Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:25][NH:26][CH3:27].C(N(CC)CC)C.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:27])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: Oc1cccc(-c2nc(-c3ccnc(F)c3)c3sccc3n2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)c1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Temperature: 130 °C
Yield: 61.9 %

Procedure:
A mixture of 3-[4-(2-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-2-yl]-phenol, (60 mg), dimethylamine hydrochloride (151 mg), triethylamine (0.31 mL) and 1,4-dioxane (3 mL) was heated to 130° C. in a sealed tube. After heating for 24 hours the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield the title compound (40 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:45][CH2:46][CH3:47])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]=1[C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:45][CH2:46][CH3:47])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]=1[C:21]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)c(C(=O)N2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C(=O)N2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogen carbonate (0.79 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(morpholin-4-ylcarbonyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.22 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C1C=CC(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([N:35]=[N+:36]=[N-:37])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/C(=O)N=[N+]=[N-])c1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of (E)-3-(3-methoxyphenyl)acrylic acid (15 g, 84 mmol) in benzene (100 ml) was added triethylamine (11.73 ml, 84 mmol) followed by DPPA (23.17 g, 84 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as a white solid (15 g, 88%). 1H NMR (400 MHz, CDCl3): δ ppm 7.75-7.70 (d, J=20 Hz, 1H), 7.36-6.97 (m, 4H), 6.45-6.40 (d, J=20 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: C[C:2]1([C:11](O)=O)[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH2:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH2:22])[CH3:15].C1(N=C=NC2CCCCC2)CCCCC1.[O:38]1CCC[CH2:39]1>>[CH2:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH:22][C:39]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:11])=[O:38])[CH3:15]
Reactant: C1CCOC1
Reactant: CC1(C(=O)O)C=c2ccccc2=N1
Reactant: CCN1CCCC1CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCN1CCCC1CNC(=O)c1c(C)[nH]c2ccccc12

Procedure:
To a solution of 8 g of 2-methylindolecarboxylic acid and 6 g of 1-ethyl-2-pyrrolidinylmethylamine in 140 ml of tetrahydrofuran was added 9.5 g of dicyclohexylcarbodiimide, and the whole mixture was refluxed under heating for 1.5 hours. After cooling, the precipitated dicyclohexylurea was filtered off and the filtrate was concentrated. The resulting residue was crystallized with 20 ml of ethyl acetate and the crystals were filtered with suction and then recrystallized from ethyl acetate to give 10 g of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methylindole-3-carboxamide as white crystals, melting at 132°-135° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][C:11]#[N:12])[N:6]=1.Cl.[C:14](C1C=CNN=1)(=[NH:16])[NH2:15].CN1CCN(C)C1=O>O>[NH:1]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][C:11]#[N:12])[N:6]=1)[C:14]([NH2:16])=[NH:15]
Reactant: N=C(N)c1cc[nH]n1
Reactant: N#CCCSCc1csc(N)n1
Agent: Cl
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: N#CCCSCc1csc(NC(=N)N)n1
Yield: 38.5 %

Procedure:
To 5 g of 3-(2-aminothiazol-4-ylmethylthio)propionitrile were added 11 g of amidinopyrazole hydrochloride and 15 ml of 1,3-dimethyl-2- imidazolidinone and the mixture was heated to 110°-120° C. for 4 hours. After cooling, 120 ml of water was added to the reaction mixture and then the product was extracted twice with 50 ml of ethyl acetate and washed. The aqueous layer thus formed was collected, added with 11 g of anhydrous potassium carbonate and 10 ml of isopropanol, the crystals thus formed were collected by filtration to provide 2.33 g of 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile having a melting point of 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][C:23]=1[CH3:32])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][C:23]=4[CH3:32])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(CCC(=O)O)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(CCC(=O)O)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid (54.4 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The reaction was concentrated, the residue was dissolved in water and acidified with 1N HCl to pH=2. The resultant solid was then washed with water, ethanol and dried to give 93.9 mg (85%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.18 (br s, 1H, NH), 12.19 (br s, 1H, COOH), 11.61 (br s, 1H, NH), 9.09 (s, 1H), 8.27 (s, 1H), 7.70 (m, 1H), 7.39 (m, 1H), 7.30-7.35 (m, 2H), 6.07 (s, 1H), 2.90 (t, J=7.2 Hz, 2H, CH2), 2.60 (t, J=7.2 Hz, 2H, CH2), 2.16 (s, 3H, CH3). MS 442 [M++1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:26]([O:30][N:31]1N=NC2C=CC=N[C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C=O)C>[CH3:26][O:30][N:31]([CH3:32])[C:18]([C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)=[O:19]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 6.5 mmol) was taken into DMF (10 mL) followed by addition of HATU (2.48 g, 6.5 mmol), N,N-diisopropylethylamine (2.5 mL, 14.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (652 mg, 6.7 mmol), and the mixture was stirred at room temperature over 12 hours. The resulting solution was partitioned with ethyl acetate and water then the organic phase washed with water (3×), 10% aqueous citric acid (2×) then 0.5M aqueous sodium hydroxide and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated, then purified by silica gel flash chromatography with ethyl ether as eluent to provide tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (1.45 g). MS (EI) for C17H26N4O4: 351 (MH+).
Reaction SMILES: C(O)C(O)C[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23]CCCCCC>>[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9]
Reactant: OCC(O)COCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCC(=O)O
Product: OCC(O)CO

