Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:3]([CH3:11])([CH3:10])[O:4][Si](C=C)(C)C)=[CH2:2].[Cl:12][Si:13]([Cl:16])(Cl)[Cl:14].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:12][Si:13]([Cl:16])([Cl:14])[O:4][Si:3]([CH:1]=[CH2:2])([CH3:11])[CH3:10]
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: C=C[Si](C)(C)O[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
A mixture containing 595 g (3.2 mol) of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane, 136 g (0.8 mol) of tetrachlorosilane and 2 ml of a 25% solution of phosphonitrile chloride in methylene chloride is stirred at room temperature for 8 hours. About 2.3 ml of tri-n-butylamine are then added to deactivate the phosphonitrile chloride. The reaction mixture is stirred for 30 minutes and then subjected to fractional distillation. About 216 g of 1,1,1-trichloro-3-vinyl-3,3-dimethyldisiloxane are obtained at 20° to 22° C. and at 2 mbar; about 53 g of 1,5-divinyl1,1,5,5-tetramethyl 3,3-dichlorotrisiloxane are obtained at 23° to 42° C. and at 2 mbar, and 9 g of a 1:1 mixture of 1,5divinyl-1,1,5,5-tetramethyl-3,3-dichlorotrisiloxane and 1,5-divinyl-1,1,5,5-tetramethyl-3-chloro-3-trimethylsiloxytrisiloxane are obtained at 42° to 72° C. and at 2 mbar. About 372 g of vinyldimethylchlorosilane are collected in the cold trap. The desired 1,5-divinyl-1,1,5,5-tetramethyl-3,3-bis(vinyldimethylsiloxy)trisiloxane is not obtained.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:28]#[N:29].C1N2CCN(CC2)C1>CN1C(=O)CCC1.CCOC(C)=O>[C:28]([C:27]1[CH:30]=[CH:31][C:32]2[NH:33][C:2]([CH2:3][C:4]3[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]4[C:5]=3[CH:6]=[CH:7][N:8]4[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:24][C:25]=2[CH:26]=1)#[N:29]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=C(Br)Br
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-(2,2-dibromovinyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.3 g, 2.92 mmol), 3,4-diaminobenzonitrile (700 mg, 5.26 mmol) and DABCO (819 mg, 7.30 mmol) in NMP (12 mL) was stirred at 110° C. for overnight. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using FCC eluting with heptane/EtOAc(60-80%) to provide the title compound. MS (ESI+) m/z 417.2 (M+H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:15]
Reactant: CCN
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Product: CCNCC1(O)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.7 g (30.8 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of ethylamine solution (50% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:13])([CH3:14])[C:7](=[O:15])[C:6]([C:16]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:17])=[C:5]2[OH:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(F)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a mixture of ethyl 6,7-difluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (570 mg, 1924 μmol) in 1,4-dioxane (3848 μL) and N-ethyl-N-isopropylpropan-2-amine (1005 μL, 5772 μmol), was added tert-butyl 2-aminoacetate hydrochloride (484 mg, 2886 μmol). The reaction was then heated at 80° C. for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (312 mg) as a white solid after flash chromatography. MS (m/z)=404 (M+Na)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)[CH2:3][CH2:2]1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][OH:17].[H-].[Na+]>O1CCCC1>[CH2:20]([O:19][C:15](=[O:18])[CH2:16][O:17][C:11]1[CH:10]=[C:9]([Cl:14])[N:8]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:12]=1)[CH3:21]
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
2-Morpholino-4,6-dichloropyrimidine (2.34 g; 10 mmol) and ethyl glycolate (1.3 g; 12 mmol) were dissolved in tetrahydrofuran (100 mL), and chilled in an ice bath. To the solution was added sodium hydride (300 mg; 12 mmol), and it was stirred overnight at ambient temperature. The solvents were evaporated, and the solid was dissolved in ethyl acetate (200 mL) which was then washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, and evaporated to give (6-chloro-2-morpholin-4-yl-pyrimidin-4-yloxy)-acetic acid ethyl ester (3.16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18]C(OC)=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC(=O)OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 83.7 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-6-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (500 mg, 0.80 mmol) and potassium carbonate (222 mg, 1.6 mmol) in methanol (5 mL) was stirred at room temperature overnight. A small amount of water was added, and the methanol was removed in vacuo. Additional water (20 mL) was added and the aqueous mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with a saturated sodium bicarbonate solution (10 mL), brine (10 mL), and then dried over sodium sulfate, filtered and concentrated in vacuo to give 412 mg crude product. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded 378 mg of the title compound (84%): MS m/z 565 (M+ +1), 582 (M+ +18); 1H NMR (CDCl3) δ 7.08 (C8, s, 1H), 6.52 (C5, s, 1H), 1.15 (C2-Me, d, 3H, J=6.0 Hz).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:30]1>>[OH:28][CH:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:37][CH:36]=2)[CH2:30]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCC(O)C2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCC(O)C2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-aniline Rf value: 0.1 (silica gel, methylene chloride/methanol=10:1) C28H27N3O4
