Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[Cl:9][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)cc(Nc2ccccc2)n1
Yield: 64.7 %

Procedure:
2-Methyl-4,6-dichloropyrimidine (430 mg; 2.64 mMol) was refluxed in p-dioxane 10 mL with DIEA (575 uL; 426 mg; 3.3 mMol) and aniline (239 uL; 247 mg; 2.65 mMol) for 48 hrs under N2. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 0.5 N HCl. The organic fraction was washed with water, brine, and dried over Na2SO4) and the solvent removed under reduced pressure. Crude material was triturated with MTBE, suction filtered to isolate and washed with more MTBE and air dried to afford 375 mg of white solid, 64.5% yield. 1H NMR (500 MHz DMSO-d6) d 8.9 (s, 1H), 7.7 (s, 1H), 7.55 (m, 2H), 7.27 (t, 2H), 6.95 (t, 1H), 6.0 (s, 1H) 2.25 (s, 3H) ppm
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11]2[N+:12]([O-:17])=[N:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1.ClCCl.[Br:23]Br>CC#N>[Br:23][C:14]1[N:13]=[N+:12]([O-:17])[C:11]([NH:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:19])[CH3:18])=[N:16][CH:15]=1
Reactant: BrBr
Reactant: CC(C)(CNc1nccn[n+]1[O-])c1ccc(F)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(CNc1ncc(Br)n[n+]1[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a solution of N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide (1.2 g, 7.4 mmol) in a 1:1 mixture of dichloromethane and CH3CN (40 mL) was added Br2 (1.0 mL, 19 mmol). The mixture was stirred at room temperature for 72 h. The solvents were evaporated and the residue was dissolved in ether. The solution was filtered through a plug of silica gel and the solvents evaporated to give the desired product (1.5 g, 58%) as an orange sticky solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]([C@@H:42]1[CH2:47][NH:46][CH2:45][CH2:44][N:43]1[CH3:48])=[O:41]>>[CH3:38][O:39][C:40]([C@@H:42]1[CH2:47][N:46]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:45][CH2:44][N:43]1[CH3:48])=[O:41]
Reactant: COC(=O)[C@@H]1CNCCN1C
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)[C@H](C(=O)OC)C1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with (S)-1-methyl-piperazine-2-carboxylic acid methyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H45N4O4Cl2 [(M+H)+] 679.2813, observed 679.2805.
Reaction SMILES: Br.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17]C(=O)OCC)[CH:14]=[CH:15][CH:16]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4].[OH-].[K+]>C(O)C>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CCOC(=O)Nc1cccc(-c2csc(NC(=N)N)n2)c1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Yield: 70.3 %

Procedure:
A mixture of 47.1 gm of ethyl N-[3-(2-guanidino-4-thiazolyl)-phenyl]-carbamate hydrobromide, 210 ml of ethanol and 210 ml of a 50% potassium hydroxide solution was refluxed for 15 minutes. After cooling, the white precipitate which had formed was filtered off, dissolved in water and carefully acidified with hydrochloric acid. The resulting solution was made alkaline with an excess of sodium hydroxide solution, and the precipitate formed thereby was filtered off, washed with water and dried, yielding 20 gm of the title compound, m.p. 222°-224° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:6]=1[OH:12].Cl.CCOC(C)=O>CN(C=O)C.[Cu-]=O>[Br:4][C:5]1[CH:10]=[C:9]([S:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:12]
Reactant: Oc1ccc(I)cc1Br
Reactant: C[S-]
Agent: O=[Cu-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(O)c(Br)c1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
Sodium thiomethoxide (8.64 g) and copper (I) oxide (8.79 g) were mixed with 2-bromo-4-iodophenol (XX, 14.72 g) in anhydrous DMF (100 mL). The mixture was stirred and heated at 80° C. for 48 h under nitrogen atmosphere. Then, the resultant slurry was treated with concentrated HCl (5 mL) and EtOAc (200 mL), and was filtered and rinsed with EtOAc (200 mL). The organic layers were partitioned with 1N HCl (150 mL), water (150 mL) and brine (150 mL) and dried over MgSO4, filtered and solvent removed in vacuo. Product was purified by silica gel column chromatography, the product eluted with dichloromethane/hexane (2:3), to give the desired product (5.22 g, 39%) as a light brown oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1.[CH3:18][N:19]=[C:20]=[S:21]>C(O)C>[CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:20]([NH:19][CH3:18])=[S:21])[CH2:11]2)[N:9]=1
Reactant: CN=C(N)Nc1nc(C2CCCC(N)C2)cs1
Reactant: CN=C=S
Solvent: CCO
Product: CN=C(N)Nc1nc(C2CCCC(NC(=S)NC)C2)cs1
Yield: 90.5 %

