Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[Br:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.O.OS(O)(=O)=O.[I:17]Cl>C(Cl)Cl>[I:17][C:9]1[CH:10]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: ClI
Reactant: Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(Br)cc1I
Reaction time: 8 h

Procedure:
To a mixture of 900 mL of MeOH and 100 mL water 4-bromoaniline (40.0 g, 0.232 mol) was added and the resulting solution was cooled in an ice bath. To this 35 mL of concentrated H2SO4 was added followed by a 1 M solution of ICl (255 mL 0.232 mol) in CH2Cl2. The bath was then removed and the reaction was stirred overnight. The volatiles were then removed by rotary evaporation, 200 mL of ice water was added to the product along with 500 mL CH2Cl2. The mixture was made strongly basic with 1 M NaOH and then extracted (3×CH2Cl2). The combined extracts were dried with Na2SO4 and then concentrated and dried in vacuo to give 2-iodo-4-bromoaniline. 1H-NMR (400 MHz, CDCl3): δ 4.1 (s, 2H, NH), 6.60 (m, 1H, NCH), 7.22 (m, 1H, CHCH), 7.77 (s, 1H, ICCHCBr). The crude product was then added to a mixture of acetyl chloride (36.0 g, 0.472 mol) and pyridine (56.0 g, 0.708 mol) in 1 L of dry THF cooled in an ice bath. The bath was then removed and the resulting mixture was stirred at room temperature overnight. THF was removed by rotary evaporation and then 400 mL of ice water was added. The product was extracted with CH2Cl2 (3×300 mL) and then the layers were combined and dried with Na2SO4. Silica column chromatography using mixtures of EtOAc and hexanes gave 12 g of 2-Iodo-4-bromoacetanilide. 1H-NMR (400 MHz, CDCl3): δ=2.24 (s, 3H, CH3), 7.39 (s, 1H, NH), 7.46 (d, 8.4 Hz, 1H, BrCCH), 7.90 (s, 1H, ICCHCBr), 8.13 (d, 8.0 Hz, 1H, NCCH).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]#[C:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)C=O.O>[CH2:21]([N:2]([CH3:1])[C:3](=[O:18])[C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CNC(=O)C#Cc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#CC(=O)N(C)CC=Cc2ccccc2)cc(OC)c1OC
Reaction time: 15 h

Procedure:
The solution of 10.0 g of N-methyl-3,4,5-trimethoxyphenylpropiolamide in 80 ml of dimethylformamide is added dropwise to the suspension of 1.05 g of sodium hydride in 10 ml of dimethylformamide while stirring and cooling with ice. The mixture is stirred for 1 hour at room temperature whereupon the solution of 8.0 g of cinnamyl bromide in 40 ml of dimethylformamide is added dropwise and stirring is continued for 15 hours at room temperature. The mixture is poured into the solution of 20 ml of 3N hydrochloric acid in 600 ml of water and the whole is extracted with 250 ml of toluene. The extract is washed with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and filtered, to yield the desired toluene-solution of the N-cinnamyl-N-methyl-3,4,5-trimethoxyphenylpropiolamide.
Reaction SMILES: [N:1]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([N:5]([CH3:17])[C@H:6]([C:14](O)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:28][C@H:29]([C:38]([O:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:42])=[O:39])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34]C=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([N:5]([CH3:17])[C@H:6]([C:14]([NH:28][C@H:29]([C:38]([O:40][C:41]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:42])=[O:39])[CH2:30][C:31]1[CH:32]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: N[C@@H](CCc1ccccc1)C(=O)OC(=O)c1ccccc1
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)c1ccccc1
Yield: 76 %

Procedure:
Condensation of BocProOH (4.30 g.) and HMePheOMe (2.74 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MePheOMe in 77% yield. Demethylation of BocPro-MePheOMe (3.0 g.) using aqueous sodium hydroxide gave BocPro-MePheOH in 83% yield. Condensation of BocPro-MePheOH (1.71 g.) and HPheOBz (2.14 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MePhe-PheOBz in 76% yield. Debenzylation of BocPro-MePhe-PheOBz (2.0 g.) by hydrogenation with palladium catalyst gave BocPro-MePhe-PheOH in 100% yield.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2](C)[CH3:3].C([Li])CCC.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cu]C#N.C(Br)C=C>C1COCC1>[CH2:3]([C:13]1[CH:14]=[CH:15][C:16]([Cl:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:1]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., isobutylmagnesium bromide (2.0 M ether solution, 1.2 eq.) and n-butyl lithium (2.5 M hexane solution, 2.4 eq.) were added to anhydrous THF (0.3 M). After stirring at 0° C. for 30 min, the reaction mixture was cooled to −40° C. and tert-butyl 5-bromo-2-chlorobenzoate from the previous step (1 eq.) was added over 15 min. The now red solution was stirred at −40° C. for 1 h before copper (I) cyanide (30% loading) was added. The resulting suspension was stirred at −40° C. for 15 min and then added allyl bromide (3 eq.). After stirring at −40° C. for another 2 h, the reaction mixture was quenched with sat. aq. NH4Cl and warmed to RT. The biphasic mixture was poured into more sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→19:1 (v/v) Hex:ether) afforded the title compound as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H](CO)[C@@H](O)[C@H](O)[C@H:3]1O.C(Cl)Cl.[BrH:16]>C(O)(=O)C>[Br-:16].[C:2]([O-:10])(=[O:1])[CH3:3].[C:2]([O-:10])(=[O:1])[CH3:3].[C:2]([O-:10])(=[O:1])[CH3:3].[C:2]([O-:10])(=[O:1])[CH3:3].[C:2]([O-:10])(=[O:1])[CH3:3].[C:2]([O-:10])(=[O:1])[CH3:3].[C:2]([O-:10])(=[O:1])[CH3:3]
Reactant: Br
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: [Br-]
Reaction time: 2 h

