Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:7][C:8]=1[O:9][CH3:10].[Br:21][C:22]1[CH:23]=[C:24]([C:35](O)=[O:36])[C:25]2[C:26]([CH3:34])=[CH:27][N:28]([CH:31]([CH3:33])[CH3:32])[C:29]=2[CH:30]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([C:35]([NH:1][CH2:2][C:3]2[C:4]([CH3:20])=[CH:5][C:6]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[N:7][C:8]=2[O:9][CH3:10])=[O:36])[C:25]2[C:26]([CH3:34])=[CH:27][N:28]([CH:31]([CH3:32])[CH3:33])[C:29]=2[CH:30]=1
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CN
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a stirred solution of tert-butyl ((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.55 g, 1.955 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.63 g, 2.127 mmol), and HOAt (0.27 g, 1.984 mmol) in Dichloromethane (20 mL) and DMF (5 mL) was added EDC free base (0.34 g, 2.190 mmol). The reaction was stirred at RT for 2 hr then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 40% EtOAc in hexanes) to give the product tert-butyl ((5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (1.07 g, 1.912 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.47 (t, J=4.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.35 (t, 1H), 7.33 (d, J=1.0 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.67 (s, 1H), 4.74 (quin, J=6.6 Hz, 1H), 4.44 (d, J=4.8 Hz, 2H), 4.08 (d, J=6.3 Hz, 2H), 3.85 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.41 (s, 9H), 1.38 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 559.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH2:18][C:19]([O:21]C)=[O:20])[C:14]([O:16]C)=[O:15].CO>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18](\[CH:13]([CH3:12])[C:14]([OH:16])=[O:15])/[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in paraffin oil, 31g, 686 mmol) in toluene (150 mL) was added a solution of 4-fluorobenzaldehyde (30 g, 214 mmol) and dimethyl methylsuccinate (58 g, 312 mmol) in toluene (150 mL) over 1 hour at 0° C. under nitrogen. The reaction was initiated by addition of a drop of methanol at room temperature and was stirred at room temperature for 2 hours. The reaction was quenched by slow addition of 2.0 N aqueous NaOH (300 mL) at 0° C. The resulting mixture was stirred at 110° C. for 4 hours. The mixture was then cooled to room temperature and the aqueous layer was diluted with water (300 mL) and washed with Et2O (2×300 mL). The aqueous phase was cooled in an ice-water bath. Addition of concentrated HCl was followed by extraction with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (50 mL) followed by brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-hexanes to give 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid. The procedure above was repeated using a separate amount of 4-fluorobenzaldehyde (30 g, 214 mmol). The products of the two reactions were combined to provide 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid as a pale yellow solid (28g, 27.5% overall). MS cald. for C12H12FO4 [(M+H)+]: 239, obsd. 239.2.
Reaction SMILES: [Cl:1]Cl.[N+:3]([C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:9]1[CH:10]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[NH2:8]
Reactant: ClCl
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(OC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Chlorine gas was passed through a solution of 2-nitro-4-trifluoromethoxy-aniline (14.5 g) in carbon tetrachloride (175 ml). As the mixture was stirred it became solid and more carbon tetrachloride (50 ml) was added. Chlorine gas was passed through the reaction mixture until thin layer chromatography (silica gel, using petroleum ether (boiling range 60°-80° C.) containing ethyl acetate (30% by volume) as eluent) demonstrated the absence of starting material. Evaporation of the solvent under reduced pressure gave a dark orange solid, which on trituration with petroleum ether (boiling range 60°-80° C.) gave a 2-chloro-4-trifluoromethoxy-6-nitro-aniline as an orange solid.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCC[CH2:2]1.[F:23][C:24]([F:46])([F:45])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][C:34]([C:37]3[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=3)=[N:33]2)=[CH:28][CH:27]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:23][C:24]([F:46])([F:45])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][C:34]([C:37]3[CH:44]=[CH:43][C:40]([CH:41]=[CH2:2])=[CH:39][CH:38]=3)=[N:33]2)=[CH:28][CH:27]=1
Reactant: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Methyltriphenylphosphonium bromide (32.2 g, 90.0 mmol) and 1,8-diazabicycloundec-7-ene (14.9 mL, 99.0 mmol) were dissolved in tetrahydrofuran (260 mL) and refluxed for 30 minutes. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (15.0 g, 45.0 mmol) was added, and the reaction was heated at 65° C. for 5 hours. The solution was cooled and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with hexanes. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound was purified by flash column chromatography using 0-70% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (10.4 g, 67%): 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.58-7.47 (m, 2H), 7.39 (d, J=9.1 Hz, 2H), 6.77 (dd, J=17.6, 10.9 Hz, 1H), 5.84 (dd, J=17.6, 0.8 Hz, 1H), 5.32 (dd, J=10.9, 0.8 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 332 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([OH:19])=O)=[CH:8]1)[CH3:2].Cl.[NH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:49])[C@@H:37]([CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH2:48])=[N:44][N+:45]([O-:47])=[O:46])[NH2:38])=[CH:30][CH:29]=1)=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:36](=[O:49])[C@@H:37]([CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH2:48])=[N:44][N+:45]([O-:47])=[O:46])[NH:38][C:17](=[O:19])[CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:20][CH3:21])[CH:8]=2)=[CH:32][CH:33]=1)=[O:25]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Reactant: CCN(CC)CCCn1cc(CC(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCN(CC)CCCn1cc(CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccccc21
Yield: 27 %