Procedure:
To a solution of 2-(2-methylguanidino)-4-(3-aminocyclohexyl)thiazole (0.3 g.) in ethanol (50 ml.) was added methylisothiocyanate (0.1 g.) and the solution heated under reflux for 2 hours. Evaporation of the reaction mixture and crystallisation of the residue from methanol/ethyl acetate gave 2-(2-methylguanidino)-4-[3-(3-methylthioureido)cyclohexyl]thiazole (0.35 g.), m.p. 214°-215° (decomp.).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].C(=O)([O-])O.[OH:29][CH2:30][CH2:31][N+:32]([CH3:35])([CH3:34])[CH3:33]>C(O)C>[C:21]([C:6]1[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]([C:9]#[N:10])=[C:3]([CH:2]([F:1])[F:24])[N-:4][C:5]=1[CH3:23])#[N:22].[OH:29][CH2:30][CH2:31][N+:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)N1
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: CCO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)[N-]1

Procedure:
To a suspension of 75 mg (0.23 mmol) 2-(difluoromethyl)-6-methyl-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Enantiomer 1; Example 2) in ethanol (1.6 ml) under argon atmosphere was added 32.6 μl (0.23 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 1 h. Subsequently, the solution was evaporated, and the residue was dried in vacuo. The precipitate was stirred in 1.5 ml THF for 3 days and then centrifuged to yield 56 mg (56% of th.) of the title compound as a yellow solid.
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CSCCC(CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [1-hydroxy-4-(methylsulfanyl)butan-2-yl]carbamate (18.5 g, 84.5 mmol) in THF (400 mL) was added phthalimide (14.9 g, 0.101 mol) and triphenylphosphine (26.9 g, 0.101 mol) under a nitrogen atmosphere. Diethylazodicarboxylate (27.3 g, 0.135 mol) was added dropwise at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel to give tert-butyl {1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfanyl)butan-2-yl}carbamate. MS ESI calc'd. for C18H25N2O4S [M+H]+ 365. found 365. 1H NMR (400 MHz, CDCl3) δ 7.87-7.71 (m, 4H), 4.72 (s, 1H), 4.16-4.07 (m, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.68-2.54 (m, 2H), 2.13 (s, 3H), 1.75-1.55 (m, 2H), 1.35 (s, 9H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH:14]1[C:19]2[C:20](=O)[CH2:21][CH2:22][C:18]=2[CH:17]=[CH:16][N:15]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:14]1[C:19]2[CH:20]([CH2:3][C:1]#[N:2])[CH2:21][CH2:22][C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCc2ccncc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC1CCc2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (346 mg, 1.95 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride (54.0 mg, 1.35 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The mixture was added to a solution of 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (130 mg, 0.976 mmol) in tetrahydrofuran (5 mL) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→80/20). To a solution of the purified product in methanol (10 mL) was added palladium-carbon powder (30 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→70/30) to give the title compound (95.0 mg, yield 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:32]1[N:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]=[C:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:33]=1>CN(C)C=O>[C:44]1([C:34]2[N:35]=[C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:37]=[C:32]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:28])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:33]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2ccccc2)cc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5ccccc5)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (27.7 mmol) of 12,12-dimethyl-7-phenyl-10,12-dihydro-10-azaindeno-[2,1-b]fluorene are dissolved in 275 ml of dimethylformamide under a protective-gas atmosphere, and 1.45 g of NaH, 60% in mineral oil (36 mmol), are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (8.2 g, 30.5 mmol) in 75 ml of dimethylformamide is added dropwise. The reaction mixture is then stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 14.7 g (24.9 mmol, 90%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=O)=[CH:10][C:9]2=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][OH:59])[CH2:53]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:59][CH2:58][CH:54]1[O:55][CH2:56][CH2:57][N:52]([C:17]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[NH:15][C:16]2[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:7][C:8]3=2)=[O:19])[CH2:53]1
Reactant: OCC1CNCCO1
Reactant: COc1ccccc1-c1cc(C(N)=O)c2[nH]c3ccc(C(=O)O)cc3c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(C(N)=O)c2[nH]c3ccc(C(=O)N4CCOC(CO)C4)cc3c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
8-Carbamoyl-6-(2-methoxyphenyl)-9H-carbazole-3-carboxylic acid (31.5 mg, 0.061 mmol), HATU (75 mg, 0.197 mmol), DMAP (25 mg, 0.205 mmol), morpholin-2-ylmethanol (35 mg, 0.299 mmol) and DMF (3 ml) were combined and stirred at room temperature for 18 hours. The reaction mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC chromatography (water/CH3CN/NH4OAc eluent system). Product containing fractions were collected and evaporated in SPEEDVAC®. 13.4 mg 6-(2-(hydroxymethyl)morpholine-4-carbonyl)-3-(2-methoxyphenyl)-9H-carbazole-1-carboxamide were isolated as an off-white solid. MS (ESI) m/z 460 [M+H]. 1H NMR (CD3OD) δ ppm 8.45 (d, 1H, J=1.5), 8.27 (bs, 1H), 8.09 (d, 1H, J=1.5), 7.71 (d, 1H, J=8.6), 7.56 (dd, 1H, J=8.4, 1.7), 7.47 (dd, 1H, J=7.5, 1.7), 7.37 (dt, 1H, J˜8, ˜8, 1.7), 7.14 (d, 1H, J=8.5), 7.09 (dt, 1H, J=0.9, 7.5, 7.5), 4.05-3.90 (b, 2H), 3.86 (s, 3H), 3.70-3.55 (b, 4H), 3.5-3.0 (b, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 48.3 %

