Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH2:19][NH2:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH2:19][NH:20][C:7]([C@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:16])=[O:15]
Reactant: O=C1N[C@@H](C(=O)O)CS1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1N[C@@H](C(=O)NCCO[N+](=O)[O-])CS1
Yield: 31.3 %

Procedure:
Following a procedure similar to that described in Example 1, but using 1.0 g of (4S)-2-oxothiazolidine-4-carboxylic acid and 1.15 g of N-(2-nitrooxyethyl)amine nitrate, 0.50 g of the title compound was obtained as pale yellow needles, melting at 129°-130° C. (with decomposition).
Reaction SMILES: [CH:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc2c(C3CCCCC3)noc2c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: c1cc2c(C3CCCCC3)noc2cc1OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 3-cyclohexyl-1,2-benzisoxazol-6-ol (2.69 g, 12 mmol), 1-(2-chloroethyl)-piperidine hydrochloride (2.39 g, 13 mmol) and K2CO3 (3.59 g, 26 mmol) in CH3CN (30 ml) was heated at reflux for 3 h and stirred at room temperature overnight. The reaction mixture was poured into H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated to give a residue (3.78 g). This residue was purified by flash chromatography (toluene/1,4-dioxane 8/2). Crystallisation from EtOH gave white crystals (0.53 g, 13.4%). mp 69° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[C:24]([CH3:37])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@@H:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[C:24]([CH3:37])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@@H:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(O)c2C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C[C@H]1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 309.2 %

Procedure:
To a solution of pyridine (440 μL, 5.45 mmol) in dichloromethane (5.0 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (840 μL, 4.99 mmol) was added. The resultant mixture was stirred for 5 min, and methyl (R)-(5-hydroxy-4-methyl-indan-1-yl)acetate (1.00 g, 1.34 mmol, from Step H) was added as a solid. The reaction mixture was warmed to ambient temperature, stirred for 1 hr and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 1.46 g of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 1.69-1.91 (m, 1H), 2.33 (s, 3H), 2.38-2.56 (m, 2H), 2.69-2.79 (m, 1H), 2.79-3.01 (m, 2H), 3.49-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (s, 2H).
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([N:27]([CH2:37][CH2:38][CH2:39][CH3:40])[C:28]([C:30]1[C:34]([Cl:35])=[C:33]([CH3:36])[NH:32][N:31]=1)=[O:29])[CH2:24][CH2:25][CH3:26]>>[Cl:35][C:34]1[C:30]([C:28](=[O:29])[N:27]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:31][N:32]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:33]=1[CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Yield: 78.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 1-benzyl 3-ethyl 4-fluoroisophthalate (1.50 g, 4.96 mmol) and N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Intermediate 1B, 2.02 g, 7.44 mmol) were converted to the title compound (2.15 g, 78%). 1H NMR (CDCl3) δ 8.69 (d, J=2.0 Hz, 1H), 8.33 (dd, J=8.1, 2.0 Hz, 1H), 7.51-7.36 (m, 6H), 5.43 (s, 2H), 4.19 (d, J=7.0 Hz, 2H), 3.50 (s, 2H), 3.41 (s, 2H), 2.15 (s, 3H), 1.70-1.60 (m, 2H), 1.58-1.50 (m, 2H), 1.46-1.34 (m, 2H), 1.25-1.16 (m, 5H), 0.96 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 554.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:31]#[N:32]>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[NH:36][C:35]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=3[N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2nc3cc(C#N)ccc3[nH]2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To the mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.5 g, 6.6 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (1.06 g, 6.8 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (0.87 g, 6.6 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 3-(5-cyano-1H-benzoimidazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.8 g, 65%) as pale solid.
Reaction SMILES: [C:1]([NH:8]C1C=CC(C(F)(F)F)=CC=1C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[C:1]([NH:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:29]=[CH:30][CH:31]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-Boc 2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, et al., Synlett 1992, 360) was transformed into its methyl ester as described in procedure (80a). A solution of this ester (125 mg, 0.39 mmol) in DMF (6 mL) was charged with K2CO3 (216 mg, 1.6 mmol) and para-chlorobenzyl bromide (160 mg, 0.78 mmol). After 1.5 h, the solution was diluted with EtOAc and was washed with brine solution followed by 1N HCl solution. The organic layer was then washed with Na2CO3 solution, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue provided the desired N-Boc benzylamine (69 mg), which was dissolved in THF (0.9 mL). The solution was charged with 1N LiOH (0.3 mL) and MeOH (0.3 mL). After stirring for 18 h, the THF was removed and the solution was made acidic (pH=5) with 1N HCl. This solution was extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to give N-Boc 2-(para-chlorobenzyl)amino-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:46])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccncc3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylisonicotinamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:30]([CH3:31])[CH3:29])=[NH:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:26])([F:27])[F:28])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Reactant: CNC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)N(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.050 g, 0.127 mmol) was dissolved in 1:1 MeOH/CHCl3 (15 mL). Hydrogen chloride gas was bubbled through the solution for 15 min. The reaction was tightly capped and sealed, stirred overnight at rt, and concentrated to dryness. The crude intermediate was dissolved in methanol (15 mL), and 2M dimethylamine (0.45 mL, 0.892 mmol) was added. The reaction was tightly capped and sealed and stirred overnight at rt, concentrated, and purified by reverse phase HPLC freeze-dried to afford the title compound (0.050 g, 89%): 1H NMR (CHCl3) δ9.30 (bs, 0.5H), 8.76 (bs, 0.5H), 7.42 (d, j=9.1 Hz, 2H), 6.96 (d, j=8.8 Hz, 2H), 3.84 (s, 3H), 3.68 (t, j=6.8 Hz, 2H), 3.51 (t, j=6.3 Hz, 2H), 3.14 (s, 3H), 3.10(s, 3H), 3.01 (t, j=6.8 Hz, 2H), 2.66–2.62 (m, 2H), 1.72–1.60(m, 4H) ppm; Mass Spec 438.3(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:1]=[CH:23][C:21]2[O:22][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:25])([F:10])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Product: Cc1ccc(O)c(N=Cc2ccc(-c3ccccc3C(F)(F)F)o2)c1

