Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.Br[C:27]1[C:32](OCC)=[CH:31][CH:30]=[CH:29]N=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:27]2)[C:15]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CCOc1cccnc1Br
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1N(C1CCCC1)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 70, and making non-critical variations but substituting 1-benzyl-4-(1-cyclopentylamino)piperidine (EXAMPLE 103) for 1-benzyl-4-(methylamino)piperidine and 2-chloro-3-nitropyridine for 2-bromo-3-ethoxypyridine and using a reaction time of 2 hrs, the title compound is obtained, NMR (CDCl3) 8.26, 7.91, 7.33-7.21, 6.67, 3.78, 3.47, 2.97-2.86, 2.11, 1.98-1.75 and 1.50δ.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:16]1[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH2:13][CH2:14][CH3:15]>C(Cl)(Cl)Cl>[CH2:12]([C:16]1[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:6])=[CH:20][C:19]=2[N:28]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid 3-chloroperoxybenzoic acid (2.1 g of ˜60%) was added in portions over a period of 3 minutes to a solution of 2-butyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline (2.7 g, 7.2 mmol) in chloroform (72 μL). The reaction mixture was stirred at ambient temperature for 30 minutes then additional 3-chloroperoxybenzoic acid (0.4 g) was added. The reaction mixture was stirred at ambient temperature for 15 minutes and then partitioned between dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL). The organic layer was washed sequentially with saturated aqueous sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to provide 2-butyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline 5-oxide as an orange foam.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 193. MS (ESI+) 491.1. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.27 (d, J=8.3, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H), 7.31 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0, 2H), 4.03 (s, 2H), 3.47 (t, J=5.0, 2H), 1.10 (s, 6H)
Reaction SMILES: C([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:34][C@H:35]([C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH:36]([CH3:38])[CH3:37].N1CCCCC1>C(Cl)Cl>[C:21]1([CH2:20][C@@H:19]([C:31]([OH:33])=[O:32])[NH2:18])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.[NH2:34][C@H:35]([C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH:36]([CH3:38])[CH3:37]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C=CCOC(=O)[C@@H](N)C(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
Fmoc-3-(1-naphtyl)-L-alanine-Val-OAllyl (0.67 g, 1.16 mmol) was solvated in CH2Cl2 (5 mL) followed by addition of piperidine (0.920 mL). After 45 min, the mixture was evaporated to dryness and co-evaporated with CH2Cl2 (20 mL*2) followed with high vacuum (without heating) for 10 min to remove the excess of piperidine. The sample was purified on silica with a gradient of MeOH/CH2Cl2 (0 to 5%) to get 0.396 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH3:29][N:30]([CH:32]=[C:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O

Procedure:
A mixture of 1.35 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 15 ml of tert-butoxy-bis(dimethylamino)methane is heated for on a steam bath for 2 hours. The volatiles are evaporated in vacuo to a residue which is stirred with ether and filtered. The cake is washed with ether and the combined filtrates evaporated in vacuo to a residue which is dissolved in 30% ethyl acetate in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is dissolved in 30% ethyl acetate in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue to give 1.60 g of yellow crystalline product, m.p. 180°-183° C.
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25](OC)=[O:26])[CH2:3][C:4]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:6](=[CH:7][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=2)[CH:5]=1.[O:32]=[C:33]1[N:42]([CH:43]2[CH2:48][CH2:47][N:46]([C:49](OC3C=CC([N+]([O-])=O)=CC=3)=[O:50])[CH2:45][CH2:44]2)[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34]1.[H-].[Na+].[O:63]1CCCC1>>[CH3:13][C:11]1[C:10]2[C:6](=[CH:7][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[N:9]=2)[CH:5]=[C:4]([CH2:3][CH:2]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=2)[C:25]([OH:26])=[O:63])[O:1][C:49]([N:46]2[CH2:45][CH2:44][CH:43]([N:42]3[CH2:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]3=[O:32])[CH2:48][CH2:47]2)=[O:50])[CH:12]=1
Reactant: COC(=O)c1ccnc(C(O)Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)O)ccn2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a suspension of (±)-methyl 2-(1-hydroxy-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl)isonicotinate (233 mg, 0.527 mmol 1.0 equiv) and 4-nitrophenyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (251 mg, 0.632 mmol, 1.2 equiv) in tetrahydrofuran (6 mL) was added sodium hydride (91 mg, 7 equiv) in one portion. The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was acidified to pH 5 with acetic acid. The aqueous portion was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash column chromatography (20% methanol in methylene chloride) to afford the desired acid (227 mg, 62.8%) as a tan solid. (ESI) 685 (MH)+. HPLC tR=2.19 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH:10]([CH2:12][O:13][CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N[C@H](C(O)=O)CCSC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CC(C)CC(=O)C>[CH2:1]([O:8][C:9](=[O:15])[C@@H:10]([CH2:12][O:13][CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(N)C(=O)OCc1ccccc1
