Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH2:10]([SH:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C>[CH2:10]([S:12][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])[CH3:11]
Reactant: O=[N+]([O-])c1cc[nH]c1Cl
Reactant: CCS
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCSc1[nH]ccc1[N+](=O)[O-]
Temperature: 175 °C

Procedure:
Using a microwave chemical reactor (CEM Explorer Microwave System manufactured by CEM Corporation, 3100 Smith Farm Road, Matthews N.C., 28106-0200), 0.1 gram (0.70 millimole) of 2-chloro-3-nitropyrrole (prepared in Steps D-F of Example 1), 0.5 mL (excess) of ethylmercaptan and 0.2 mL of ethyldiisopropylamine (excess) in 5 mL of acetonitrile were placed in an appropriate 10 mL vile. The vile was sealed and placed in the reaction chamber of the microwave chemical reactor. At 150 watts of power, the microwave reactor was brought to 100° C. during a five-minute period, where it was maintained for a 30-minute period. In a like manner the reactor was brought to 150° C. where it was maintained for a 30-minute period, and finally to 175° C. where it was maintained for a 30-minute period, after which time the reaction was considered to be complete. Upon completion of the reaction the microwave reactor was cooled, and the vile containing the reaction mixture was removed from the reactor and absorbed onto silica gel. The silica gel-reaction mixture combination was then subjected to column chromatography. Elution was accomplished using 33% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.03 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][CH:16]2O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:42])CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][C@@H:16]2[F:42])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN2CCC(N3CCC(c4ccc(OCc5ccccc5)cc4)C(O)C3)C2=O)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(OCc5ccccc5)cc4)[C@@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0° C. was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].Cl>CCOC(C)=O>[ClH:1].[C:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3[C:3]=2[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=3)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2nc(C)[nH]c3cc(-c4ccccc4)nc2-3)CC1
Temperature: 180 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (500 mg, 2.05 mmol) and 1-acetyl-piperazine (Aldrich Chemical Company) (525 mg, 4.10 mmol). The flask was purged with N2 and the mixture was heated to 180° C. for 30 min. The reaction was allowed to cool to room temperature and the crude material was purified by flash chromatography on silica gel with 10% MeOH/EtOAc as eluant to give 600 mg (87% yield) of an off white solid. The free base (400 mg, 1.2 mmol) was dissolved in hot EtOAc (10 mL) and anhydrous ethereal HCl (1.2 mL, of a 1.0 M soln, 1.2 mmol) was added dropwise. The mixture was stirred for 2 h and allowed to cool to room temperature. The resulting solid was filtered and dried under high vacuum to give 205 mg (96% yield) of the title compound as a light yellow solid. Mp: 282-283° C. 1H NMR (DMSO-d6; 400 MHz): d 2.09 (s, 3), 2.61 (s, 3), 3.7 (s, 4), 4.14 (dt, J=5.3, 14), 6.95 (s, 1), 7.54 (m, 3), 8.00 (d, 2, J=6.88). MS m/z: 366 (M+1); 364 (M−1). Anal. Calcd for C19H21N5O.HCl. C, 60.76; H, 5.95; N, 18.65; O, 4.45; Cl, 10.19. Found: C, 60.76; H, 5.90; N, 18.64; Cl, 10.15.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C([Li])CCC.[CH2:16]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH:17]=[CH2:18]>O1CCCC1.[Cl-].[Na+].O>[OH:25][C:22]1([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])[CH2:23][CH2:24][N:19]([CH2:16][CH:17]=[CH2:18])[CH2:20][CH2:21]1
Reactant: C=CCN1CCC(=O)CC1
Reactant: Cc1csc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1CCC(O)(c2sc3ccccc3c2C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Scheme IA, step A: To a solution of 3-methylbenzothiophene (2.863 g, 19.3 mmol) in tetrahydrofuran (80 mL) at −78° C. was added a solution of n-butyllithium (13.3 mL, 21.2 mmol, 1.6 M in hexanes). The solution was warmed to 0° C. for one hour then recooled to −78° C. A solution of 1-(2-propenyl)-4-piperidone (2.957 g, 21.2 mmol) in tetrahydrofuran was added dropwise and the mixture was warmed to 20° C. After stirring for 18 hours at 20° C. the mixture was diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 4.61 g (83%) of the intermediate title compound as a white amorphous solid. FDMS m/e=288 (M++1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[O:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=2)[CH:30]=O)=[CH:21]1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:30][C:29]2[CH:32]=[C:25]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:26]=[CH:27][C:28]=2[O:33][CH3:34])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Reactant: COc1ccc(-c2ccoc2)cc1C=O
Product: COC(=O)C1CCC(NCc2cc(-c3ccoc3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 5-(furan-3-yl)-2-methoxybenzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92). NMR (400 MHz, CDCl3): δ 7.63-7.61 (m, 1H), 7.46 (t, 1H, J=2 Hz), 7.31 (dd, 1H, J=9,2 Hz), 7.18 (dd, 2H, J=9,5 Hz), 7.12 (d, 1H, J=2 Hz), 7.01 (t, 2H, J=9 Hz), 6.75 (d, 1H, J=9 Hz), 6.62 (dd, 1H, J=2,1 Hz), 3.73 (d, 1H, J=13 Hz), 3.61 (s, 3H), 3.54 (s, 3H), 3.53-3.38 (m, 2H), 3.45 (d, 1H, J=13 Hz), 3.27-3.22 (m, 1H), 2.41-2.29 (m, 1H), 2.02-1.87 (m, 3H), 1.69 (br, 1H). Mass spectrum (NH3 /CI): 424 (M+1).
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9]([C:11]1[C:12](=[O:28])[NH:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([Cl:27])=[CH:16][CH:15]=2)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].S(Cl)(Cl)=O>C(Cl)Cl>[Cl:27][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:28])[C:11]([C:9]1[O:10][CH2:2][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[N:8]=1)=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)CC(CO)NC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)CC1COC(c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (1-hydroxymethyl-3-methylbutyl)amide (b) (30.0 mg, 0.075 mmol) in DCM (8.0 mL) was added thionyl chloride (31.0 gL, 0.40 mmol) at rt. The reaction was stirred for 0.5 h at rt, cooled to 0° C., quenched with a cold solution of NaOH (1 N), and extracted with DCM (3×10 mL). The solvent was then removed in vacuo to provide 6-chloro-3-(4-isobutyl-4,5-dihydro-oxazol-2-yl)-4-phenyl-1H-quinolin-2-one (c) (25 mg, 87%). 1H NMR (CDCl3): δ 12.60 (b s, 1 H), 7.55-7.35 (m, 7 H); 7.20 (d, 1 H), 4.40 (t, 1 H), 4.30-4.20 (m, 1 H), 3.7 (t, 1 H), 1.60-1.50 (m, 1 H), 1.20-1.00 (m, 2 H), 0.80(dd, 6 H). MS: 381.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=O)[C:6]3=[CH:5][C:4]=2[CH:3]=1.[C:15]([O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[CH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1CCn2c1cc1cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(Br)ccc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (0.50 g, 1.999 mmol) in THF (10 mL) was added (tert-butoxycarbonylmethylene)triphenylphosphorane (1.881 g, 5.00 mmol). The mixture was stirred at 65° C. for 16 h and concentrated. The residue was purified by silica gel flash chromatography to provide the title compound (0.50 g). LCMS m/z=348 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC/[CH:50]=[CH:51]\[C:52]([CH3:62])([O:54][Si:55]([CH2:60][CH3:61])([CH2:58][CH3:59])[CH2:56][CH3:57])[CH3:53].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24]/[CH:50]=[CH:51]\[C:52]([CH3:53])([O:54][Si:55]([CH2:60][CH3:61])([CH2:56][CH3:57])[CH2:58][CH3:59])[CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:43])[CH3:42])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 64.3 %

