Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH2:17]=O>CO>[CH2:17]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: C=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: CO
Product: COC(=O)C1Cc2c([nH]c3ccccc23)CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of L-tryptophane methyl ester (25.4 g, 100 mmol) and 37% formaldehyde solution (12.5 mL) in aqueous methanol (170 mL; H2O:MeOH, v/v 10:1) was stirred at room temperature for 5 h. The reaction mixture was evaporated to dryness in vacuo. The residue was basified with sodium bicarbonate to give methyl 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate, 14.4 g (63%); mp 161-162° C. (lit.19 mp 164-165° C.). 1H NMR (DMSO-d6) δ 2.78 (1H, m, CH2), 2.98 (1H, m, CH2), 3.66 (3H, s, COOMe), 3.85 (1H, m, CH), 4.02 (2H, q, J=15.8 Hz, NCH2), 6.92-6.96 (1H, m, ArH), 7.00-7.04 (1H, m, ArH), 7.27-7.29 (1H, m, ArH), 7.37-7.39 (1H, m, ArH), 10.78 (1H, s, exchangeable NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][O:18][CH3:19])=[C:11]([CH3:20])[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([O:16][CH2:17][O:18][CH3:19])=[C:13]([CH3:15])[CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCOc1c(C)cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Yield: 90.7 %

Procedure:
Using 0.96 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate, 0.84 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.44 g of the desired compound were obtained.
Reaction SMILES: C(S([CH:6]1[N:9]([CH:10]([C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:25])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:33])[CH2:7]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[O:33]=[C:8]1[N:9]2[CH:6]([S:25][C:24]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:10]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[CH2:7]1
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccccc2)SC2CC(=O)N12
Temperature: 110 °C
Yield: 17.3 %

Procedure:
A mixture of 1550 mg of 4-nitrobenzyl 2-(4-allylsulphinylazetidin-2-on-1-yl)-3-phenoxy-3-thioxo-propanate (containing 10% pivalic acid), 808 mg of triphenylphosphine and dioxan was heated under an argon atmosphere at 110° C. for 15 minutes. The mixture was evaporated in vacuo to dryness, and the resulting oil was chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 219 mg of a solid. This was taken up in ethyl acetate and extracted with sodium bicarbonate to afford, after evaporation in vacuo, 192 mg of the title compound (11% of the theoretical yield).
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:15]1[N:14]=[C:13]([NH2:12])[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Cc1cc(N)nc(S)n1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (2.9 g, 10.5 mmol), 4-amino-6-methylpyrimidine-2-thiol (1.0 g, 7.1 mmol), and triethylamine (3 mL, 21.5 mmol) in absolute EtOH (80 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (20 mL), and dried in vacuo. The solid residue was treated with water (150 mL). The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and dried in vacuo, affording the title compound (1.9 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 4.78 (s, 2H), 6.29 (s, 1H), 8.45 (s (br), 2H), 8.69 (s, 2H); M+302.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][O:16]C3CCCCO3)[C:6]=2[CH:23]=1.CC(O)=O.C1COCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][OH:16])[C:6]=2[CH:23]=1
Reactant: O=c1cc(OCCCOC2CCCCO2)c2cc(Br)ccc2o1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(OCCCO)c2cc(Br)ccc2o1
Yield: 39.6 %