Agent: CSCC[C@H](NC(C)=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COC[C@@H](N)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of O-methyl-D,L-serine benzyl ester (50 mg, 0.239 mol) in 4-methyl-2-pentanone (500 mL) was added N-acetyl-L-methionine (45.7 g, 0.239 mol) at 25° C. The reaction mixture was heated to 50° C. and stirred for 2 hours, then allowed to cool to 25° C. and stirred for 16 hours at 25-30° C. The resulting solid material was filtered and dried at 60° C. for 3 hours. The mother liquors were evaporated. The isolated solid material (66 g) was dissolved in water (132 mL) at 25° C. The aqueous solution was basified with aqueous Na2CO3 solution (1M; 0.28 mol) at 5-10° C. The reaction mixture was extracted with dichloromethane (3×330 mL) at 25-30° C. The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford O-methyl-D-serine benzyl ester as a light brown liquid (32.6 g, 66%). Chiral purity: 94.6%. Chemical purity: 98.3%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 101 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel, heptane/EtOAc 7:3) to yield 118 mg (79%) product as a light yellow viscous oil. MS (ISP) 497.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])[CH:12]=[C:11]([F:35])[N:10]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CO>[F:35][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])[CH:14]=[C:9]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:10]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(F)nc(F)c1
Reactant: C1COCCN1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(F)nc(N2CCOCC2)c1
Temperature: 55 °C

Procedure:
To a solution of triethylamine (3.0 equiv.) and N-(3-(2,6-difluoropyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) at RT in MeOH (0.12 M) was added morpholine (2.0 equiv) in one portion, the resulting mixture was then heated at 55° C. for 8 hours. LCMS analysis indicated 90% conversion to the desired product (M+H=460.1, Rt=0.43 min/non-polar). Water was then added, and the mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield N-(3-(2-fluoro-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide as a light brown solid (>100%). LCMS (m/z) (M+H)=460.1, Rt=0.43 min/non-polar.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]=2[CH:19]=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][NH:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2)(=[O:25])=[O:24]>>[CH3:21][NH:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:19]\[C:11]1[NH:12][C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[C:10]=1[CH2:9][CH2:8][CH2:7][N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)(=[O:25])=[O:24]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCNCC1)CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCNCC1)CCCC3)C(=O)N2

Procedure:
3-(3-Piperazin-1-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (61 mg, 0.22 mmol), prepared as described in Steps 1-3, Example 8 above, was condensed with 5-methylaminosulfonyloxindole (46 mg, 0.2 mmol) following the procedure used in Example 1 to precipitate 24 mg of the desired product as as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27]C4C(=CC=CC=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].[CH2:45]([NH:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([N:52]([CH2:53][CH2:54][CH2:55][CH3:56])[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:20]=[CH:11][C:10]4[C:27](=[CH:12][CH:13]=[CH:8][CH:9]=4)[CH:28]=3)(=[O:17])=[O:18])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:33][CH2:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41]2)=[O:31])[N:4]=1)=[O:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Reactant: CCCCNCc1ccccc1
Product: CCCCN(Cc1ccccc1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 135.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 125, 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (Intermediate 122F, 25 mg, 0.040 mmol) and N-benzylbutan-1-amine (Aldrich, 11 μL, 0.064 mmol) were converted to the title compound (21 mg, 68%). 1H NMR (1:1 CD3OD:CDCl3) δ 8.62 (br s, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.07-7.82 (m, 5H), 7.64-7.50 (m, 1H), 7.46-7.36 (m, 1.5H), 7.28-6.93 (m, 9H), 6.86 (d, J=7.3 Hz, 0.5H), 4.62 (d, J=5.9 Hz, 1H), 4.47-4.11 (m, 2.5H), 3.77-3.36 (m, 2.5H), 3.21-2.94 (m, 1.5H), 2.81-2.65 (m, 2.5H), 2.35-2.14 (m, 3H), 1.74-1.13 (m, 3H), 1.08-0.77 (m, 3H), 0.72-0.58 (m, 1H); MS(ESI+) m/z 774.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[NH:9][C@@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[CH:19]=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:22][CH2:23][CH2:24][C:13]=12)([CH3:6])([CH3:5])[CH3:4].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br.O>CS(C)=O.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:32])[CH2:30][O:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:22][CH2:23][CH2:24][C:13]3=[C:12]([CH2:11][C@@H:10]([NH:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:26])[CH3:25])[C:20]=2[CH:19]=1