Procedure:
From table 8 it appears that for esters of diglycerol and oleic acid optimum wearing reduction properties are provided by partial esters with a molar ratio diglycerol mono laurate/diglycerol dilaurate of more than 1.0.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][Br:12].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:12].[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1ccc2c(n1)CCCC2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc([P+](Cc2ccc3c(n2)CCCC3)(c2ccccc2)c2ccccc2)cc1

Procedure:
In 300 ml of acetonitrile was dissolved 14.7 g (65 mmol) of (5,6,7,8-tetrahydroquinolin-2-yl)methyl bromide, and 25.5 g (97.5 mmol) of triphenylphosphine was added to the mixture and the resulting mixture was refluxed for 2 hours. After cooling the mixture with an ice-bath, precipitates were collected by filtration and washed with diethyl ether to obtain (5,6,7,8-tetrahydroquinolin-2-yl)methyltriphenylphosphonium bromide as pale yellowish solid. Then, the obtained solid was dissolved in 250 ml of chloroform, 9.50 g (117 mmol) of 37% formaldehyde and 8.10 g (76 mmol) of an aqueous sodium carbonate solution (20 ml) were added to the solution and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)=[O:4].[C:28](Cl)(=O)C>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]([CH3:28])=[CH:27][CH:26]=[CH:25][CH:24]=[CH2:23])=[CH:8][C:9]=1[NH:10][CH:11]([CH3:21])[CH2:12][OH:13])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: C=CC=CC=C(C)c1cc(NC(C)CO)c(C(=O)OC)s1
Yield: 79 %

Procedure:
To a solution of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.08 g, 2.69 mmol) in MeOH (10 ml) at 21°, under N2 was added a solution of acetylchloride premixed in MeOH (100 μL/1 mL, 210 μL 2.96 mmol, 1.1 eq). The reaction was followed by tlc. On completion the reaction was stripped-off solvent and the residue purified over silica using progressively 5%, 20%, and then 30% EtOAc/Hexane as eluent to give 3-(2-Hydroxy-1-methyl-ethylamino)-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester as a yellow solid (518 mg, 79%); 1H NMR (300 MHz, CDCl3) 1.25 (d, 6.6 Hz, 3H), 3.52-3.62 (m,1H), 3.73-3.77 (m, 2H), 3.84 (s, 3H), 6.92 (s, 1H), 7.36-7.42 (m, 3H), 3.62 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC(CO)CC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 78.8 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (97.6 mg, 0.170 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was treated with 4-piperidine methanol (0.196 mL, 1.70 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-hydroxymethylpiperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (87.2 mg, yield 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][C:18]#[CH:19])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:43])[CH2:23][CH:24]1[CH2:33][C:32]2[C:27](=[CH:28][C:29](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42].CCOC(C)=O.CCCCCC>CN1CCCC1.[Cu]I>[CH3:20][O:21][C:22](=[O:43])[CH2:23][CH:24]1[CH2:33][C:32]2[C:27](=[CH:28][C:29]([C:19]#[C:18][CH2:17][CH2:16][N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42]
Reactant: C#CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2NC1=O
Agent: [Cu]I
Agent: CN1CCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CC1Cc2ccc(C#CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2NC1=O
Temperature: 60 °C
Reaction time: 22 h
Yield: 61.8 %

