Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][CH3:35])[CH2:29]1)([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:34]([CH2:33][CH:30]4[CH2:31][CH2:32][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29]4)[CH3:35])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCC1CCN(C(C)C)C1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CC3CCN(C(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(1-isopropylpyrrolidin-3-yl)-N-methylmethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (br. s., 5 H) 2.09 (br. s., 1 H) 2.42 (s, 3 H) 2.60-2.78 (m, 1 H) 2.90-3.09 (m, 4 H) 3.09-3.44 (m, 5 H) 7.44 (d, J=8.49 Hz, 1 H) 7.47 (s, 1 H) 7.76-7.80 (m, 1 H) 7.85 (d, J=7.33 Hz, 1 H) 8.30 (d, J=8.34 Hz, 1 H) 8.45 (br. s., 1 H) 8.55 (d, J=8.59 Hz, 1 H); ESI-MS m/z [M+H]+ 459.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37][Li]>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]([OH:12])[CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: [Li]C
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C(C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.1 %

Procedure:
To a solution of Intermediate AW (N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (25 mg, 0.05 mmol)) in THF (1 ml) at −78 C under N2 was added methyllithium (0.18 ml, 0.25 mmol) and stirred for 10 min. The reaction was quenched by the addition of H2O and after warming to rt, the reaction mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography (5:95 v/v MeOH—CH2Cl2) to afford 13 mg of the title compound (yield 50%). 1H-NMR (DMSO-d6) 9.32 (s, 1H), 8.97 (d, J=2 Hz, 1H), 8.63 (dd, J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.53 to 7.31 (m, 4H), 5.49 to 5.45 (m, 1H), 5.19 (d, J=6 Hz, 1H), 4.52 (d, J=10 Hz, 1H), 4.19 (d, J=10 Hz, 1H), 3.16 (s, 3H), 1.50 (d, J=6 Hz, 3H) ppm; MS [M+H]+=519.1; LCMS RT=2.74 min.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([NH:14][C:15]3[N:16]=[C:17]([N:25]4[CH2:30][CH2:29][N:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27](=[O:37])[CH2:26]4)[C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[C:39]1C2C(=CC=CC=2)C=C(NC(C2(C3C=CC(OC)=CC=3)CC2)=O)N=1.C1(N2CCNCC2=O)C=CC=CC=1>>[CH3:39][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([NH:14][C:15]3[N:16]=[C:17]([N:25]4[CH2:30][CH2:29][N:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27](=[O:37])[CH2:26]4)[C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:13])[CH2:10][CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)Nc3cc4ccccc4c(N4CCN(c5ccccc5)C(=O)C4)n3)CC2)cc1
Reactant: COc1ccc(C2(C(=O)Nc3cc4ccccc4c(Br)n3)CC2)cc1
Agent: O=C1CNCCN1c1ccccc1
Product: Cc1ccc(C2(C(=O)Nc3cc4ccccc4c(N4CCN(c5ccccc5)C(=O)C4)n3)CC2)cc1

Procedure:
1-(4-methoxyphenyl)-N-(1-(3-oxo-4-phenylpiperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide and 1-phenylpiperazin-2-one.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2=[CH:9][CH2:10][S:11][C:6]2=[CH:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.CO>O1CCCC1>[S:11]1[C:6]2[CH2:5][N:4]3[CH:12]=[CH:13][CH:14]=[C:3]3[CH2:2][NH:8][C:7]=2[CH:9]=[CH:10]1
Reactant: O=C1NC2=CCSC2=Cn2cccc21
Solvent: CO
Solvent: C1CCOC1
Product: c1cc2n(c1)Cc1sccc1NC2
Temperature: 25 °C

Procedure:
To a suspension of 7.0 g of 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10M boranedimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed to give a solid.
Reaction SMILES: N([O-])=O.[Na+].[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][C:15]=2N)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[ClH:24]>O>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][C:15]=2[Cl:24])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c(N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c(Cl)c1
Reaction time: 2 h

Procedure:
A solution of 4.5 g of sodium nitrite in 10 ml of water is added dropwise at 0°, with stirring, to a suspension of 16 g of N-acetyl-4-(2-amino-4-acetyl-phenyl)-piperidine in 75 ml of concentrated hydrochloric acid and 75 ml of water; stirring is continued at 0° for 2 hours; the reaction solution, which is now clear, is transferred to a dropping funnel precooled to 0°, and is slowly added dropwise to a solution, cooled to 0° and being stirred, of 16 g of copper-I-chloride in 150 ml of semi-concentrated hydrochloric acid. Stirring is maintained at 15° until the evolution of nitrogen has ceased (about 1 hour). An addition of 300 ml of water is made, and extraction is performed three times with 150 ml of ethyl acetate each time. The organic phases are extracted three times at 0° with 150 ml of 2 N sodium hydroxide solution each time; they are then cleared by filtration, washed neutral, dried over sodium sulphate and concentrated in vacuo. The oily N-acetyl-4-(2-chloro-4-acetyl-phenyl)-piperidine obtained in this manner can be used without purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][CH2:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(N3CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[3-(piperazin-1-yl)-pyridin-5-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 170, triethylamine (42.3 uL, 0.30 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:6])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][N:10]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:9][CH2:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 92 %

Procedure:
The above 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester (606 mg, 3.82 mmol) was mixed with 2-chloro-5-nitropyridine (760 mg, 3.82 mmol) in 10 mL of tetrahydrofuran. To this solution was added diisopropylethylamine (1.33 mL). The mixture was heated in a microwave at 140° C. for 30 minutes. Solvents were evaporated and the residue was extracted with methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-methyl-2-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid ethyl ester as a solid (1.13 g, 92%). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]2[NH:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:31]=2)[CH2:27]1>>[Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:26]4[CH2:27][CH:28]([C:30]5[N:31]=[C:32]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:33][N:34]=5)[CH2:29]4)=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: O=Cc1ccc(-c2nc3ncc(Cl)n3cc2-c2ccccc2)cc1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: Cl
Product: Clc1cnc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn12
Yield: 52 %

Procedure:
200 mg (0.6 mmol) 4-(3-chloro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)benzaldehyde was reacted with 197 mg (0.72 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazol-3-yl)-pyridine hydrochloride salt according to the procedure in example 1. After four and a half hours the reaction mixture was worked up and purified in the usual way as described in example 1. 162 mg of the desired product were obtained
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1I.F[P-](F)(F)(F)(F)F>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([C:17]([O:16][CH3:15])=[O:29])=[CH:19][C:20]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Reactant: Oc1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a solution of 4-fluorophenol (1.25 g, 11.15 mmol) in toluene (50 mL) was added cesium carbonate (6.10 g, 18.7 mmol) and the mixture was stirred for 15 min at rt. 2-Iodoterephthalic acid dimethyl ester (3.0 g, 9.37 mmol) and tetrakisacetonitrilecopper hexafluorophosphate (435 mg) were added, and the mixture was heated to reflux for 18 h. The mixture was allowed to cool to rt and poured into an ice-cold saturated ammonium chloride solution. The organic layer was separated, washed with a saturated potassium carbonate solution and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified via flash column chromatography (elent gradient 1% to 20% EtOAc in heptane) to yield 1.25 g (43.8%) of title compound 2-(4-fluorophenoxy)-terephthalic acid dimethyl ester, 1e. MS m/z (MH+) 305.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[C:4](Cl)[N:3]=1>C1COCC1.CCN(CC)CC.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1

Procedure:
24.4 g (77.5 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid in 3.5 l THF and 100 ml Et3N are hydrogenated in the presence of 15 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off and washed extensively with THF. Partial concentration of the filtrate precipitates the title compound: MS: [M+1]+=282.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCC#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C#CCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A solution of 3-(4-fluorophenyl)prop-2-yn-1-ol (1 g, 6.80 mmol) in DCM (13.6 mL) under N2 was cooled in a ice bath at 0° C. 2.70 g (8.2 mmol, loading 3 mmol/g) of triphenylphosphine polymer supported was then added followed by 2.70 g (8.2 mmol) of carbon tetrabromide. The reaction mixture was stirred 15 min at 0° C. and warmed to room temperature for 90 min. After filtration through celite, the solvent was evaporated under reduce pressure. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.44 g of 1-(3-bromoprop-1-ynyl)-4-fluorobenzene as a yellow oil (Yield: 99%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F-].[K+].[CH:19]1([CH2:22][S:23][C:24]2[S:25][C:26]([SH:29])=[N:27][N:28]=2)[CH2:21][CH2:20]1>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:29][C:26]1[S:25][C:24]([S:23][CH2:22][CH:19]3[CH2:20][CH2:21]3)=[N:28][N:27]=1)=[N:3]2
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: Sc1nnc(SCC2CC2)s1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(SCC2CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (65 mg, 0.23 mmol) in DMF (4 ml) was added potassium fluoride 40% wt on alumina (103 mg, 0.71 mmol) followed by addition of 2-cyclopropylmethylsulfanyl-5-mercapto-1,3,4-thiadiazole (53 mg, 0.26 mmol). The reaction was stirred overnight at room temperature. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:20 affording the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:14]=[C:13]([CH:12]([CH3:15])[CH3:11])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(I)c(O)c1
Reactant: C#CC(C)C
Product: COc1ccc2cc(C(C)C)oc2c1
Yield: 38 %