Procedure:
6-Bromo-4-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-1-benzopyran-2-one (0.893 mmol, 0.342 g) is treated with 5 mL of 4:2:1 HOAc:THF:H2O and is heated to 45° C. for 1 hr. The solvent is removed under reduced pressure and the residue is purified by HPLC to afford the title compound (105.8 mg, 60%); 1H NMR (DMSO-d6, 300 MHz) δ 7.90 (1H, d, J=2.5 Hz), 7.82 (1H, dd, J=2.25, 8.75 Hz), 7.39 (1H, d, J=8.75 Hz), 5.96 (1H, s), 4.29 (2H, t, J=6.25 Hz), 3.61 (2H, t, J=6 Hz), 1.97 (2H, m); MS (ESI, Pos.) calcd for C12H11BrO4 m/z [M+H]=299.0, found 299.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=[O:23])[C:11]3[C:15]=2[C:14](=[O:16])[NH:13][C:12]=3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:28][N:13]1[C:14](=[O:16])[C:15]2=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10](=[O:23])[C:11]2=[C:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc(Br)cc3)=C12
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C2=C(c3ccc(Br)cc3)OC(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of furopyrrole 6 (1.5 g, 4.08 mmol), methyl tosylate (1.14 g, 6.12 mmol), potassium carbonate (1.13 g, 8.16 mmol) and dimethylformamide was stirred at room temperature overnight. Water was then added, and the organic component extracted with DCM. The solvent was removed, and washing with water then methanol gave the methylated compound 7 as a red solid (0.831 g, 53%), m.p. 215-216° C. δH (CDCl3) 8.19 and 7.61 (each 2H, AA′BB′, p-C6H4Br), 7.78-7.73 (2H, m, o-Ph), 7.54-7.50 (3H, m, m/p-Ph) and 3.38 (3H, s, NCH3). λmax (abs) (DCM)/nm 454 (ε 15,878)
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[C:7](Cl)(=O)C(Cl)=O.[F:13][C:14](=[CH:17][CH2:18]C)[CH2:15]O.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:1]([CH2:3][C:4]([O:6][CH2:15][C:14]([F:13])=[C:17]([CH3:18])[CH3:7])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC=C(F)CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=C(F)COC(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A solution of cyano acetic acid (2.25 g, 26.4 mmol) in 30 mL dry CH2Cl2 was cooled in ice water before 2.3 mL (26.4 mmol) of oxalyl chloride and 3 drops of DMF were added. The mixture was warmed to room temperature with stirring overnight before being added dropwise to an ice-cooled solution of 2.5 g (24 mmol) of 2-fluoro-4-methyl-2-buten-1-ol (Cane, D. E.; Yang, G.; Xue, Q.; Shin, J. H. Biochemistry (1995), 3418, 2471–9) and 3.7 mL (26.4 mmol) triethylamine. After stirring 3 h at room temperature, solvent was removed and the residue was partitioned between water and ether. The ether layer was separated and washed with brine. The combined aqueous washings were extracted with ether which was washed with brine. The combined ether extracts were dried (MgSO4), and solvent was removed to afford 3.5 g of the title compound of Step A as an oil, 1H NMR (CDCl3) δ 1.7 (m, 6H), 3.5 (s, 2H), 4.85 (d, J=22 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH:40]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[O:38][CH3:39])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[C:42](=O)([O-])[O-].CI>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH:40]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N:29]([CH3:42])[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[O:38][CH3:39])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: O=C([O-])[O-]
Reactant: COc1cc(NC(=O)c2ccncc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N(C)C(=O)c2ccncc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(pyridin-4-ylcarbonylamino)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 14-21, 13.9 mg, 0.0251 mmol), cessium carbonate (41.7 mg, 0.128 mmol), and methyl iodide (4.7 μL, 0.075 mmol) was suspended in anhydrous N,N-dimethylformamide (0.5 ml) and stirred for 3 hours at room temperature. The mixture was diluted with ethyl acetate (10 mL). The mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (4.6 mg) as a yellow amorphous product. (Yield 32%)
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].N1C=CC=CC=1.[CH2:31]([OH:34])[CH2:32][OH:33]>C1COCC1.O>[CH3:17][C:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:18])[C:2]3([O:33][CH2:32][CH2:31][OH:34])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: OCCO
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(OCCO)(c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.6 %

