Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28](O)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:27][C:28](=[O:29])[NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (10 ml) was dissolved 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (1.00 g), followed by the addition of carbonyldiimidazole (1.06 g). The resulting mixture was heated overnight under reflux. After cooling to room temperature, methanesulfonamide (415 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.64 ml) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Dichloromethane was added to the residue and the resulting mixture was washed successively with 1N hydrochloric acid, and saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ3.0×10.0 cm, dichloromethane:methanol=100:1), whereby the title compound (518 mg, 44%) was obtained as colorless foam.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[CH2:3][CH:4]([N:10]([CH2:27][C:28]1[C:43]([O:44][CH3:45])=[CH:42][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:30][C:29]=1[O:46][CH3:47])[C:11](=[O:26])[C@H:12]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:13][C:14](=[O:21])[C@H:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:16])[CH:5]([O:8][CH3:9])[O:6][CH3:7].[C:50](=O)([O-])[O-:51].[K+].[K+].[CH:56]1[C:68]2[CH:67]([CH2:69][O:70]C(ON3C(=O)CCC3=O)=O)[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]=2[CH:59]=[CH:58][CH:57]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[CH:65]1[C:66]2[CH:67]([CH2:69][O:70][C:50]([NH:16][C@H:15]([C:14]([NH:13][C@H:12]([C:11]([N:10]([CH2:27][C:28]3[C:43]([O:44][CH3:45])=[CH:42][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:30][C:29]=3[O:46][CH3:47])[CH:4]([CH:5]([O:8][CH3:9])[O:6][CH3:7])[CH2:3][C:2]([F:48])([F:1])[F:49])=[O:26])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])=[O:51])[C:68]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]=2[CH:62]=[CH:63][CH:64]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCCOc1cc(OC)c(CN(C(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)C(C)(C)C)C(CC(F)(F)F)C(OC)OC)c(OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OCCCCC(=O)O)cc(OC)c1CN(C(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C)C(CC(F)(F)F)C(OC)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.6 %

Procedure:
4.0 g (5.7 mmol) of ethyl 5-[4-[[N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]-N-[N-(3-methyl-L-valyl)-L-leucyl]-amino]methyl]-3,5-dimethoxyphenoxy]-valerate were dissolved in 40 ml of methanol. 2.4 g (17.3 mmol) of potassium carbonate and 8.0 ml of water were then added and the mixture was stirred for 2 days at room temperature. The solvent was removed by evaporation and the residue was dissolved in 20 ml of water and 20 ml of dioxan. 2.9 g (8.6 mmol) of N-[(9-fluorenyl)-methoxycarbonyloxy]-succinimide were then added and the mixture was stirred for 3 hours. The mixture was adjusted to pH 3 with 10% citric acid and then washed with three equal aliquots of dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using 4% tert-butyl methyl ether in dichloromethane for the elution. There were obtained 5.12 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]valeric acid as a white foam; MS: m/e 870.8 [M+H-MeOH], 888.7 [M+H-CH3 ], 889.7 [M-CH3 ]902.7 [M+H], 924.7 [M+Na].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C1(C2[O:21]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:12])=[O:21])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(Cl)c1C#N
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred suspension of 2.00 g (9.97 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 6 ml dichloromethane and 20 ml DMF was added 5.21 g (19.9 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue recrystallised from ether/dichloromethane to afford 1.50 g (69%) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 239 (M+Na+, 45), 234 (M+NH4+, 55), 217 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>C(O)C.O.CCOC(C)=O>[CH2:16]([NH:18][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)[CH3:17]
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: CCN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNc1cc(Oc2ccc(N)cc2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 5.0 g, 22.6 mmol) in ethylamine dissolved in ethanol (≈35%; 5 ml) under Nratmosphere is stirred for 16 h at rt. Then the resulting brown solution is diluted with water and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with 3 portions of water and brine, dried (Na2SO4) and concentrated. Re-crystallisaton from boiling AcOEt gives the title compound: m.p.: 143-145° C.; 1H-NMR (CDCl3): 8.24 (s, 1H), 7.24 (s, HN), 6.91 (d, 2H), 6.69 (d, 2H), 5.63 (s, 1H), 4.97 (s, H2N), 3.25 (m, 2H), 1.25 (t, 3H). More product can be isolated from the filtrate of the re-crystallization by column chromatography (SiO2; AcOEt→AcOEt/EtOH 19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:7]1[C:2]([Cl:1])=[C:3]([C:17]#[N:18])[C:4](=[O:16])[N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)c(Br)cn(-c2c(F)cccc2F)c1=O
Temperature: 50 °C
Yield: 43.8 %