Procedure:
Prepared analogously to Example 69a) from 1-[3-(diethylamino)propyl]-1H-indole-3-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 27% of theory.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>>[CH3:40][S:37]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOS(C)(=O)=O)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Reaction of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with mesyl chloride analogously to the procedure described in Example 54(h) gave tert-butyl (3RS,4RS)-4-[4-(3-methylsulphonyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; Rf : 0.50 (SiO2, hexane:ethyl acetate=1:1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(#N)C.ClCCl>[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]([NH2:16])=[O:15])=[O:23])=[CH:20][CH:19]=1
Reactant: NC(=O)c1cccn1N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C(=O)Nn2cccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (277 μl, 2.00 mmol) is added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (250 mg, 2.00 mmol) in acetonitrile (4.0 ml). Under external cooling with ice, a solution of 4-methylbenzoyl chloride (264 μl, 2.00 mmol) in dichloromethane (0.6 ml) is added dropwise. The reaction mixture is stirred at room temperature for 18 hours. The solvents are evaporated and the residue is taken up in dichloromethane and saturated NaHCO3 solution. A precipitate forms which is filtered off, washed with water and dried under vacuum to give 1-(4-methyl-benzoylamino)-1H-pyrrole-2-carboxylic acid amide as white crystals; HPLC/MS 1.57 min (A), [M+H] 244;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:19](=[O:20])[CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH3:23])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1nc2c(s1)C(=O)CCC2)c1ccccc1
Reaction time: 16 h

Procedure:
2-Amino-5,6-dihydro-4H-benzothiazol-7-one (34 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (31 mg, 0.099 mmol, 49%). ESI-MS m/z calc. 314.1. found 315.3 (M+1)+ Retention time 2.90 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[H-].[Na+]>C1COCC1>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]2[N:22]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:1]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 7.9 g portion of 2-aminobenzophenone, 4.7 g of 4-methylbenzonitrile and 2.0 g of 60% sodium hydride were suspended in 40 ml of THF and heated at 60° C. with stirring for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool and the precipitate was collected by filtration, thus giving 5.7 g of 2-(4-methylphenyl)-4-phenylquinazoline as a crude product. Then 4.4 g of the compound thus obtained, 2.7 g of NBS and 0.2 g of benzoyl peroxide were suspended in 50 ml of carbon tetrachloride and refluxed with heating for 2 hours. The reaction mixture was allowed to cool and 20 ml of diethyl ether was added thereto. The crystals precipitated were separated by filtration. The filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-n-hexane to provide 1.9 g of 2-(4-bromomethylphenyl)-4-phenylquinazoline as colorless needles. Then 1.9 g of the crystals thus obtained were suspended in 10 ml of triethyl phosphite and heated with stirring at 130° C. for 2 hours. After completion of the reaction, an excess of triethyl phosphite was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform: n-hexane=1:1) and recrystallized from diethyl ether-n-hexane to provide 0.2 g of the objective compound as colorless needles. Table 1 shows the structure and physical property (melting point) of the compound.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:16][CH:17]=3)[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:11]=2[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:16][CH:17]=3)[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:11]=2[CH:10]=1
Reactant: CN(C=O)c1ccc2c3ccc(OCc4ccccc4)cc3n(C(=O)OC(C)(C)C)c2c1
Agent: [Pd]
Solvent: CO
Product: CN(C=O)c1ccc2c3ccc(O)cc3n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To tert-butyl 2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate (120 mg, 0.28 mmol) in 50 mL MeOH was added Palladium on activated carbon (50 mg). The mixture was stirred at rt under H2 atmosphere for 3 h. Solid was filtered off and the filtrate was concentrated to afford tert-butyl 2-hydroxy-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a brown solid (95 mg, 100%). This material was used directly for the next reaction without purification. MS (ESI) m/z 341 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:28]=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:15][CH:14]([CH3:16])[CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:31]1[CH2:30][CH2:29][CH2:28][CH2:26]1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid (1.0 g, 4.32 mmol), HATU (1.97 g, 5.19 mmol) and pyrrolidine (0.76 mL, 8.65 mmol) in DCM (30 mL) was added Et3N (1.2 mL, 8.65 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.17 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20]C=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:16](=[C:12]1[NH:11][C:10](=[O:24])[C:9](=[CH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)[NH:14][C:13]1=[O:15])[C:17]1[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Reactant: BrCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=Cc2ccc(OCc3ccncc3)cn2)c(=O)[nH]c1=Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
A mixture of Compound C (1 g), 4-(bromomethyl)pyridine (2 g), sodium carbonate (2 g), and DMF (50 mL) were stirred at 100° C. for 16 hr and cooled at an ice bath to produce a yellow precipitate. The precipitate was then collected and washed with water to give 0.38 g (30%) of 3-benzylidene-6-((5-(pyridin-4-ylmethoxy)pyridin-2-yl)methylene)piperazine-2,5-dione (Compound 1). mp 254-255° C.; 1H-NMR (400 MHz, CDCl3), 5.26 (s, 2H) 6.78 (s, 1H), 7.11 (s, 1H), 7.31-7.59 (m, 9H), 8.20 (s, 1H), 8.48 (dd, J=2.8 Hz, 1H),), 8.72, (s, 2H), 12.50 (s, 1H).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[OH:33][C:27]1([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=2)[CH2:32][CH2:31][N:30]([C:7]([Cl:10])=[O:6])[CH2:29][CH2:28]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 203.6 %