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](OC)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27].[OH-].[Na+].O.[CH3:39][N:40](C)C=O>>[CH3:27][N:26]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:14](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)/[C:15]2[CH:16]=[CH:17][C:18]([C:39]#[N:40])=[CH:19][CH:20]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: CN(C)C=O
Reactant: COC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1cccc(I)c1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccc(C#N)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.07 g of 1-acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VII) and 0.54 g of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 10 ml of dimethylformamide and stirred at 80° C. for 3 hours. After cooling, 1 ml of 6N aqueous sodium hydroxide is added, and the mixture is stirred at room temperature for 30 minutes. Water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed twice with water, dried over sodium sulphate and concentrated using a rotary evaporator, and the product is recrystallized from diethyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Reactant: Oc1cccc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2cccc(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 62 mg (0.55 mmol) of 3-fluorophenol and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) of azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed twice with 2N aqueous NaOH solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 90 mg (40%) product as a white solid. MS (ISP) 445.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[K].[CH3:16]C(C)([O-])C.CI.CC(C)([O-])C.[K+]>CN(C)C=O.C1C=CC=CC=1>[CH3:16][C:6](=[C:2]1[CH2:3][CH2:4][CH2:5][NH:1]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: O=C(C=C1CCCN1)c1ccccc1
Agent: [K+]
Agent: [K]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C(=O)c1ccccc1)=C1CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.0 g of α-(2-pyrrolidinylidene-acetophenone and 11.3 g of potassium-tert.-butoxide are dissolved in a mixture of 8 ml of dimethylformamide and 170 ml of benzene. A solution of 25 g of methyl iodide in 25 ml of benzene is added dropwise within 30 minutes. The reaction mixture heats up to 38°. It is stirred for 2 hours at room temperature; to the reaction mixture is then added a further 2.5 g of potassium tert.-butoxide and it is subsequently stirred for 15 hours at room temperature. The cloudy reaction mixture is filtered clear with the aid of diatomaceous earth; it is concentrated by evaporation and the evaporation residue is chromatographed on a silica-gel column with an ethyl acetate/hexane mixture (volume ratio 1:1). There is obtained 2-methyl-2-(2-pyrrolidinylidene)-acetophenone, m.p. 91°-92° (from cyclohexane).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][C:8]([O:11][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)Oc1ccc2ccc(O[Si](C)(C)C)cc2c1

Procedure:
2,7-Bis(trimethylsilyloxy)naphthalene 5b was prepared from naphthalene-2,7-diol following the general procedure for the preparation of bis-silyl “BB” monomers, with substitution of tert-butyldimethylsilyl chloride with trimethylsilyl chloride. 5b was isolated as a yellow oil (13.1 g, 43.5 mmol, 99%): IR (neat) λmax 2958, 2856, 1630, 1604, 1507, 1460, 1427, 1365, 1250, 1211, 1151, 1110, 909, 833, 743, 697, 612, 489 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.9 Hz, 2H), 7.12 (d, J=2.3 Hz, 2H), 6.99 (dd, J=2.3, 8.8 Hz, 2H), 0.37 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.6, 136.2, 129.3, 125.4, 120.0, 114.0, −0.42; LRMS (EI) m/z=304.1 [M]+.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO.C1COCC1.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S(C)(=O)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 2-methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionate (Step A, 0.45 g, 1.6 mol) in 5 mL MeOH, 10 mL THF and 10 mL water was added sodium hydroxide (0.19 g, 4.7 mmol). After stirring at room temperature for 3 days, the reaction mixture was partially concentrated, and was added 2 M hydrochloric acid to pH>2. The resulting mixture was extracted with EtOAc (2×20 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.60 (d, 1H), 8.16 (dd, 1H), 7.17 (d, 1H), 3.15 (s, 3H), 1.71 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCCCOCCSCCc1ccccc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCOCCSCCc2ccccc2)cc1Cl