Procedure:
To a solution of 4-chloro-1-(2,6-difluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (670 mg) in N,N-dimethylformamide (5.0 mL) was added N-bromosuccinimide (548 mg) at room temperature. The reaction mixture was heated at 50° C. for 4 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg).
Reaction SMILES: [Cl-].C[Al+]C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.C[O:14][C:15]([C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[O:24]2)=[C:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH:18]=1)=O.C[O:39][C:40]([C:42]1[C:43]2[CH2:44][CH2:45][C:46]([CH3:62])([CH3:61])[O:47][C:48]=2[CH:49]=[C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[Cl:60])[CH:51]=1)=O>>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[O:24]3)=[C:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH:18]=2)=[O:14])=[N:10][CH:11]=1.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:40]([C:42]2[C:43]3[CH2:44][CH2:45][C:46]([CH3:62])([CH3:61])[O:47][C:48]=3[CH:49]=[C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=3[Cl:60])[CH:51]=2)=[O:39])=[N:10][CH:11]=1
Reactant: COC(=O)c1cc(OCc2ccccc2Cl)cc2c1CCC(C)(C)O2
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)c1cc(OCc2ccccc2Cl)c2c(c1)OC(C)(C)CC2
Agent: C[Al+]C
Agent: [Cl-]
Product: Cc1ccc(NC(=O)c2cc(OCc3ccccc3Cl)c3c(c2)OC(C)(C)CC3)nc1
Product: Cc1ccc(NC(=O)c2cc(OCc3ccccc3Cl)cc3c2CCC(C)(C)O3)nc1
Yield: 10 %
Yield: 23 %

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from dimethylaluminum chloride (1.0 M in hexanes, 2.9 mL, 2.9 mmol), 5-methyl-2-aminopyridine (314 mg, 2.9 mmol), and a mixture of 5-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid methyl ester and 7-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid methyl ester (374c) (crude 104 mg). Purification by reverse phase chromatography gave 5-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid(5-methyl-pyridin-2-yl)-amide (374) (11 mg, 10% yield) and 7-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid(5-methyl-pyridin-2-yl)-amide (375) as a white solid (25 mg, 23% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC#N.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>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([N:8]3[C:6]4=[N:7][C:2]([C:24]5[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=5)=[CH:3][N:4]=[C:5]4[N:10]=[CH:9]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Brc1cnc2ncn(-c3ccc4[nH]ccc4c3)c2n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3ncn(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
Following a method described in Pteridines, 2002, Vol. 13, 65-72, Intermediate BB was heated in anhydrous DMF at 175° C. for 15 min. in a Personal Chemistry Optimizer. To the resulting 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazine 1 in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 4.7 mg of the title compound. HPLC retention time: 2.43 minutes; MS ESI (m/z): 402.8 (M+1)+, calc. 401.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=[C:23]([Cl:31])[N:22]=1>CN(C)C=O>[ClH:31].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:23]1[N:22]=[C:21]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)nc2c1CCCC2
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc2c(c(N3CCc4ccccc4C3C)n1)CCCC2
Product: Cl
Yield: 55.1 %

Procedure:
After 4-fluoro-2-methylaniline(0.60 ml, 5.4 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline(0.75 g, 2.40 mmol) and dimethylformamide(5 ml), 0.58 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(F)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(F)c(Br)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
A solution of 3-bromo-4-fluorophenol (4.5 g, 23 mmol) [Ark Pharm, AK-26802] in dichloromethane (96 mL) at 0° C. was treated with triethylamine (4.9 mL, 35 mmol) followed by acetyl chloride (2.3 mL, 33 mmol) dropwise and stirred at 20° C. for 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL), washed with 0.5 M hydrogen chloride in water (100 mL), saturated sodium bicarbonate (100 mL), and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (5.5 g, quantitative) as a tan solid. This material, which did not ionize in the mass spectrometer, was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[Mg+].[Br-].[CH2:21](OCC)C>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([C:10]([OH:11])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOCC
Reactant: Cn1cncc1C(=O)c1ccc(C#N)c(F)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile (as described above in Step C) (0.603 g, 2.63 mmol) was dissolved in anhydrous THF (30 mL). A solution of 3.0M MeMgBr in diethyl ether (2.55 mL, 7.65 mmol) was added and stirred for 15 min. The reaction was quenched with NH4Cl solution, diluted with CH2Cl2 and saturated NaHCO3 solution and seperated. The aqueous layer was back extracted with CH2Cl2 (3×), the combined organic layers dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH2:28])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH:28][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)ccn1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Cl)ccn1
Yield: 81.8 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.26 g, 85%) was prepared by following general procedure A from commercially available 4-chloro picolinic acid (0.7 g, 4.4 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[Cl:18][C:17]1[C:12]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([CH:9]([CH3:11])[CH3:10])[C:23](=[O:24])[NH:1][C:2]=3[CH:3]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: CC(C)Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21