Procedure:
Using 2-amino-4-methylphenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.82 g of 4-methyl-2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 92%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O>CO>[Br:11][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4](=[O:10])[NH:5][C:6]=1[CH3:9]
Reactant: CCc1ccc(C)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: CCc1cc(Br)c(C)[nH]c1=O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 3-ethyl-6-methyl-1H-pyridin-2-one (23.92 g, 174.4 mmol) and N-bromosuccinimide (32.67 g, 183.5 mmol) in methanol (450 ml) was stirred under nitrogen at room temperature. A thick suspension formed after some hours and was stirred at RT for a further 24 h. The reaction mixture was concentrated to one half to one third of the original volume and diluted with 200 ml of water. The mixture was cooled in an ice bath with stirring and then filtered with suction. The residue was washed with cold water and dried at 65° C. 35.93 g (95%) of 5-bromo-3-ethyl-6-methyl-1H-pyridin-2-one were obtained in the form of a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH:10]=1.N>Cl.CCO.C(OCC)(=O)C>[CH:17]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[O:8][C:7]1[C:6]([Cl:21])=[CH:5][C:4]([NH2:22])=[CH:3][C:2]=1[Cl:1])([CH2:19][CH3:20])[CH3:18]
Reactant: CCC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1OC
Yield: 100.5 %

Procedure:
To a solution of Stannous chloride dihydrate (194.6 g, 0.86 mol) in concentrated HCl (80.0 mL) was added to 3,5-dichloro-4-(4′-methoxy-3-sec-butyl-phenoxy)nitrobenzene (80 g, 0.21 mol) in EtOH (400 mL). The reaction mixture was refluxed for about 2 h. The resulting mixture was brought at 20-30° C. and diluted with ethyl acetate. The mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite. The organic phase was washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine (71.8 g; 98% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([NH:21][C:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[NH:23])([CH3:20])[CH3:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:23][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[N:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)NC(=N)NC(=O)OC(C)(C)C
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=NC(=O)OC(C)(C)C)N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 22.6 %