Procedure:
A solution of triphosgene (3.26 g, 0.011 mol) and anhydrous tetrahydrofuran (1000 mL) cooled to −20° C. was treated with pyridine (4.45 mL, 0.055 mol). The resulting cloudy suspension was slowly treated with a solution of 4-(3-trifluoromethyl-phenyl)-piperidin-4-ol (9 g, 0.036 mol) in anhydrous tetrahydrofuran (45 mL) while the internal temperature was maintained between −20° C. to −30° C. The resulting mixture was transferred to an ice bath which was allowed to come to 25° C. overnight to give a light brown solution with a small amount of brown precipitates. The reaction mixture was then concentrated in vacuo to give a brown solid. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidine-1-carbonyl chloride (6.89 g, 61%) as a clear, viscous oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:27][C:25](=[NH:26])[CH2:24][O:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)=[O:6]
Reactant: N=C(N)COCCc1cccc(Cl)c1
Reactant: CCc1cnc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cccc(Cl)c2)c1

Procedure:
In analogy to the procedure described in example 78.3, 2-chloro-5-ethyl-nicotinic acid (example 124.1) was reacted with 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 79.2) in the presence of TBTU and DIPEA to give 2-chloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide as yellow oil. MS: m/e=380.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccc3[nH]ccc23)c(F)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a mixture of 4-bromoindole (6.2 g, 31.7 mmol), and 2,4-difluorophenylboronic acid (5 g, 31.7 mmol) in THF (108 mL) were added Palladium catalyst Pd(PPh3)4 (0.67 g, 0.95 mmol) and the freshly prepared sodium hydroxide solution (3.8 g, 95 mmol in 45 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 80° C. oil bath for over the weekend. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 6.55 g (90%) of 4-(2,4-difluoro-phenyl)-1H-indole.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:44])C(=O)C1>ClCCl>[Br:44][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCCCCCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCCBr
Reaction time: 24 h
Yield: 93.3 %

Procedure:
In a 100 mL two-neck flask with a reflux condenser and magnetic anchor, under a static head of nitrogen, ethyl 12-hydroxydodecanoate (1.65 g, 6.7 mmol) is dissolved in dichloromethane (20 mL). PPh3 (1.93 g, 7.4 mmol) and NBS (1.6 g, 7.0 mmol) are added. The mixture is left stirring under reflux conditions for 24 hours. It is concentrated in the Rotavapor and the product is purified with column chromatography on silica gel with an eluant mixture of petroleum ether/ethyl acetate 5/1. 1.92 g (yield=92%) of ethyl 12-bromododecanoate are isolated as a light yellowish oil.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:8]([CH:10]([CH3:19])[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])#[N:9]>C(Cl)Cl>[CH2:1]([NH:5][C:6]([N:12]([CH2:11][CH:10]([C:8]#[N:9])[CH3:19])[CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: CC(C#N)CNCCCN(C)C
Solvent: ClCCl
Product: CCCCNC(=O)N(CCCN(C)C)CC(C)C#N

Procedure:
Under nitrogen, a solution of 99.1 g of butyl isocyanate in 100 ml of methylene chloride is added dropwise in the course of 1 hour to a solution of 169.3 g of N-(β-cyanopropyl)-dimethylaminopropylamine in 500 ml of methylene chloride. The mixture is then refluxed for 2 hours, concentrated, and the residue is treated at 80° C. in a high vacuum in order to remove all low boiling constituents. Yield: 249.2 g (90.8%) of product in the form of an oil. Titration: 1 equivalent=261.9 g (theory 268.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:38]=[N:39][CH:40]=[N:41][CH:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:37]4[CH:38]=[N:39][CH:40]=[N:41][CH:42]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1cncnc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cncnc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromopyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.332, m/z=436.1; 1H NMR (CD3OD) 1.49 (d, 3H), 1.83 (m, 2H), 2.14-2.28 (m, 4H), 2.42 (m, 1H), 3.08 (m, 1H), 3.49 (m, 2H), 5.52 (m, 1H), 6.99 (t, 2H), 7.08 (d, 2H), 7.23 (m, 2H), 7.42 (d, 2H), 8.91 (s, 2H), 9.06 (s, 1H).