, 67%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(O)(=O)C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: COS(=O)(=O)OC
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 100 ml of acetone and treated with 6.3 g of potassium carbonate and 3.5 ml of dimethyl sulphate. After stirring for 2 hours at room temperature, a further 1 g of potassium carbonate and 1 ml of dimethyl sulphate are added, after which the mixture is stirred for a further hour at room temperature. The mixture is treated with 3 ml of glacial acetic acid and the acetone is distilled off. The residue is treated with 10% sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a column of silica gel (eluant: methylene chloride and methylene chloride/ethyl acetate 10:1) and crystallized from ether/ petroleum ether. There is obtained (+)-5-(o-chlorophenyl)--1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 156°-158° C. and exhibits a rotation of [α]25 D =+376.2° (in methylene chloride, 1%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:23][CH2:24][N:25]=3)[C:8]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[N:9][C:10]=2[C:11]=1[O:12][CH3:13].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:44][C@@H:45]1[O:47][CH2:46]1)(=O)=O>CN(C=O)C>[CH3:13][O:12][C:11]1[C:10]2[N:9]=[C:8]([NH:14][C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[N:7]3[CH2:23][CH2:24][N:25]=[C:6]3[C:5]=2[CH:4]=[CH:3][C:2]=1[O:1][CH2:44][C@H:45]1[CH2:46][O:47]1
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reactant: CS(=O)(=O)OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC[C@H]2CO2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of N-{8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide (Intermediate I, Step 2 (used as bis-TFA salt), 1.50 g, 2.65 mmol) and caesium carbonate (4.32 g, 13.3 mmol, 5.0 equiv.) in DMF (37 mL) was stirred at room temperature for 1 h, then was treated with (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 21.2 mL, 0.25 M in DMF, 5.31 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 16 h at 60° C., then was cooled to room temperature and concentrated under reduced pressure. The resulting residue was seperated between water (50 mL) and a 4:1 CH2Cl2/isopropanol solution (50 mL). The organic phase was washed with a concentrated sodium bicarbonate solution, dried (anh. sodium sulfate), and concentrated under reduced pressure. The resulting material was triturated with EtOH and dried under reduced pressure to give N-{7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide (0.72 g, 69%): HPLC ret. time 0.94 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.75 (dd, J=2.5, 5.1 Hz, 1H), 2.88 (app t, J=4.7, 1H), 3-42-3.47 (m, 1H), 4.01 (s, 3H), 4.14 (dd, J=6.6, 11.6 Hz, 1H), 4.20-4.29 (m, 3H), 4.52-4.59 (m, 2H), 4.68 (dd, J=2.3, 11.6 Hz, 1H), 7.47 (d, J=9.4 Hz, 1H), 7.92 (dd, J=5.6, 7.8 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.90 (br d, J=7.8 Hz, 1H), 8.97 (dd, J=1.5, 5.6 Hz, 1H), 9.49 (d, J=1.5 Hz, 1H); mass spectrum m/z 394 ((M+1)+, 11%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([C:35]#[N:36])=[CH:30][CH:29]=4)[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH2:25][C:26]3[N:27]([CH3:39])[C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([C:35]#[N:36])=[CH:30][CH:29]=4)[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1cc2cc(C#N)ccc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc2cc(C#N)ccc2n1C)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.17 h

Procedure:
3.0 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-indolyl)propionate was dissolved in 30 ml of N,N-dimethylformamide, and then stirred under ice cooling. 270 mg of 60% sodium hydride was added to the above solution, and the stirring was continued for 10 minutes. The resulting reaction solution was mixed with 0.4 ml of methyl iodide, and the mixture was stirred at room temperature for 1 hour. The thus treated reaction solution was diluted with a toluene/ethyl acetate mixture, and then washed with an aqueous solution of ammonium chloride. After drying the resulting organic layer to distill off the solvent, the residue thus obtained was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an elution solvent. In this way, 2.0 g of the title compound was obtained in a viscous and oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1Br.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>CN(P(N(C)C)(N(C)C)=O)C.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:17]=[CH2:18]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1nc2c(cc1Br)N(C)C(=O)C2(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cc2c(nc1OC)C(C)(C)C(=O)N2C
Temperature: 65 °C
Yield: 735.5 %