Yield: 64.1 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (1.53 g), [2-[[2-(4-bromobutoxy)ethyl]thio]ethyl]benzene (1.0 g) and DEA (0.71 g) in DMF (20 ml) was stirred under nitrogen at 100° for 2 h. The solvent was evaporated in vacuo and the residue purified by FCC eluting with System G (95:5:1) to give an oil. The oil was partitioned between dichloromethane (50 ml) and 8% sodium bicarbonate (75 ml) and the aqueous solution re-extracted with dichloromethane (50 ml). The organic extracts were dried and evaporated in vacuo to give the title compound (924 mg,) as a white solid m.p. 74°-77°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl.Cl[CH2:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=2>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:28][C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cccc2ncc(CCl)cc12
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc2cccc(OC)c2c1)c1ccc(OC)c(OC)c1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
To a solution of methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 (73 mg, 347 μmol) in dry THF (10 mL) at −66° C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added LiHMDS (1.0 N in TBME, 0.70 mL, 700 μmol) and the mixture was stirred for 20 min at that temperature. 3-(Chloromethyl)-5-methoxyquinoline hydrochloride CCH 34144B (84 mg, 344 μmol) was then added and the mixture was stirred for 2 h allowing the temperature to reach RT. The mixture was then quenched by carefully adding H2O (4 mL) and diluted with EtOAc (30 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (40 mL). Both organic phases were washed with brine (10 mL), then combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) provided methyl 2-(3,4-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate 34144-5 as a pale yellow oil (46 mg, 35% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23]1>>[OH:22][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: CCCC1CO1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Product: CCCC(O)COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 24 with 1,2-epoxypentane gave 2-(2-(3-(2-hydroxypentyloxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.1 g, 84%): 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=6.8 Hz, 1H), 7.44-7.56 (m, 2H), 7.12-7.16 (m, 1H), 6.68-6.73 (m, 1H), 6.46-6.52 (m, 3H), 4.10 (t, J=5.2 Hz, 2H), 3.90-4.0 (m, 2H), 3.77-3.82 (m, 3H), 1.32-1.56 (m, 4H), 0.94 (t, J=6.8 Hz, 3H).
Reaction SMILES: [ClH:1].[Cl-].[CH3:3][O:4][CH:5]([O:25][CH3:26])[CH2:6][NH:7][CH2:8][CH2:9][C:10]12[CH2:17][CH2:16][N+:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>CO>[Cl-:1].[CH2:18]([N+:13]12[CH2:16][CH2:17][C:10]([CH2:9][CH2:8][Cl:1])([CH2:15][CH2:14]1)[CH2:11][CH2:12]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:3][O:4][CH:5]([O:25][CH3:26])[CH2:6][NH2:7]
Reactant: Cl
Reactant: COC(CNCCC12CC[N+](Cc3ccccc3)(CC1)CC2)OC
Agent: [Cl-]
Solvent: CO
Product: COC(CN)OC
Product: ClCCC12CC[N+](Cc3ccccc3)(CC1)CC2

Procedure:
The N-[2-(1-benzyl-1-azoniabicyclo[2.2.2]-octan-4-yl)ethyl]aminoacetaldehyde-dimethylacetal-chloride-hydrochloride [melting point: 202°-204° C. (decomp.); Rf -value: 0.62 (Reversed Phase Silica gel, methanol/5% aqueous saline solution=6:4)]1 used as amine component is obtained by reaction of 1-benzyl-4-(2-chloroethyl)-1-azoniabicyclo[2.2.2]octane-chloride with aminoacetaldehyde-dimethylacetal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH:14]([O:16]C(=O)C)[CH3:15])=[O:13])[NH:7][C:6](=[O:20])[CH2:5]2.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[C@@H:14]([OH:16])[CH3:15])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
The stirred mixture of acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 2.67 mmol) in methanol (5 ml) and water (5 ml) was added with sodium hydroxide (240 mg, 60 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was extracted with ethyl acetate (100×3) and water (100×3). The organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)—N-(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide (270 mg, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[CH:3]=1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(CN2CCCC2)c1
Yield: 35 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), pyrrolidine (0.14 mL, 0.12 g, 1.7 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(pyrrolidin-1-ylmethyl)phenoxy]benzonitrile fumarate (117 mg, 35%) as a white solid.