Procedure:
Glc 1β,4 glc is converted to its octaacetate form by conventional methods as disclosed in Methods in Carbohydrate Chemistry 1, 334. A 20 g. portion of this octaacetate is dissolved in 200 ml. of methylene chloride and the solution is cooled to 0° C. An 80 ml. portion of 32% hydrobromic acid in glacial acetic acid is added and the mixture is allowed to stand in an ice bath for 2 hours. The mixture is then poured into crushed ice and diluted with 200 ml. of methylene chloride. The organic layer is separated, washed repeatedly with ice water until neutral, dried over anhydrous sodium sulfate and evaporated in vacuo, giving glc 1β,4 glc heptaacetate bromide as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]([NH2:24])[C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[Cl:25][C:26]1[C:27]([O:45][CH3:46])=[C:28]([C:42](O)=[O:43])[CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:31]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@@H:17]([NH:24][C:42]([C:28]3[CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=4)[CH:31]=[C:26]([Cl:25])[C:27]=3[O:45][CH3:46])=[O:43])[C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: Cc1noc(C(N)Cc2cccc(-c3ccc(F)c(Cl)c3)c2)n1
Agent: Cl
Product: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1cccc(-c2ccc(F)c(Cl)c2)c1)c1nc(C)no1

Procedure:
5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.087) was prepared using the general procedure A, from 2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.077 g, 0.21 mmol, prepared from [2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butylester following general procedure N) and 5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.07 g, 0.21 mmol).
Reaction SMILES: [C:1]([OH:11])(=O)[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].CN(C)C=O.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:12]([O:3][C@H:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:1]([Cl:26])=[O:11])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Cl)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(R)-Mandelic acid (10 g, 65.7 mmol) was dissolved in toluene (20 mL) at which point pivaloyl chloride (10.2 mL, 82.9 mmol) was added. This mixture was stirred at 60° C. for 3 hours. After cooling the reaction mixture to 30° C., toluene (10 mL), N,N-dimethylformamide (0.3 mL) and thionyl chloride (10 mL) were added. The reaction mixture was stirred at 35° C. for 2 hours and then at 50° C. for 4 hours. Then the mixture was evaporated to dryness to furnish 14.5 g (R)-2-chloro-2-oxo-1-phenylethyl pivalate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:57]1([CH2:62][C@H:63]2[CH2:67][CH2:66][CH2:65][NH:64]2)[CH2:61][CH2:60][CH2:59][CH2:58]1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:64]1[CH2:65][CH2:66][CH2:67][C@@H:63]1[CH2:62][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 11 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine in tetrahydrofuran. Yield: 11%; C26H29Cl2N5O2 (514.454); mass spectrum: (M+H)+=514/516/518 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH3:35])=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:26][CH:25]=5)[CH:23]=4)=[O:16])[CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.IC>O1CCCC1.CN(C)C=O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH2:35][O:3][CH:7]([CH3:8])[CH3:6])=[C:22]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:29]=5)[CH:23]=4)=[O:16])[CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)OCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Yield: 75.7 %