Procedure:
A mixture of 138 mg (0.048 mmol) 5-methoxy-6-bromo-1,3,3-trimethyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one, 138 mg (0.48 mmol) of tri-n-butyl-vinyltin and 15 mg of bis(triphenylphosphine-palladium(II) chloride in 1 ml of HMPA was heated under nitrogen to 65° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The ethyl acetate solution was washed with water several times. To this ethyl acetate solution was added 1 ml of saturated KF, and the mixture filtered. The filtrate was dried (Na2SO4), evaporated, and the residue chromatographed on silica using 1:1 ethyl acetate/hexanes as the elutant. Appropriate fractions were combined and evaporated to afford 82 mg of 5-methoxy-1,3,3-trimethyl-6-vinyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one. 1H NMR (CDCl3) δ 6.90 (d,d 1H), 5.75 (d, 1H), 5.30 (d, 1H), 3.95 (s, 3H), 3.20 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[CH2:7]([O:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:7]([O:25][C:26](=[O:29])[CH2:27][CH2:28][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Reactant: CCN(O)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCON(CC)CC

Procedure:
The procedure of Example I is repeated using 4.46 g of N,N-diethylhydroxylamine, 16.03 g of n-octadecylacrylate and 0.56 g of potassium-tert-butoxide in 100 ml of tetrahydrofuran, to afford the title compound as a colorless liquid.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[N:13]([CH:29]([F:31])[F:30])[CH:12]=2)=[C:6]([O:32][CH3:33])[CH:5]=1.O1CCCC1.CO.O.[OH-].[Li+].Cl>O>[F:31][CH:29]([F:30])[N:13]1[C:14]2[C:19](=[CH:18][C:17]([NH:20][C:21]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])=[CH:16][CH:15]=2)[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][C:6]=2[O:32][CH3:33])=[CH:12]1
Reactant: COC(=O)c1ccc(Cc2cn(C(F)F)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(F)F)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.40 grams, 0.84 mmol) in a 5:5:2 ratio of methanol tetrahydrofuran:water (24 mL) was added lithium hydroxide monohydrate (0.18 grams, 4.18 mmol). The resulting solution was stirred for 24 hours at room temperature. The reaction mixture was then acidified with 1 M hydrochloric acid (aq) and extracted with ethyl acetate. The combined organics were washed with water and brine, then dried over sodium sulfate. Concentration in vacuo gave 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid as a white solid (0.40 grams, 1005 yield). An analytical sample was attained by recrystallization from ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH:12]=O.[CH3:18][C:19]1([CH3:27])[C:24](=[O:25])[CH2:23][C:22](=O)[CH2:21][O:20]1>>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]2[C:23]3[C:24](=[O:25])[C:19]([CH3:27])([CH3:18])[O:20][CH2:21][C:22]=3[NH:1][C:2]3[CH2:6][CH2:5][C:4](=[O:7])[C:3]2=3)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: NC1=CC(=O)CC1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1(C)OCC(=O)CC1=O
Product: CC1(C)OCC2=C(C1=O)C(c1ccc(F)c(Br)c1)C1=C(CCC1=O)N2
Yield: 54.2 %

Procedure:
3-Amino-2-cyclopenten-1-one (Kikani, B. B., Synthesis, (1991), 2,176) (0.099 g, 1.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.21 g, 1.0 mmol) and the product from Example 66C (0.15 g, 1.0 mmol) were processed as described in Example 31 to provide the title compound (0.22 g).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH2:25]([NH2:27])[CH3:26]>>[ClH:1].[CH2:25]([NH:27][CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23])[CH3:26]
Reactant: Cc1ccc(N2c3ccccc3N(C/C=C\CCl)S2(=O)=O)c(F)c1
Reactant: CCN
Product: CCNC/C=C\CN1c2ccccc2N(c2ccc(C)cc2F)S1(=O)=O
Product: Cl

Procedure:
In an analogous manner to general procedure V, 1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide was reacted with ethylamine to provide (2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-en-1-amine hydrochloride: