Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:11][C:12]=1[Br:13]
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncc(CO)cc1Br
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of ethyl 6-amino-5-bromonicotinate (2.31 g, 10 mmol) in tetrahydrofuran (20 mL) at RT was added LAH (10 mL, 1M in tetrahydrofuran) dropwise. After stirring for 1 h, the mixture was quenched with water (0.2 mL) and the resultant precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford (6-amino-5-bromopyridin-3-yl)methanol (2.0 g, 99%) as a solid. LC/MS; (M+H)+=203, 205 (1:1 ratio). 1H NMR (CD3OD, 300 MHz) δ 7.79 (s, 1H), 7.67 (s, 1H), 4.35 (br S, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH:20]([CH2:25][C:26](OCC)=[O:27])[C:19]=3[CH:18]=[N:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15].O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH:20]([CH2:25][CH2:26][OH:27])[C:19]=3[CH:18]=[N:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CCOC(=O)CC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of DlBALH (1 M) in toluene (13 mL, 13.0 mmol) is slowly added, maintaining the reaction temperature under −65° C., to a solution of ethyl 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)acetate (1.83 g, 5.2 mmol) in 20 mL of dried Cl2CH2 cooled at −75° C. under N2 atmosphere. The resulting mixture is maintained under stirring at −70° C. during 30 minutes, effecting a follow-up of the reaction by TLC. Next, the temperature is raised to 0° C., and 10 mL of cold water are added, while the temperature is maintained at 0° C. A precipitate is formed, which is filtered and washed with Cl2CH2. The organic phase is washed twice with water, dried, and evaporated under reduced pressure. The resulting crude is purified by silica-gel chromatography, giving 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (1.06 g, 3.41 mmol, 66%, oil).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)C=Cc1ccncc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccncc1
Yield: 93 %

Procedure:
3-(4-Pyridyl)acrylic acid (16.18 g, 0.1085 mol) was slurried in 200 ml of absolute ethanol. Concentrated sulfuric acid (8 ml) was added and the reaction was refluxed for 3 hours. After cooling, the solvent was evaporated and the residue was cautiously neutralized with saturated sodium bicarbonate solution. The resulting mixture was then extracted twice with diethyl ether. The organic extracts were washed with water and then brine, dried over MgSO4 and concentrated to afford 17.88 g (93% yield) of the subtitle compound.
Reaction SMILES: [Na+].[CH:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:5]=[C:4]([S:16]([O-:19])(=O)=[O:17])[CH:3]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[CH:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:5]=[C:4]([S:16]([Cl:22])(=[O:19])=[O:17])[CH:3]=1
Reactant: O=S(=O)([O-])c1ccc2ccc3c(c2c1)CCCC3
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2ccc3c(c2c1)CCCC3
Temperature: 60 °C

Procedure:
5,6,7,8-Tetrahydrophenanthrene-3-sulfonic acid sodium salt (1 g, 3.68 mmol) is suspended in 5 mL of thionyl chloride. DMF (2 drops) is added and the solution is heated to 60° C. for 30 minutes. After this time, the reaction mixture is concentrated. The residue is triturated with CH2Cl2 and the resulting solid is filtered off. The collected organic solution is concentrated. The crude product is purified by column chromatography eluting with 10% EtOAc/hexanes to give the title compound (0.60 g, 2.3 mmol) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:26](O)(=O)[CH3:27]>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.009 moles), glacial acetic acid (20 ml), and sodium borohydride (2.5 g, 0.066 moles). The free base is obtained crystalline. Recrystallization from isopropyl ether gave the product (1.9 g), mp 83°-85° C.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[OH:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[Si:5]([O:14][CH:15]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:16]([O:18][CH3:19])=[O:17])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
TBDMSCl (1.5 g, 9.94 mmol) and imidazole (1.0 g, 14.6 mmol) were added to a solution of methyl hydroxy-(4-methoxyphenyl)acetate (Teodozyj Kolasa et al., J. Org. Chem., 1987, 22, 4978-4984) (1.3 g, 6.62 mmol) in DMF (8 mL) and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (2.0 g, 97%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[CH:6]=[N:5][CH:4]=1)[CH3:2].B(Br)(Br)Br.[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cncc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCc1cncc2ccc(O)cc12
Yield: 62.7 %

Procedure:
1.69 g of 4-Ethyl-6-methoxy-isoquinoline (153) were dissolved in dichloroethane and stirred with 1.7 mL of boron tribromide at room temperature for 3 hours and one additional hour at 40° C. The solution was poured on ice water, pH was adjusted to 9 by addition of sodium hydroxide and the solution was extracted with dichloromethane:isopropanol 3:1. The organic layer was evaporated to dryness and the product was purified by silica gel chromatography to yield 980 mg of 154. Detected Mess: 173.9 (M+H+) (ESI)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]1
Reactant: O=C1CC=C(c2ccccc2Cl)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(c2ccccc2Cl)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 2 by the hydrogenation of 6.5 grams (0.026 mole) of 1-(2-chlorophenyl)-1-cyclohexen-4-one in the presence of 0.4 gram (catalyst) of 10% palladium on charcoal in 50 mL of ethanol, yielding 4-(2-chlorophenyl)cyclohexanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[OH-].[K+]>CS(C)=O.O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: N#Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccc(C#N)cc2)c1
Yield: 49.3 %