Procedure:
30 mg (0.088 mmol) of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one and 139 mg (0.176 mmol) of pyridine were dissolved in 5 ml of THF. After the addition of 54 mg (0.88 mmol) of ethane-1,2-diol, the reaction solution was stirred for 5 h at room temperature. Subsequently, the solution was diluted with water. The aqueous phase was extracted with 2×25 mL of EtOAc. The combined organic phases were washed with aqueous NaHCO3 and with water, dried and concentrated in vacuo. The resulting residue was purified by Pre-TLC (eluent: Hexane/EtOAc=1/1) to give product (5 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 7.32-7.35 (m, 6H), 7.20 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.65 (t, J=5.6 Hz, 1H), 3.23-3.52 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 365.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:17]([C:19]1([NH:22][C:23]([C@@H:25]2[CH2:29][C@@H:28]([S:30]([C:33]3[CH:38]=[CH:37][C:36](F)=[CH:35][C:34]=3[C:40]([F:43])([F:42])[F:41])(=[O:32])=[O:31])[CH2:27][N:26]2[C:44]2[N:45]([CH:50]3[CH2:53][CH2:52][CH2:51]3)[N:46]=[C:47]([CH3:49])[CH:48]=2)=[O:24])[CH2:21][CH2:20]1)#[N:18]>C(#N)C>[C:17]([C:19]1([NH:22][C:23]([C@@H:25]2[CH2:29][C@@H:28]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:35][C:34]=3[C:40]([F:43])([F:42])[F:41])(=[O:32])=[O:31])[CH2:27][N:26]2[C:44]2[N:45]([CH:50]3[CH2:53][CH2:52][CH2:51]3)[N:46]=[C:47]([CH3:49])[CH:48]=2)=[O:24])[CH2:21][CH2:20]1)#[N:18]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: CN1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
Methylpiperazine (10 ul, 116 umol; CAS Reg. No. 109-01-3) and DIEA (20 ul, 93 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 46 umol; example 388 g) in acetonitrile (400 ul) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 72 h, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (14 mg, 23 umol; 49%) as colorless oil. MS (ESI): m/z=618.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:12][CH:13]([CH3:14])[N:9]3[C:10]=2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]3)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[ClH:1].[N:19]1([C:2]2[C:11]3[CH2:12][CH:13]([CH3:14])[N:9]4[C:10]=3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]4)=[CH:4][CH:3]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: CC1Cc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: CC1Cc2c(N3CCNCC3)ccc3c(=O)c(C(=O)O)cn1c23
Product: Cl
Yield: 42.4 %

Procedure:
20 ml of dimethyl sulfoxide was added to a mixture of 1.6 g of 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid and 3 g of anhydrous piperazine and the mixture was heated on an oil bath at 140° to 150° C. for 6 hours. After completion of reaction the solvent was removed therefrom under reduced pressure and 50 ml of water was added to the residue to dissolve it. The solution was shaken with 100 ml of chloroform and the water layer was separated and treated with activated carbon. The aqueous solution was rendered acidic with a 10% aqueous hydrochloric acid solution and filtered. The filtrate was again treated with activated carbon followed by concentration. The addition of ethanol to the concentrate gave rise to crystals which were recrystallized from ethanol-water to obtain 0.9 g of 9-(1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid hydrochloride as light yellow needles having a melting point of 269° to 273° C. (decomposed).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:53][C:54]([F:69])([F:68])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[O:18]=[C:16]([N:65]1[CH2:64][CH2:63][CH:62]([NH:61][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[C:54]([F:53])([F:68])[F:69])[CH2:67][CH2:66]1)[CH2:15][C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)=[O:19]
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
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(CC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (2 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole) After 2 minutes (2-trifluoromethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.075 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 73.7 mg (64%) of 3-oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-propionamide. LC-MS purity: 483.19 (M+1)+, 95.78%, 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (dd, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.5-7.4 (m, 4H), 7.0 (d, 1H), 6.8 (t, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 4.0 (d, 1H), 3.8-3.6 (m, 3H), 3.3-3.2 (m, 1H), 2.9-2.8 (m, 1H), 2.0 (m, 1H), 1.6-1.5 (m, 1H), 1.5-1.4 (m, 1H).
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11].Cl.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH:29]([NH:31][C:32](=[O:38])[CH:33]([NH2:37])[CH:34]([CH3:36])[CH3:35])[CH3:30])=[CH:26][C:25]=2[CH:39]=1.O>ClCCl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH:29]([NH:31][C:32](=[O:38])[C@H:33]([CH:34]([CH3:35])[CH3:36])[NH:37][C:10]([N:9]([CH3:8])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[CH3:30])=[CH:26][C:25]=2[CH:39]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(NC(=O)C(N)C(C)C)c1cc2cc(Cl)ccc2o1
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(NC(=O)[C@@H](NC(=O)N(C)c1ccccc1)C(C)C)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.4 %