Reactant: C[C@@H](Cc1c2n(c3ccc(O)cc13)CCC2)NC(=O)OC(C)(C)C
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)COc1ccc2c(c1)c(C[C@H](C)NC(=O)OC(C)(C)C)c1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
0.42 g sodium hydride 55-65% in oil was added to a solution of 3.3 g (S)-[2-(6-hydroxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 30 mL dimethylsulfoxide and the mixture stirred at room temperature for 30 min. 1.68 g bromoacetic acid methyl ester was added to the resulting solution and the mixture stirred at room temperature for 2 h. The mixture was distributed between water and ethyl acetate. The phases separated and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue crystallised under hexane and was dried to constant weight to yield 3.61 g of (S)-[8-(2-tert-butoxycarbonylamino-propyl)-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-6-yloxy]-acetic acid methyl ester as off white crystals melting at 87-88° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[C:56]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:64]=[CH:63][C:62]([C:56]2[C:57]([F:61])=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[CH:67][CH:66]=1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2c(F)cccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 36 %

Procedure:
DIPEA (198.6 mg, 0.26 mL, 1.5 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (144.1 mg, 0.4 mmol) in DMF (4 mL). HOBT (50.7 mg, 0.37 mmol) and EDCI (163.6 mg, 0.85 mmol) were then added at room temperature. After 2 minutes, 2′,6′-difluoro-biphenyl-4-carboxylic acid (80 mg, 0.34 mmol) (prepared by the method as described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 65 mg (35.8% yield) of 2′,6′-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 82.25%. 1H NMR (DMSO-d6): δ 8.8-8.7 (t, 1H), 8.0 (d, 2H), 7.9-7.7 (m, 2H), 7.7-7.6 (m, 1H), 7.6-7.5 (m, 4H), 7.3-7.2 (m, 2H), 4.2 (dd, 2H), 3.8-3.7 (m, 2H), 3.7-3.5 (m, 3H), 3.2-3.1 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=1)[C:5]2=[O:29].[C:30](Cl)(=[O:32])[CH3:31].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1>[C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:17][CH:18]=1)[C:5]2=[O:29])(=[O:32])[CH3:31]
Reactant: Cc1nc2ccc(N)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2nc(C)n(-c3ccc(OCCCN4CCCCC4)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone (228 mg, 0.58 mmol) were dissolved in a mixed solvent of dry tetrahydrofuran (5 mL) and dry pyridine (1 mL), and cooled on an ice bath. Acetyl chloride (68 mg, 0.87 mmol) was dripped in, and the mixture stirred at room temperature overnight. Ethyl acetate and 1N sodium hydroxide aqueous solution were added, the mixture was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=20/1), and the title compound (156 mg, 62%) was obtained as colorless crystals by recrystallization from diethyl ether/heptane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:27][C:28]1[S:29][C:30]([CH2:33][NH2:34])=[CH:31][N:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:34][CH2:33][C:30]1[S:29][C:28]([CH3:27])=[N:32][CH:31]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(CN)s1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)s1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (0.200 g, 0.605 mmol) and (2-methylthiazol-5-yl)methanamine dihydrochloride salt (0.135 g, 0.67 mmol) in acetonitrile (15 ml) was treated at 25° C. with triethylamine (0.40 ml, 2.9 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.30 g, 0.68 mmol). After 3 hours, the reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution ethyl acetate) followed by crystallization from ethyl acetate gave 0.246 g (92% yield) of the title amide as white crystals; mp 167° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.64 (6H, s, 2×CH3), 2.70 (3H, s, CH3), 4.0-4.08 (4H, m, 2×CH2), 4.68 (2H, d, J=5.8 Hz, NCH2), 5.32 (2H, s, OCH2), 7.34-7.39 (3H, m, aromatics), 7.49 (1H, s, CH), 7.50-7.53 (2H, m, aromatics), 7.72 (1H, broad t, NH). Anal. Calcd for C22H24N4O4S: C, 59.98; H, 5.49; N, 12.71; Found: C, 59.99; H, 5.31; N, 12.61.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=3)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](=[O:42])[NH:27][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=3)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3cn(CCN4CCOCC4)nc3c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3cn(CCN4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
To a solution of Intermediate 24b (86 mg, 0.23 mmol) in THF (10 mL) was added DIPEA (80 μL, 0.46 mmol), followed by the dropwise addition of a solution of 2,2,2-trichloroethylchloroformate (32 μL, 0.23 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by FCC, using 0-20% MeOH in EtOAc, gave the title compound (32 mg, 26%) as a yellow solid. LCMS (Method 4): Rt 2.64, 0.2 m/z 543, 545 [MH+].