Procedure:
Example 15(a) was prepared from 2-iodo-5-methoxyphenol (896 mg, 3.6 mmole) and 3-methyl-1-butyne in a manner as previously described for example 12a to give 265 mg (38%) of an amber oil. 1H NMR (CDCl3) δ 7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.07–3.01 (1H, m), 1.31 (6H, d, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:13]([O:17][C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.Cl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:24])[CH:19]([NH:20][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:21]([CH3:22])[CH3:23])([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (20 g, 0.070 mol) and (L)-valine-tert-butyl ester, hydrochloride (16.4 g, 0.078 mol) in aqueous tetrahydrofuran (400 mL, 1:1) was added dropwise triethylamine (15.6 g, 0.15 mol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with aqueous HCl (1M, 300 mL) and ethyl acetate (300 mL). The layers were separated and the organic portion was washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo leaving a white solid. The crude product was recrystallized from hexane/ethyl acetate to give the title compound as white crystalline needles. Yield: 19.7 g (67%); mp 108°-110°;
Reaction SMILES: C(C(CCCC)C([O-])=O)C.[Na+:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][C:44]1[N:45]=[C:46]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:47][C:48]=1[CH3:49])[CH2:17][N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH:34]([CH3:38])[C:35]([OH:37])=[O:36])[C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][C:44]1[N:45]=[C:46]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:47][C:48]=1[CH3:49])[CH2:17][N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH:34]([CH3:38])[C:35]([O-:37])=[O:36])[C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2.[Na+:11]
Reactant: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)[O-])cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium 2-ethylhexanoate (479 mg) was added to the solution of 1.5 g of 4-{9-[3-methoxy-4-((5-methyl-2-phenyl-oxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-methyl-butyric acid prepared by the example 52(b) in ethyl acetate (15 mL) at room temperature. After stirring at room temperature for 30 minutes, the precipitate was isolated by filtration, washed with ethanol, dried under reduced pressure, and 1.49 g of the subject compound was prepared as white powder. Optical purity>99% ee (HPLC)
Reaction SMILES: C(O[CH:4](OCC)[CH:5]([NH:7]/[C:8](/[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)=[CH:9]\[C:10]#[N:11])[CH3:6])C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:21][O:20][C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:8]2[NH:7][C:5]([CH3:4])=[CH:6][C:9]=2[C:10]#[N:11])=[CH:17][CH:16]=1)=[O:19]
Reactant: CCOC(OCC)C(C)N/C(=C\C#N)c1ccc(C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2[nH]c(C)cc2C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture (117.0 g) of (E)-3-(2,2-diethoxy-1-methylethylamino-3-(4-methoxycarbonylphenyl)acrylonitrile and (Z)-3-(2,2-diethoxy-1-methylethylamino)-3-(4-methoxycarbonylphenyl)acrylonitrile was treated with trifluoroacetic acid (200 ml) at 0° C. for 30 minutes and then at ambient temperature for 30 minutes. To the mixture ethyl acetate (300 ml) was added at 0° C. and this mixture was stirred at 0° C. for 15 minutes. The precipitates were collected by vacuum filtration to afford 2-(4-methoxycarbonylphenyl)-5-methylpyrrole-3-carbonitrile as an orange powder (54.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1>ClCCCl>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([N:1]2[CH:23]=[CH:27][CH:26]=[CH:25]2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC1CCC(OC)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc(-n3cccc3)cc2)cc1
Temperature: 75 °C
Yield: 61.8 %

Procedure:
To a solution of 4-aminobiphenyl (1.0 g, 5.9 mmol) in 1,2-dichloroethane (20 mL) was added TFA (0.46 ml, 5.9 mmol). To the resultant suspension of the TFA salt was added 2,5-dimethoxy-tetrahydrofuran (0.92 mL, 7.1 mmol). The suspension was heated at 75° C. for 17 hours. The mixture was allowed to cool, partitioned between EtOAc and 1 M pH 7 phosphate buffer, and the aqueousueous layer was extracted again with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to a crude residue, which was purified via flash column chromatography with 10-25% CH2Cl2/hex gradient eluent. The purified material was triturated with MTBE/hex to give 800 mg(62%) of N-biphenyl-4-yl-1H-pyrrole as an off-white solid, mp190-2° C. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.61 (d, 2H, J=7.0 Hz), 7.48-7.43 (m, 4H), 7.36 (t, 1H, J=7.0 Hz), 7.14 (t, 2H, J=2.0 Hz), 6.37 (t, 2H, J=2.0 Hz). Anal. Calculated for C16H13N: C, 87.63; H, 5.98; N, 6.39. Found: C, 87.48; H, 6.01; N, 6.30.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:39])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20](=[O:27])[N:19]4CC4C=CC(OC)=CC=4OC)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:39])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20](=[O:27])[NH:19]4)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc(CN2C(=O)c3ccccc3C23CCN(CC(=O)N2CCN(C4CCC4)CC2)CC3)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2)c2ccccc21
Temperature: 60 °C

Procedure:
At 0° C., 1′-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-2-(2,4-dimethoxybenzyl)spiro [isoindole-1,4′-piperidin]-3(2H)-one (1.4 mmol) is added to trifluoroacetic acid (10 ml) and the resulting solution is heated at 60° C. for 4 h. Solvent is removed and the residue is partitioned between aqueous NaHCO3 solution (20 ml) and EtOAc (20 ml). The layers are separated and the aqueous layer is extracted with EtOAc (20 ml). The combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give the title compound as a off-white solid. LC-MS (M+1): 382.2.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:14](=[O:16])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[CH3:18])=[CH:63][N:64]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)O
Reactant: Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Intermediate 3 (Example 5) (0.070 g, 0.215 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.046 g, 0.26 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.05 mL, 0.43 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 23 (Example 31) (0.074 g, 0.226 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.027 g, 20%).