Procedure:
A solution of ethyl 3-hydroxyphenylacetate (28 g, 0.15 mole) and 4-fluorobenzonitrile (25 g, 0.21 mole) in dimethylsulfoxide (150 ml) was stirred with 87% potassium hydroxide (10 g, 0.15 mole) at 75-80° C. for 80 minutes under nitrogen. The resulting mixture was allowed to cool, diluted with water (1000 ml), and extracted with diethyl ether (2×50 ml). The organic solution was washed with water (100 ml), dried (MgSO4), concentrated in vacuo and the residue eluted on silica gel (500 g) with ethyl acetate:hexane (0 to 1:6). A solution of the product in diethyl ether (125 ml) was washed with 1N NaOH (15 ml) to remove some residual phenol, dried (K2CO3 and MgSO4), and concentrated in vacuo to give ethyl 3-(4-cyanophenyloxy)phenylacetate (20.8 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.18 (t, J=7 Hz, 3H, CH3), 3.71 (s, 2H, Ar CH2), 4.08 (q, J=7 Hz, 2H, ester CH2), 7.02-7.13 (m, 4H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 7.85 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C17H15NO3 : C, 72.58; H, 5.37; N, 4.98. Found: C, 72.67; H, 5.43; N, 4.94.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][CH2:6][CH2:7][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][CH3:23])[CH2:2]1.[SH:24][CH2:25][CH2:26][OH:27].C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[OH:1][CH:3]([CH2:4][O:5][CH2:6][CH2:7][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][CH3:23])[CH2:2][S:24][CH2:25][CH2:26][OH:27]
Reactant: OCCS
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(O)CSCCO
Reaction time: 2 h

Procedure:
In toluene (5 ml) were dissolved 1,2-epoxy-3-octadecyloxypropane (9.85 g), 2-mercaptoethanol (2.4 g) and triethylamine (1.5 ml), and the solution was stirred for 2 hours at 55°-60 ° C. The reaction mixture was cooled, and then ethyl acetate (100 ml) and hexane (100 ml) were added. The mixture was washed with 0.001 N sodium hydroxide (50 ml) and water (50 ml). The solvent was distilled off under reduced pressure to give a crude product of 2-(2-hydroxy-3-octadecyloxypropylthio)ethanol. The whole amount of this crude product was dissolved in pyridine (25 ml). To the solution was added triphenylmethyl chloride (12.5 g), and the mixture was stirred for 13 hours at 50 ° C. To the reaction mixture was added methanol (10 ml), and the resulting mixture was stirred at 60 ° C. for 0.5 hour, and then the mixture was concentrated to dryness. The residue was dissolved in a mixture of ethyl acetate (100 ml) and hexane (100 ml). The solution was washed with water, and concentrated to dryness under reduced pressure. The residue was purified by means of a silica gel column chromatography [carrier; 700 g, developing solvent ; hexane: ethyl acetate =9:1-4:1] to obtain the above-titled compound (13.4 g).
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C1C=CC=CC=1)C=C2)C(O)=O)(C)(C)C.[C:37]([O:41][C@@H:42]([C:48]1[C:49]([C:69]2[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([C:59](=[O:68])[N:60]([CH3:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH:52]=[CH:51]2)[C:43]([O:45]CC)=[O:44])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C@@H:42]([C:48]1[C:49]([C:69]2[CH:70]=[CH:71][C:72]([Cl:75])=[CH:73][CH:74]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([C:59](=[O:68])[N:60]([CH3:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH:52]=[CH:51]2)[C:43]([OH:45])=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)N(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(C(=O)N(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl)quinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)acetic acid of Example 14, except that (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl)quinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl) quinolin-6-yl)acetate. 1H-NMR 300 MHz, (CD3OD) δ 7.80-7.50 (m, 6H), 7.40-7.10 (m, 6H), 5.16 (s, 1H), 3.54 (s, 3H), 2.62 (s, 3H), 0.95 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C30H30ClN2O4: 518.0. Found: 517.2, 519.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25](=[O:57])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]2[C@@H:37]([S:38]SC3C([N+]([O-])=O)=CC=CN=3)[C:36](=[O:49])[N:35]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].CCN(CC)CC.Br[CH2:66][C:67]([C:69]1[CH:77]=[CH:76][C:72]2[CH2:73][CH2:74][O:75][C:71]=2[CH:70]=1)=[O:68]>CC(C)=O.O>[C:20]([O:24][C:25](=[O:57])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]2[C@@H:37]([S:38][CH2:66][C:67]([C:69]3[CH:77]=[CH:76][C:72]4[CH2:73][CH2:74][O:75][C:71]=4[CH:70]=3)=[O:68])[C:36](=[O:49])[N:35]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)=[CH:30][CH:29]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)OCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCC4)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
Triphenyl phosphine (50 mg, 0.191 mmol) was added to a solution of {4-[(2R,3R)-1-(4-fluoro-phenyl)-3-(3-nitro-pyridin-2-yldisulfanyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetic acid tert-butyl ester (100 mg, 0.179 mmol) in acetone/water (3 mL/0.5 mL) at room temperature. The mixture was stirred for 15 min. The solvent was removed under reduced pressure and the residue was dissolved in DCM (3 mL). Et3N (75 μL, 0.534 mmol) and 2-bromo-1-(2,3-dihydro-benzofuran-6-yl)-ethanone (91 mg, 0.377 mmol) were added and the solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of 40-80% MeCN in a 0.1M ammonium acetate buffer as eluent. The pure fractions were pooled and most of the MeCN was removed under reduced pressure. The residue was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4 and concentrated. The title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[N:33]=2)=[CH:28][CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].C(N(CC)CC)C>CS(C)=O.CCOC(C)=O.[Cu]I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:27][CH:28]=4)=[N:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)nc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 135 °C
Reaction time: 20 h
Yield: 56.6 %