Procedure:
Under the same conditions as in Example 3, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (91.2 mg, 0.131 mmol), (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (192 mg, 0.655 mmol), tetrahydrofuran (1.5 ml) and 1M KOH solution in methanol (1.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:dichloromethane:ethyl acetate=160:40:1, developed once) to give the title compound as a colorless oil (66.3 mg, 64%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1>CC#N>[Br:8][C:12]1[C:13]([NH2:16])=[N:14][CH:15]=[C:10]([F:9])[CH:11]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2-ylamine (55) (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to obtain a residue, which was purified by silica gel chromatography (10% to 20% EtOAc in petroleum ether) to give 3-bromo-5-fluoro-pyridin-2-ylamine (56) (5.2 g, 27.2 mmol, 31% yield) as a yellow solid.
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][NH:14][CH2:13]1.Br[CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][CH3:29])[CH2:13]1
Reactant: Clc1cccc(OC2CNCCc3ccccc32)c1
Reactant: CCCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCc2ccccc2C(Oc2cccc(Cl)c2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4 (6.4 g, 0.023 mole), 1-bromopropane (5.7 g., 0.047 mole) and sodium bicarbonate (8.4 g, 0.10 mole) in DMF (100 ml) was stirred at 70° C. for three hours. The mixture was concentrated under high vaccum to an oil which was stirred with water then extracted with ether. The ether extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil (6.3 g, 86%) which was distilled to yield an oil of 1-(m-chlorophenoxy)-3-(n-propyl)-2,3,4,5-tetrahydro-3-benzazepine, 190°-210° C./0.1 mm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:29]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=3)[CH2:12][N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH2:42][CH2:41]1)(=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Product: O=C(c1ccccc1)N1CCN(C(=O)[C@@H]2C[C@H](NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2ccccc2)CC1
Yield: 12.1 %