Procedure:
Sodium hydride (2.2 mg, 0.055 mmol, 60% by weight dispersion in oil) was slowly added to a stirred solution of 5′(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N,2′-trimethylbiphenyl-4-carboxamide (21 mg, 0.048 mmol) in a mixture of 0.90 mL of anhydrous tetrahydrofuran (THF) and 0.10 mL of anhydrous N,N-dimethylformamide (DMF). The resulting suspension was allowed to stir for 3 minutes before iodomethane (0.0048 mL, 0.072 mmol) was added to the reaction mixture. An additional aliquot of sodium hydride and iodomethane were required to consume all of the starting material which was monitored by LCMS. The crude reaction product was evaporated to dryness, redissolved in a minimum of DMF and purified by preparative LCMS chromatography to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(isopropoxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 42%) ESI-MS m/z calc. 456.2, found 457.5 (M+1)+. Retention time of 2.94 minutes. 1H-NMR (400 MHz, CD3CN) δ 0.91-0.93 (m, 2H), 1.41-1.45 (m, 2H), 2.23 (s, 3H), 3.00 (s, 3H), 3.07 (s, 3H), 3.20 (s, 3H), 5.81 (s, 2H), 6.29-6.36 (m, 2H), 6.56 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.92 (dd, J=1.6, 7.9 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 7.46 (dd, J=1.8, 6.4 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12.C[Si]([C:16]#[C:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)(C)C.[F-].[CH2:26]([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:26][C:23]1[CH:22]=[CH:21][C:20]([NH2:24])=[CH:19][C:18]=1[C:17]#[C:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)C#Cc1cccc(N)c1
Reactant: Cn1ncc2c(Br)cncc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1C#Cc1cncc2c1cnn2C
Temperature: 80 °C
Yield: 58.5 %

Procedure:
In an adaption of GP 3c, 640 mg of 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (Intermediate 2.1, 3 mmol, 1 eq), 1000 mg 3-trimethylsilanylethynyl-phenylamine (4.92 mmol, 1.63 eq.), 106 mg dichlorobis(triphenylphosphine)palladium (II) (PdCl2(PPh3)2) (0.15 mmol, 5 mol %) and 115 mg copper (I) iodide (0.6 mmol, 0.2 eq.) were dissolved in 15 mL THF (0.2 M) and treated with 3.6 mL tetra-n-butylammonium fluoride solution (1.0 M in THF, 3.6 mmol, 1.2 eq.). The resulting mixture was heated to 80° C. in a Biotage Initiator microwave oven for 30 min. Extractive work-up followed by column chromatography provided the 460 mg of the target compound (58% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32].O>CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:31](=[O:32])[C:30]([F:37])([F:36])[F:29])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Nc3ccccc3[C@H]12
Reactant: CCOC(=O)C(F)(F)F
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Nc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-amine (Structure 35 of scheme IX where X=N(H), R1=H, R2=H, R3=Cl, R4=H, R5=H, R10=H) (350 mg, 1.17 mmol) in methanol (22 mL) and triethylamine (0.7 mL) was added ethyl trifluoroacetate (1.5 mL). The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ethyl acetate (3×). The organic layers were washed with brine, dried (Na2SO4) and evaporated. After purification on silica with heptane/ethyl acetate 6:4 the title compound (90 mg, 19%) was obtained. Data: 1H-NMR (400 MHz, CDCl3) 1.69 (m, 1H), 1.86-1.94 (m, 2H), 2.11 (m, 1H), 2.99-3.09 (m, 2H), 4.47 (d, 1H), 4.86 (m, 1H), 5.79 (s, 1H, NH), 6.62 (d, J=8.2, 1H), 6.75 (dd, J=7.8, 1H), 6.89 (t, J=7.8, 1H), 6.91 (dd, J=8.2, J=2.7, 1H), 7.10 (d, J=2.7, 1H), 7.18 (t, J=7.8, 1H), 7.24 (d, J=7.8, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]1=[O:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C>[OH:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]2=[O:12])[CH2:15][CH2:16]1
Reactant: CC(C)n1ccn(CCCl)c1=O
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ccn(CCN2CCC(CO)CC2)c1=O
Temperature: 70 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of 1-(2-chloroethyl)-1,3-dihydro-3-(1-methylethyl)-2H-imidazol-2-one (12 g), 4-piperidinemethanol hydrochloride (9.1 g), N,N-diethylethanamine (21 ml) and KI (catalytic amount) in DMF (200 ml) was stirred for 20 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding 6.9 g (43%) 1,3-dihydro-1-[2-[4-(hydroxymethyl)-1-piperidinyl]ethyl]-3-(1-methylethyl)-2H-imidazol-2-one (intermediate 3).
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH2:28])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1.[Cl:43]CCl>>[ClH:43].[NH2:28][C:9]1[NH:8][C:12]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=2)=[CH:11][N:10]=1
Reactant: CCCCCCC(=O)Nc1ccc(-c2cnc(N)n2C(=O)OC(C)(C)C)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)Nc1ccc(-c2cnc(N)[nH]2)cc1
Product: Cl
Temperature: 0 °C
Yield: 97 %