Procedure:
A suspension of tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (105 mg, 0.28 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one (50 mg, 0.18 mmol), 8-hydroxyquinoline (6 mg, 0.04 mmol) and Cs2CO3 (0.12 g, 0.37 mmol) in DMSO (5.0 mL) was degassed under reduced pressure for 30 min. CuI (61.9 mg, 0.33 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. Triethylamine (0.025 mL, 0.18 mmol) was added to the above solution. The resulting suspension was stirred at 135° C. for 20 h. The reaction mixture was cooled and diluted with EtOAc. The resulting solution was washed sequentially with aqueous ammonium chloride and aqueous LiCl (5%), dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was dissolved in DCM, treated with charcoal and purified by preparative TLC (DCM/MeOH 95:5) to afford the title compound (55.0 mg, 72%) as a brown yellow solid and as a mixture of rotamers: 1H NMR (500 MHz, CDCl3) δ 9.35 (d, J=1.5 Hz, 1H), 8.75 (d, J=8.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 0.3H), 7.59 (d, J=8.5 Hz, 0.7H), 7.40 (s, 1H), 7.09-7.06 (m, 1H), 6.93 (d, J=7.0 Hz, 1H), 4.72 (s, 0.7H), 4.64 (s, 1.3H), 3.79-3.67 (m, 2H), 3.69 (s, 3H), 2.99-2.97 (m, 2H), 2.08-2.02 (m, 2H), 1.44 (s, 3.3H), 1.38 (s, 5.7H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K62) (286 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown foam (433 mg, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:11])[CH3:10].[H-].[Na+].[CH2:14]([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1>[C:9]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:30]=1)(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)Cl)c1
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)N(Cc2ccccn2)C(C)=O)c1

Procedure:
The title compound prepared by the procedure of Example 27 using 0.462 g of product from Example 12 in 4 ml of dry tetrahydrofuran, 0.147 g of washed 50% sodium hydride and 1.03 g of product from Example 26 in 4 ml of dry tetrahydrofuran. The residue is purified by column chromatography (silica ge1:35% ethyl acetate/hexane) to give 0.178 g of the desired product as a yellow oil which crystallized on standing.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:21](=O)[CH3:22])[C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16].[NH2:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]#[N:28].CC(C)([O-])C.[K+]>CC(O)C>[C:27]([C:26]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:21]([CH3:22])[NH:24][C:25]=1[C:29]([F:32])([F:31])[F:30])#[N:28]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CCCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C#N)C1c1cccc2c(=O)cc(C)oc12

Procedure:
A solution of 295 mg (0.94 mmol) of propyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate in 20 ml of 2-propanol is mixed with 127.71 mg (0.94 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to K. Krespan, J. Org. Chem. 34, 4245 (1969)] and 15.8 mg (0.14 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). After concentration of the product fractions, the residue is crystallized from diethyl ether. 88.4 mg (20.7% of theory) of the title compound are obtained as white crystals.
Reaction SMILES: I[C:2]1[C:3]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C.O.[Cu](I)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>[CH3:13][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([C:32]#[C:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:4]1
Reactant: C#Cc1ccccc1
Reactant: Cn1nc(N2C(=O)c3ccccc3C2=O)c(I)c1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nc(N2C(=O)c3ccccc3C2=O)c(C#Cc2ccccc2)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Nitrogen was bubbled through a mixture of 2-(4-iodo-1-methyl-5-phenyl-pyrazol-3-yl)isoindoline-1,3-dione (660 mg, 1.49 mmol), phenyl acetylene (182 mg, 1.78 mmol), triethylamine (8 mL) and DMF (3 mL) for 15 min. Copper iodide (28 mg, 0.149 mmol) and bis(triphenylphosphine)palladium(II) dichloride (52 g, 0.074 mmol) were added and the reaction mixture was stirred at 90° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 8:2 to 6:4) yielding the title compound as a solid (600 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 94 %

Procedure:
Beginning with 0.01 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0066 mL (0.048 mMol) pentanoyl chloride, 0.013 gm (91%) of the title compound were prepared essentially by the procedure described in Example 7.