Procedure:
0.34 g of N-methylmorpholine and 0.57 g of N-methyl-N-phenylcarbamoyl chloride were successively added to a solution containing 1.1 g of N-[1-(5-chloro-2-benzofuranyl)ethyl]-2-amino-3-methylbutanamide hydrochloride dissolved in 30 ml of dichloromethane, at -15° C. The mixture was allowed to sit and warm naturally to room temperature and then stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residual crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white powder.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CCOCC.C([O-])(=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOCC
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76989.7 %

Procedure:
32 g (0.19 mmol) of 9H-carbazole was put into a 2 L Erlenmeyer flask, and then ether acetate (1.2 L) was added thereto so that the 9H-carbazole was dissolved in the ether acetate. To this solution was added 34 g (0.19 mol) of N-bromosuccinimide (NBS), and the mixture was stirred for about 15 hours in the air at room temperature. After the stirring, water was added to the mixture so that the precipitate was dissolved in the mixture. The organic layer of this mixture was washed with water three times and then with a saturated saline solution once. Magnesium sulfate was added so that the organic layer was dried. After the drying, the mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with ether acetate/hexane to give 36 g of a white powdered solid, which was the object of the synthesis, at a yield of 67%. A synthesis scheme of Step 1 is shown in (c-1) given below.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>CC(C)=O>[CH3:13][O:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
Benzyloxyacetyl chloride (25 gm, 135.5 mmol) was added dropwise to a mixture of 6-(4-aminophenoxy)hexanoic acid methyl ester 21 (25 g, 105 mmol) and triethylamine (21.4 g, 211.6 mmol) in acetone (200 ml) at 0° C. and stirred at room temp. for 12 hrs. Solids were filtered off, acetone distilled off and water (100 ml) added. Crude 70 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×100 ml), water (100 ml), dried over sodium sulphate and distilled. Crude 70 was purified by column chromatography on silica gel using benzene as eluant to get pure 70 (9 g, 22.2%) as a off-white powder. M.p: 46-49° C.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][NH:8][CH3:9].Cl[C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1.O1CCCC1>O>[CH3:7][N:8]([CH3:9])[C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1
Reactant: CNC
Reactant: CCOC(=O)C(=O)c1csc(Cl)n1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=O)c1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 10 ml of a 2M benzene solution of dimethylamine, 1.3 g of ethyl 2-chlorothiazol-4-ylglyoxylate, and 5 ml of tetrahydrofuran was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, using as eluent a 9:1 by volume mixture of benzene and ethyl acetate, giving the title compound as a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([O:21][CH3:22])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:23][CH:24]([F:27])[CH2:25]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:23][CH:24]([F:27])[CH2:25][N:18]1[CH2:17][CH2:16][CH:15]([C:6]2[CH:7]=[C:8]3[C:13](=[N:14][C:5]=2[CH:4]([O:3][CH3:2])[O:21][CH3:22])[NH:12][CH2:11][CH2:10][CH2:9]3)[CH2:20][CH2:19]1
Reactant: COC(OC)c1nc2c(cc1C1CCNCC1)CCCN2
Reactant: FC(F)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1C1CCN(CC(F)F)CC1)CCCN2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (Intermediate 342, 0.78 g, 2.14 mmol), 1,1-difluoro-2-iodoethane (0.63 g, 3.22 mmol) and K2CO3 (0.89 g, 6.43 mmol) in DMF (20 ml) was stirred at 70° C. After 16 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 35 ml/min, 0.1% TFA in H2O/acetonitrile 95:5 to 40:60 in 25 min, then to 5:95 in 1 min). The product-containing fractions were treated with NaHCO3 and then concentrated to remove acetonitrile. The watery residue was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4 and evaporated to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.41; ESI-MS 356.2 [M+H]+.