Procedure:
A suspension of N-but-3-ynyl-imidodicarbonic acid di-tert-butyl ester (4.65 g, 17.3 mmol), [2-oxo-7-(trifluoro-methanesulfonyloxy)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester (6.36 g, 17.3 mmol), tetrakis (triphenylphosphine)palladium (2.0 g, 1.7 mmol) and copper (I) iodide (0.49 g, 2.6 mmol) in N-methylpyrrolidine (50 mL; purged with N2) was heated to 60° C. The resulting solution was treated with the original amounts of both catalysts, two additional times, at 1.5 h intervals. After 22 h, the reaction mixture was filtered and concentrated. The resulting dark oil was treated with saturated aqueous NH4Cl (250 mL), extracted with chloroform (3×250 mL), dried (MgSO4) and concentrated to give a dark mixture of oil and foam (16.2 g). Flash chromatography (260 g silica; 5%, then 10%, then 20%, then 40% EtOAc-hexane) gave the title compound (5.2 g, 62% yield) as an impure yellow foam.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.ClC(Cl)([O:20][C:21](=[O:27])[O:22]C(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:21](=[O:20])([O-:27])[O-:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: OCCc1ccc(O)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C([O-])[O-]
Reaction time: 0.25 h

Procedure:
In a 500 mL 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 10 g (0.073 mol) of tyrosol, 24 ml (0.298 mol) of pyridine, 200 mL of DCM and stirred for 15 min to get a clear solution. Triphosgene (7.7 g, 0.078 mol of phosgene) was dissolved in 25 mL of DCM and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, 250 mL of water was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing was repeated with two additional 250 mL portions of DI water. The reaction mixture was then precipita-ted with 300 mL of IPA. The resulting gel was ground twice with 200 mL portions of IPA in 1 L laboratory blender. The product was isolated by vacuum filtration and dried in a vacuum oven at 60° C. The polymer had a HPSEC polystyrene equivalent molecular weight of 126 Kda (THF as mobile phase) and glass transition temperature (Tg) of 58° C. Compression molding at 195° C. gave a uniform transparent film which gave tensile modulus, tensile stress at yield, and elongation at break respectively of 19.1 ksi, 5 ksi and 450%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH:10]1([N:8]([CH3:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: CN(c1cccc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(c1cccc(C#C[Si](C)(C)C)c1)C1CC1
Yield: 83.8 %

Procedure:
Following General Procedure D and using (3-bromo-phenyl)-cyclopropyl-methyl-amine (Intermediate 113, 0.056 g, 0.25 mmol), triethyl amine (3 mL), copper(I)iodide (0.025 g, 0.13 mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.065 g, 0.09 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1.5% ethyl acetate in hexane as the eluent, the title compound (0.051 g, 84%) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([C:24](Cl)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:24]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([Cl:13])[CH:23]=3)=[O:25])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cc(Cl)nc2ccccc12

Procedure:
To 3.16 gm. (0.0195 mole) of 3-amino-1-cyclohexylpyrrolidine in 50 ml. of chloroform was added dropwise a solution of 3.5 gm. (0.015 mole) of 2-chloro-4-quinolinecarbonyl chloride in 50 ml. of chloroform. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The separated acid layer was made basic with dilute sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue recrystallized twice from isopropyl ether-ethyl acetate. The product (0.7 gm.; 13%) melted at 127°-219° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[Br:23]Br>C1COCC1.CC(OC)(C)C>[Br:23][C:15]1[S:14][C:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CCCCCc1ccc(-c2cccs2)cc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(Br)s2)cc1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
20.0 g (80.5 mmol) of 2-(3-fluoro-4-pentylphenyl)thiophene are initially introduced in 200 ml of THF, and 50.0 ml of n-BuLi (79.6 mmol, 15% soln. in hexane) are added dropwise to the solution at a temperature in the range 0-5° C. After 1 h at 0° C., the batch is cooled to −70° C., and 4.1 ml (80.0 mmol) of bromine are metered in. When the addition is complete, the mixture is stirred at 0° C. for 1 h. The batch is diluted with MTBE and washed successively with 2 N HCl, 10% sodium hydrogensulfite soln., sat. sodium hydrogencarbonate soln. and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to completion. The crude product is purified by column chromatography (SiO2, n-heptane). 2-Bromo-5-(3-fluoro-4-pentylphenyl)thiophene is obtained as a yellowish liquid.