Procedure:
To a suspension of 13.37 g (56 mmol) of 2,6-diphenyl-4(3H)-pyrimidinone and 200 mL glacial acetic acid was added 15.1 g (84.8 mmol) of N-bromosuccinimide and the mixture was left to stir at room temperature for 60 h. The reaction was poured onto 100 g crushed ice and vacuum filtered, washing well with water, then air dried to yield 8.85 g (48%) 5-bromo-2,6-diphenyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO) δ7.55 (6H, m); 7.75 (2H, m); 8.15 (2H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17](Br)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:23](=[N:36][C:17]1[C:18]2[C:19]3[CH2:20][CH2:21][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10][C:11]=3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Brc1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCc3[nH]c4cccc(N=C(c5ccccc5)c5ccccc5)c4c3CC2)cc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of 3-benzyl-10-bromo-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (0.71 g, 2.00 mmol), benzophenone imine (0.44 g, 0.40 mL, 2.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.040 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.075 g, 0.120 mmol), and sodium tert-butoxide (0.269 g, 2.80 mmol) in toluene (20.0 mL) was refluxed for 16 h. After cooling to room temperature, water and ethyl acetate were added, and the pahases separated. The aqueous layer was extracted with ethyl acetate (2×). The combined ethyl acetate solution was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 30% EtOAc/hexane, 1% Et3N) to afford a yellow fluffy solid as the title compound (0.855 g, 94%): mp>71° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 7.82-7.80, 7.65, 7.66-7.11, 6.82-6.79, 0.73, 5.95, 3.78, 3.20-3.16, 2.90-2.78; MS (ESI+) m/z 456 (M++H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:9]1)[CH2:4][C:5]#[N:6].Cl.[NH2:27][OH:28].CCN(C(C)C)C(C)C>CCO>[F:25][C:2]([F:1])([F:24])[CH:3]([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[CH2:9]1)[CH2:4]/[C:5](=[N:27]/[OH:28])/[NH2:6]
Reactant: N#CCC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In a 50 mL round-bottomed flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanenitrile (200 mg, 549 μmol) and hydroxylamine hydrochloride (37.9 mg, 549 μmol) were combined with EtOH (2 ml) to give a colorless suspension. DIEA (106 mg, 144 μl, 823 μmol) was added and the resulting mixture was stirred at 100° C. for 6 hr. The crude reaction mixture was concentrated in vacuo to give (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide as a viscous oil. 85% pure by LC-MS. MH+=398.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([O:11][CH2:12][CH2:13][F:14])[N:8]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:7]=2[CH:22]=1)#[CH:2].C([N-]C(C)C)(C)C.[Li+].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37](=[O:39])[CH3:38]>O1CCCC1>[NH2:21][C:17]1[N:16]=[C:15]([N:8]2[C:7]3[CH:22]=[C:3]([C:1]#[C:2][C:37]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:31]=4)([OH:39])[CH3:38])[CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[O:11][CH2:12][CH2:13][F:14])[CH:20]=[CH:19][N:18]=1
Reactant: CC(=O)c1ncccn1
Reactant: C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Yield: 8.8 %