Procedure:
2-amino-5-(4-heptanoylaminophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.089 g, 0.230 mmol) was dissolved in anhydrous dichloromethane (5 mL) and cooled to 0° C. Trifluoroacetic acid (0.50 mL) was added drop-wise while the reaction continued to stir at 0° C. Upon completion, the reaction was allowed to warm to room temperature over the course of 12 h. Toluene (2 mL) was added and the reaction was evaporated to dryness. The crude TFA salt was then dissolved in dichloromethane (3 mL) and a 2M solution of HCl in diethyl ether (0.10 mL) was added. The solution was again concentrated under reduced pressure and the resulting product triturated with cold diethyl ether (5 mL) to afford 0.072 g (97%) of the desired compound heptanoic acid [4-(2-amino-3H-imidazol-4-yl)phenyl]amide in its corresponding hydrochloride form as a yellow amorphous solid: 1H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 12.05 (s, 1H), 10.08 (s, 1H), 7.67 (d, 2H, J=8.1 Hz), 7.59 (d, 2H, J=8.1 Hz), 7.43 (br s, 2H), 7.27 (s, 1H), 2.31 (t, 2H, J=6.8 Hz), 1.58 (m, 2H), 1.27 (m, 6H), 0.86 (t, 3H, J=5.7 Hz); 13C NMR (75 MHz, DMSO-d6) δ 172.1, 148.2, 139.8, 127.1, 125.4, 123.0, 119.9, 109.1, 37.1, 31.7, 29.0, 25.7, 22.7, 14.6; HRMS (ESI) calcd for C16H22N4O (M+) 286.1794. found 286.1788.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[Na+]>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Agent: CCOC(=O)C(=O)c1csc(=NC=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CNc1nc(C(=O)C(=O)O)cs1

Procedure:
To a suspension of ethyl 2-(2-formylaminothiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylate, (281 g.) in water (1100 ml.) was added an 1N sodium hydroxide aqueous solution (2.23 l.) under stirring and ice-cooling, and then the mixture was stirred for 5 minutes at 10° to 15° C. After the reaction mixture was filtered, the filtrate was adjusted to pH 1 with concentrated hydrochloric acid with stirring. The precipitates were collected by filtration, washed with water and then dried to give 2-(2-formylaminothiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylic acid, (234 g.), mp 133° to 136° C. (dec.).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[C:13]([C:17]2[N:18]([CH2:43][CH3:44])[C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[CH:40]=[CH:39][C:38](=[O:41])[NH:37][CH:36]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:22]=[CH:21][C:20]=3[N:42]=2)=[N:14][O:15][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:11][C:12]1[C:13]([C:17]2[N:18]([CH2:43][CH3:44])[C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[CH:36]=[N:37][C:38]([O:41][CH2:3][CH2:4][N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)=[CH:39][CH:40]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:22]=[CH:21][C:20]=3[N:42]=2)=[N:14][O:15][N:16]=1
Reactant: ClCCN1CCOCC1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(=O)[nH]c4)c3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(OCCN5CCOCC5)nc4)c3)cc21
Temperature: 80 °C
Yield: 29.2 %

Procedure:
2-Chloroethylmorpholine hydrochloride (104 mg, 0.6 mmol) was added to a slurry of the product of Step 2 (135 mg, 0.3 mmol) and powdered K2CO3 (1 g) in DMF (2 mL) and the mixture was heated to 80° C. for 3 h. The mixture was cooled, diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried (MgSO4), filtered and the filtrate was concentrated to give a yellow oil which was purified by reverse phase HPLC to give the title compound (50 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 9.13 (s, 1H), 8.69 (s, 1H), 8.09 (d, J=9.3, 1H); 7.92 (s, 1H), 7.69 (d, J=8.0, 1H), 7.60-7.53 (m, 2H), 7.12 (d, J=8.0, 1H), 6.67 (d, J=9.4, 1H), 4.76 (br q, 2H), 4.53 (br m, 2H), 3.83-3.70 (m, 8H), 3.33 (m, 2H), 1.46 (br t, 3H). MS (ES+) m/e 572 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:18])[C:16]=2[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=3[C:19](O)=[O:20])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH:42][C:19]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[O:8][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)=[C:16]([CH3:17])[C:15]2=[O:18])=[O:20])[CH3:38]
Reactant: COc1ccc(-c2oc3c(C(=O)O)cccc3c(=O)c2C)cc1
Reactant: CCN(CC)CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)c(C)c(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6.00 g of 4'-methoxy-3-methylflavone-8-carboxylic acid and 2.70 ml of triethylamine in 70 ml of anhydrous tetrahydrofuran was added a solution of 2.03 ml of ethyl chlorocarbonate in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a solution of 2.25 g of N,N-diethylethylenediamine in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1.5 hours under ice-cooling and further 16 hours at room temperature. The reaction mixture was treated by the same procedure as in Example 3(b), to give 3.55 g of pale yellow crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 125.5°-127° C. This compound was identical with the product obtained in Example 36(a) in NMR and IR spectra, and mixed m.p.