Procedure:
To the solution of the crude dione 15 (0.7 g, 2.5 mmol) in 25 ml of dry CHCl3 was added N-isopropyl-N′-(tert-butoxycarbonyl)-guanidine (17) (0.5 g, 2.5 mmol). The reaction mixture was heated at 50° C. for 16 hours. The reaction was quenched with water, extracted with chloroform and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified with a silica gel column and was eluted with 3% EtOAc/CHCl3 to yield 4c as a white solid (0.25 g, 22%), mp 227° C. 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J=2.4 Hz, 1H), 7.53(d, J=8.6 Hz, 1H), 7.27 (dd, J=8.6 and 2.4 Hz, 1H), 4.15 (m, 1H), 1.54 (s, 9H), 1.24 (d, J=6.6 Hz, 6H); 13C NMR: δ 170.50, 168.40, 159.34, 156.09, 153.00, 132.51, 132.09, 131.34, 130.38, 128.62, 125.62, 85.59, 45.05, 29.70, 22.34. IR: 2979, 2930, 1766, 1729, 1532, 1474, 1142, 775, 734 cm−1. MS (m/z): 444 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])OC(C)(C)C)=[CH:10][C:5]=2[N:4]([CH3:19])[CH:3]=1.ClC([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O>Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[O:18])=[CH:10][C:5]=2[N:4]([CH3:19])[CH:3]=1
Reactant: Cn1cc(Br)c2cnc(NC(=O)OC(C)(C)C)cc21
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
In a 125 ml round bottom flask, tert-butyl 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (3G, 0.6 g, 1.839 mmol) was dissolved in 4N HCl (15 ml) and the mixture was stirred at room temperature for 3 h. After completion, volatiles were evaporated and the mixture was re-dissolved in DMA (10 ml). To this was added methyl 4-(chlorocarbonyl)benzoate (0.44 g, 2.2 mmol) and the mixture was stirred at 50° C. for five hours. The reaction was poured into ice water. The precipitated product was collected and dried to obtain the product methyl 4-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (3H, 0.6 g, 84%). Small amount of debrominated product was observed.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(/[CH:11]=[C:12](/[C:17]([F:20])([F:19])[F:18])\[CH:13]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)C>C(O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:1][C:2]=12
Reactant: CN(C)/C=C(\C=[N+](C)C)C(F)(F)F
Reactant: Nc1n[nH]cc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)c1cnc2c(Br)cnn2c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
3-Amino-4-bromopyrazole (4.29, 26.5 mmol) and 2-(trifluoromethyl)-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (9.00 g, 26.5 mmol) were dissolved in ethanol (52.9 mL) and acetic acid (35.3 mL) and the reaction heated to 70° C. for 16 h. The solution was cooled to room temperature and concentrated. The residue was filtered through a fritted funnel, the precipitate washed with water, and dried under reduced pressure to afford the title compound (6.22 g, 23.4 mmol). LRMS (APCI) calc'd for (C7H3BrF3N3) [M+H]+, 266.0; found 265.9. 1H NMR (CDCl3, 500 MHz) δ 8.96 (d, J=1.1, 2.1, 1H), 8.71 (d, J=2.1, 1H), 8.28 (s, 1H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1>C1COCC1.[Cu]I>[C:1]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(Cl)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of bis-triphenylphosphine palladium (II) dichloride (0.35 g, 0.5 mmol) and copper (I) iodide (95 mg, 0.5 mmol) in THF (45 mL, distilled from Na-benzophenone ketyl) is sparged with dry argon gas for 10 min. To this suspension is added 1-hexyne (2.46 g, 30 mmol) followed by triethylamine (5 mL). The suspension is stirred at room temperature under argon for 15 min. A similarly sparged solution of the 2-chloro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)pyrimidin-4-one (13, 5.75 g, 10 mmol) in THF (15 mL) is added to the suspension of catalyst and the mixture stirred for 1 hr. The dark mixture is filtered through Celite and the filtrate evaporated in vacuo to afford a dark syrup. This syrup was triturated with cold diethylether, filtered and then dissolved in dichloromethane.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[C:12](OS(C(F)(F)F)(=O)=O)=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([NH:39][C:12]2[C:9]3[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:29])([F:28])[F:1])[CH2:6][CH2:7][C:8]=3[CH:15]=[CH:14][C:13]=2[C:16]([F:19])([F:17])[F:18])[CH3:38])=[CH:33][CH:32]=1
Reactant: O=C(N1CCc2ccc(C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C[C@H](N)c1ccc(F)cc1
Product: C[C@H](Nc1c(C(F)(F)F)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(F)cc1
Yield: 66.2 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (430 mg, 0.94 mmol) with (S)-1-(4-fluorophenyl)ethylamine (195 mg, 1.40 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (S)-6-[1-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (279 mg, 65%). MS (ES+) m/z: 449 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[CH:34]=[CH:33][C:20]2/[C:21](=[CH:30]/[C:31]#[N:32])/[C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[CH2:24][CH2:25][C:19]=2[CH:18]=1.O>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:34]=[CH:33][C:20]3/[C:21](=[CH:30]/[C:31]#[N:32])/[C:22]4[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=4[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Reactant: CCc1[nH]c2ccccc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C)c2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
[step 1] 2-Ethyl-3-methylindole (196 mg, 1.23 mmol) was dissolved in DMF (3.2 mL), sodium hydride (60%; 49 mg, 1.23 mmol) was added, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added (E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (200 mg, 0.617 mmol) obtained in Reference Example B1, and the mixture was stirred at room temperature for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give (E)-[2-(2-ethyl-3-methylindol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (117 mg, 47%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:32])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:2]2[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CC(C)(O)c1cc(N2CCOCC2)nc(Cl)n1
Product: COc1cc(Nc2nc(N3CCOCC3)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1

Procedure:
Using in analogous manner the procedure described in example 1e), 2-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)-propan-2-ol (77 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound was obtained as light yellow foam (62 mg, 49%). MS ISP (m/e): 425.2 [(M+H)+].) 1 1H NMR (CDCl3, 300 MHz): (ppm)=7.82 (s, 2H), 7.16 (d, 1H), 6.98 (dd, 1H), 6.95 (s, 1H), 6.87 (s, 1H), 6.12 (s, 1H), 4.15 (br s, 1H), 3.81 (s, 3H), 3.78 and 3.65 (2 m, 2×4H), 3.16 (s, 6H), 2.30 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:23][N:24]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:30]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 10 h
Yield: 46.7 %

Procedure:
To a solution of 48 (150 mg, 0.33 mmol) and DMAP (4 mg, 0.033 mmol) in pyridine (1.0 ml) was added pivaloyl chloride (57 μl, 0.46 mmol) as dropwise at room temperature and stirred for 10 h. The crude product was purified by prep HPLC (C18) to provide the titled compound (83 mg, 47%).