Procedure:
To a solution of 4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (30 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at −78° C. was added a lithium diisopropylamide solution (0.3 mL, 3.00 equiv) dropwise with stirring. The reaction mixture was stirred at −78° C. for 15 min. A solution of 1-(pyrimidin-2-yl)ethan-1-one (48.8 mg, 0.40 mmol) in tetrahydrofuran (0.5 mL) was then added and the mixture was stirred at −78° C. for another 20 min. The resulting solution was then stirred at room temperature for 13 h. The reaction was then quenched by the addition of saturated ammonium chloride solution (1 mL) and the mixture was extracted with 10 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column (ethyl acetate/petroleum ether, 1:3) to give 3.7 mg (9%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as an off-white solid: 1H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H), 8.40 (d, J=5.6 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.51-7.44 (m, 2H), 7.25-7.22 (m, 1H), 7.10 (s, 1H), 6.96 (d, J=5.2 Hz, 1H), 6.12 (s, 1H), 4.93-4.88 (m, 2H), 4.80 (s, 2H), 1.88 (s, 3H); LC-MS: m/z=+420 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[CH:6][CH:5]=1)[CH3:2].C(OC1C=CC(N)=CC=1)C.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH2:24][CH2:23]1.C=O>CCO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][N:26]2[C:22](=[O:28])[CH2:23][CH2:24][C:25]2=[O:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1
Reactant: CCOc1ccc(NC)cc1
Agent: C=O
Agent: CCOc1ccc(N)cc1
Solvent: CCO
Product: CCOc1ccc(NCN2C(=O)CCC2=O)cc1

Procedure:
(4-Ethoxy-phenyl)-methyl-amine: A mixture of 2 g (14.57 mmol) of 4-ethoxy-phenylamine, 1.73 g (17.49 mmol) of succinimide, and 1.4 mL (17.49 mmol) of 37% aq formaldehyde in 15 mL of EtOH was heated at reflux for 18 hours. The reaction mixture cooled down and precipitate was filtered and washed with Et2O, dried to give 2.89 g (11.27 mmol) of 1-[(4-ethoxy-phenylamino)-methyl]-pyrrolidine-2,5-dione, which was dissolved in DMSO and treated with 0.428 g (11.27 mmol) of NaBH4. The reaction mixture was heated in a hot water bath for 15 min, then it was poured into 20 mL of cold water and extracted with Et2O (3×15 mL), the organic extracts were combined and concentrated to give 1.7 g of the title compound. LC-MS (ESI+; 152 ([M+H]+)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:59][O:60][C:61]([NH:63][C@@H:64]([CH:68]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:65](O)=[O:66])=[O:62]>C(Cl)Cl>[CH3:59][O:60][C:61](=[O:62])[NH:63][C@H:64]([C:65](=[O:66])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:7][OH:8])[CH:68]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(C#N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(C#N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
(S)—N-(5-Amino-1-hydroxymethyl-pentyl)-4-cyano-N-isobutyl-benzenesulfonamide (6) obtained in the previous reaction was dissolved in 50 mL CH2Cl2. BOP (1.2 eq), and triethylamine (5 eq) were added. After 10 minutes, (S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (1 eq) was added and the mixture was stirred at RT for 3 hours. LCMS indicated a complete reaction. The reaction mixture was washed with sat. NaHCO3. The aqueous phase was washed again with 100 mL CH2Cl2. The combined organic layers where dried with MgSO4, filtered over dicalite and evaporated to dryness. The residue was purified by column chromatography with CH2Cl2-MeOH(NH3) (97:3). The appropriate fraction was evaporated to dryness. (1.31 g, 84% yield over 2 steps)