Procedure:
37.4 g of 2-[3-amino-4-(1-methylethylamino)-phenyl]-3-chloro-5-trifluoromethylpyridine and 27.6 g of carbonyldiimidazole were heated at reflux temperature for four hours in 200 ml of anhydrous tetrahydrofuran, after which the reaction mixture was concentrated. The residue was treated with 100 ml of 10% strength hydrochloric acid and the mixture was extracted three times with 100 ml of methylene chloride each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. The crude product was stirred with ether, then separated off and dried. Yield: 29.8 g (74%) of colorless crystals; m.p.: 192-193° C.
Reaction SMILES: C(O)C.C1N2CN3CN(C2)C[N:5]1C3.N.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)=[O:18]>C(Cl)(Cl)Cl>[C:24]1([C:22]2[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[NH:19][C:17](=[O:18])[CH2:16][N:5]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A mixture of ethanol (300 ml) and hexamethylenetetramine (20 g., 0.143 mol) was stirred, heated to reflux, and saturated with ammonia. 2-Chloroacetamidobenzophenone (18.1 g., 0.066 mol) was added in small increments over 3 to 4 hours while a steady stream of ammonia was bubbled into the reaction mixture. Refluxing was continued for 3 hours after complete addition of 2-chloroacetamidobenzophenone. The flow of ammonia was interrupted and the ethanol removed by distillation in vacuo. The residue obtained was taken up in chloroform (200 ml), and washed with water (100 ml) at 50° C. The chloroform layer was evaporated to dryness at 30° C. and the oily solid obtained was recrystallized from toluene (100 ml) to give 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (13.2 g., 86%), melting at 184°-186° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:7][CH:8]=1)=O.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:16][C:15]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:1]=[C:23]1[S:19][C:20](=[O:25])[NH:21][C:22]1=[O:24]
Reactant: O=Cc1cccc(-c2ccccc2C(F)(F)F)c1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccccc3C(F)(F)F)c2)S1

Procedure:
To a solution of 3-formyl-(2′-trifluoromethyl-1,1′-biphenyl) (0.334 g, 1.34 mmol) and 2,4-thiazolidinedione (0.19 g, 1.6 mmol) in toluene (20 mL) were added piperidine (0.017 mL, 0.174 mmol) and benzoic acid (0.025 mg, 0.2 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].CN([CH:26]=[O:27])C>>[CH:16]1([O:15][C:14]2[C:5]([N:4]([CH2:17][CH2:16][O:15][CH:14]3[CH2:13][CH2:12][CH2:11][CH2:26][O:27]3)[C:1](=[O:3])[CH3:2])=[C:6]([CH:11]=[CH:12][C:13]=2[O:21][CH3:22])[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Reactant: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N(CCOC1CCCCO1)C(C)=O

Procedure:
Methyl 3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoate was prepared from methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (Example 1, Step 4) following the procedure outlined in Example 4 (except: solvent was DMF; temp was 33° C.; time was overnight). MS (ESI): 458.2 (M+Na).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[NH:15]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:18]=2[CH:17]=[CH:16]1>>[ClH:14].[CH2:4]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[C:18]=3[CH:17]=[CH:16]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: CCCCc1ccc(S(=O)(=O)n2ccc3c(N4CCNCC4)nccc32)cc1
Product: Cl

Procedure:
4-N-Butylbenzenesulfonylchloride (30.0 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (11.9 mg). LC/MS RT: 1.904 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 95%. MS: 400 (M+1) 1HNMR (CD3OD) δ ppm 0.90 (t, J=7.18 Hz, 3H) 1.31 (m, 2H) 1.55 (m, 2H) 2.67 (m, 2H) 3.50 (m, 4H) 4.09 (m, J=3.96 Hz, 4H) 7.25 (d, J=3.71 Hz, 2H) 7.44 (d, J=8.16 Hz, 2H) 7.91 (m, 2H) 8.02 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 3-trifluoromethylphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4(s, 1H), 8.4(s, 1H), 8.2 (m, 1H), 8.05(s, 2H), 8.03(d, 1H), 8.0(d, 1H), 7.9(m, 1H), 7.4-7.75(m, 6H), 7.0(d, 1H), 4.3(t, 2H), 3.6(m, 4H), 2.9(t, 2H), 2.55(m, 4H).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O[C:26]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[C:33]([C:38]#[N:39])[CH:32]=2)([CH3:28])[CH3:27]>O>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]2[C:20](=[O:21])[C:37]3[C:36]4[C:31](=[CH:32][C:33]([C:38]#[N:39])=[CH:34][CH:35]=4)[NH:30][C:29]=3[C:26]([CH3:28])([CH3:27])[C:18]=2[CH:17]=1
Reactant: CC(C)(O)c1cc2ccc(C#N)cc2[nH]1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
(Method 3) To nitrobenzene (5 ml) and aluminum chloride (400 mg, 3 mmol), 4-methoxybenzoyl chloride (400 mg, 2.3 mmol) was added. After stirring for 30 min at room temperature, 2-(1-hydroxy-1-methyl-ethyl)-1H-indole-6-carbonitrile (Compound AA6, 200 mg, 1 mmol) was added followed by stirring at room temperature for 3 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (127 mg, 40%).