Procedure:
As described for Example 56d, 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol) was converted, using phenyl-piperazin-yl-methanone instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (10.9 mg, 12.1%) as light yellow oil. MS m/e=619.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:20]
Reactant: COc1cccc(OC)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)cc2OC)cc1
Temperature: 25 °C

Procedure:
1,3-Dimethoxybenzene (13.8 grams, 0.1 mole) and p-anisoyl chloride (17 grams, 0.1 mole) were dissolved in 200 milliliters of methylene chloride and stirred at room temperature. Anhydrous aluminum chloride (15 grams) was added slowly to the reaction mixture over a period of 15 minutes with stirring. After stirring an additional 15 minutes, the contents of the flask were carefully poured into 200 milliliters of a mixture of ice and dilute hydrochloric acid. The organic fraction was separated and washed with water. The solvent was removed on a rotary evaporator leaving an oily product that solidified on standing. This solid was broken-up, washed with two 50 milliliter portions of pentane, and dried, yielding 2,4,4'-trimethoxybenzophenone.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][C@@H:51]([CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:52][N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]2=[O:63])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.21 g, 0.87 mmol), PyBrOP (610 mg, 1.3 mmol) and diisopropylethyl amine (0.76 mL, 4.35 mmol) in DCM (20 mL) at 25° C. was added 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione HCl (380 mg, 0.96 mmol) [prepared according to Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (200 mg, 46%) as a white solid: LC-MS (ES) m/z=505 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:23][C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[NH3:30]>CO>[NH2:30]/[C:26](/[CH3:27])=[CH:25]\[C:24]([NH:23][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]([CH3:21])([CH3:22])[CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:12]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:29]
Reactant: CC(=O)CC(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Reactant: N
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloro-4-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino) phenyl)-3-oxobutanamide (2.0 g, 4.89 mmol), MeOH (15 mL) and ammonia (15 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[NH4+:22].O>CO>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH2:22])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C

Procedure:
Methyl 4-((1H-indol-1-yl)methyl)benzoate 1 was dissolved in MeOH (10 mL) and to it was added a 30% solution of ammonium hydroxide (5 mL). The reaction was heated to reflux for 16 h after which it was cooled to RT and H2O (30 mL) was added. The organic products were extracted with EtOAc (3×15 mL), washed with brine (15 mL), dried with Na2SO4 and concentrated in vacuo. The crude product was dissolved in DMF and purified by preparatory HPLC method 1. The title compound was isolated as a white solid (37 mg, 13%). 1H NMR (400 MHz, MeOD): δ 7.79 (d, J=7.9 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.29 (m, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.11 (t, J=7.2 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 5.47 (s, 2H). 13C NMR (100 MHz, MeOD): δ 170.59, 142.41, 136.24, 132.64, 128.93, 128.14, 127.57, 126.36, 121.13, 120.32, 118.99, 109.29, 101.14, 48.93. ESI-LRMS: [M+H]+=251.1 m/z. ESI-HRMS: calc. for C16H14N2O: [M+H]+=251.1179 m/z, found: [M+H]+=251.1179 m/z.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[CH3:12][O-:13].[Na+]>C1(C)C(C)=CC=CC=1.CO>[CH3:12][O:13][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
5.3 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute methanol. Then 5.4 gram for sodium methoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 4.8 gram (98% yield). Mp: 133.8-134.9° C.; MS: 166.2.0 (M+H)
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[CH2:19]([O:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1)[C:3]([OH:37])=[O:2])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)O)c1
Yield: 98.2 %

Procedure:
A mixture of 46.3 g (0.091 mol) of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester and 45 ml (0.27 mol) of 6N NaOH in 7.50 ml of methanol and 300 ml of dioxane was stirred at reflux for 4 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was suspended in water, acidified and filtered to give 44.4 g (99% yield, mp 97°-99°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid.