Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[Cl:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(C)cc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 4-chloro-3-{[(2,4-dichloro-6-methylphenyl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate (Reference example 118, 2.17 g, 4.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (872 mg, 4.55 mmol) and triethylamine (0.70 mL) in tetrahydrofuran (20 mL) was stirred at 50° C. for 12 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-2-[(2,4-dichloro-6-methylphenyl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate as a brown wax (1.67 g).
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[CH3:20][CH:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:28][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:20])=[O:5]
Reactant: O=C(Cl)c1cc(I)cc(I)c1I
Reactant: CCCCCCC(C)O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(C)OC(=O)c1cc(I)cc(I)c1I
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The 2,3,5-triiodobenzoyl chloride was dissolved in 60 ml of dry dichloromethane. The solution was cooled to 0° C. and 6.07 g (60.0 mmol) of triethylamine was added. The brown solution was placed under nitrogen and 4.30 g (33.0 mmol) of 2-octanol was added in 10 ml of dry dichloromethane. Dimethylaminopyridine (0.367 g, 3.00 mmol) was added and the resulting solution was stirred at room temperature for 72 hrs. The brown solution was partitioned between 100 ml of dichloromethane and 100 ml of 1M HCl. The dichloromethane layer was washed with saturated NaHCO3 solution (50 ml) and brine (50 ml). The solution was dried over Na2SO4 and concentrated in vacuo to yield a dark brown oil (17.43 g). The oil was purified by flash chromatography using 436 g of silica gel and 5% ethyl acetate/hexane as the eluent. The first 600 ml to elute contained nothing while the pure product eluted with the next 700 ml. Concentration in vacuo afforded 15.68 g (85%) of the product as a yellow tinted oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(#N)C.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]2[N:3]=[N:4][CH:5]=[N:1]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: c1nnn[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Temperature: 110 °C

Procedure:
1H-tetrazole in acetonitrile solution (0.45M, 19 mL, 8.5 mmol) was combined with 4-fluoro-nitrobenzene (1 g, 7.09 mmol) in a 40 mL pressure tube, followed by addition of potassium carbonate. The tube was sealed and heated at 110° C. overnight (caution: build-up of pressure possible; use a safety shield). Pressure buildup was observed. The pressure was released carefully. The reaction was concentrated to dryness and diluted with water. The aqueous mixture was extracted 4 times with DCM. The combine organic layers were dried over sodium sulfate, filtered, concentrated and purified by column chromatography through a 40 gram biotage silica gel cartridge eluted with 5-20% ethyl acetate/hexanes (gradient) to give the product as white solid. LRMS talc: 191.0; obs: 192.3 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:17][CH:18](OC)[O:19]C)=[O:15])=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:17][CH:18]=[O:19])=[O:15])=[N:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2ncon2)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: O=CCN(C(=O)CCOCCc1cccc(-c2ncon2)c1)C1CCCCC1
Reaction time: 8 h

Procedure:
To 3-(3-(1,2,4-oxadiazol-3-yl)phenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide [Example 11, Step ii)] (500 mg) in NMP (4 mL) was added p-toluenesulfonic acid (441 mg) and the mixture stirred for 8 h. After work-up the material was used in the next step directly.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:23]([N:5]1[C:6]2[CH:7]=[C:8]([I:15])[CH:9]=[CH:10][C:11]=2[C:12]2[C:4]1=[CH:3][C:2]([I:1])=[CH:14][CH:13]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCBr
Reactant: Ic1ccc2c(c1)[nH]c1cc(I)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1c2cc(I)ccc2c2ccc(I)cc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of compound 5 (3.00 g) in 30 mL of anhydrous DMF was added 660 mg (4.78 mmol, Aldrich Co.) of anhydrous K2CO3. The solution was stirred at 80° C. for 2 h under argon after 0.93 g (4.82 mmol) of bromooctane was added. The mixture was stirred at 80° C. for 24 h and then quenched with 30 mL of water. The aqueous layer was extracted three times with 50 mL of diethyl ether. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel, hexanes as eluent) followed by recristallization in methanol to give 1.55 g of the title product as a white solid. M.P. 82-84° C. (Global yield for the last two steps: 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:24]3[C:19](=[C:20](Br)[CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=1[C:26]([O:28]CC)=[O:27])=[CH:7][CH:6]=[CH:5]2.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].CO.FC(F)(F)C(O)=O>C(COC)OC.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.O.C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:24]3[C:19](=[C:20]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH3:40])[CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=1[C:26]([OH:28])=[O:27])=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2cc(N)ccc12
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccccc1-c1cccc2c(CCCOc3cccc4cc(N)ccc34)c(C(=O)O)[nH]c12
Temperature: 160 °C

Procedure:
A mixture of EXAMPLE 563A (45 mg), o-tolylboronic acid (15.7 mg), K2CO3 (1 M, 0.17 ml) and bis(triphenylphosphine)palladium(II) dichloride (7.2 mg, 0.01 mmol) in a mixture of dimethoxyethane (2.2 ml), ethanol (0.6 ml) and water (0.9 ml) was heated at 160° C. in a microwave reactor (CEM Discover) for 10 minutes. The reaction mixture was acidified with a diluted trifluoroacetic acid methanol solution and concentrated. The residue was suspended in a mixture of DMSO and methanol (1:1) and filtered. The filtrate was purified by RP HPLC to provide the desired product. 1H NMR (400 MHz, DMSO-D6) □ 10.43 (s, 1H), 8.08 (d, J=8.90 Hz, 1H), 7.69 (d, J=6.75 Hz, 1H), 7.31-7.34 (m, 2H), 7.18-7.29 (m, 5H), 7.02-7.11 (m, 5H), 6.64 (d, J=7.67 Hz, 1H), 4.15 (t, J=5.98 Hz, 2H), 2.49-2.53 (m, 2H), 2.17-2.25 (m, 2H), 2.06 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([C@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:29][CH:30]([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:30]([F:40])[F:29])[CH:36]=3)=[C:16]([CH3:21])[N:15]([C@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC[C@@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(Br)c1C
Reactant: OB(O)c1cccc(C(F)F)c1
Product: COC[C@@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(-c2cccc(C(F)F)c2)c1C

Procedure:
Example 44 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 43c and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid. ESI mass spectrum: [M+H]+=519; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-])=O)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.N1CCOCC1>CO>[NH2:22][C:5]1[C:6]2[C:7](=[O:21])[C:8]3[C:13](=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[N+:18]([O-:20])=[O:19])[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Solvent: C1COCCN1
Solvent: CO
Solvent: Oc1ccccc1
Product: Nc1ccc(O)c2c1C(=O)c1c([N+](=O)[O-])ccc(O)c1C2=O
Temperature: 150 °C

Procedure:
8.25 parts of 1,8-dihydroxy-4,5-dinitroanthraquinone is heated in 40 parts of phenol in the presence of 1 part of morpholine for 3 hours at 140° to 150° C. Then another 1 part of morpholine is added and the whole is heated for 1 hour at 150° C. The reaction mixture is allowed to cool to 60° C, 80 parts of methanol is added and the precipitated reaction product is suction filtered. The filter residue is washed with hot water and dried. 4.9 parts of 1-amino-8-nitro-4,5-dihydroxyanthraquinone is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([F:38])[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([F:38])[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1
Yield: 84.8 %

Procedure:
100 mg of 1,1-diethyl-3-[3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl}urea in solution in 2 mL of dichloromethane with 1 mL of trifluoroacetic acid are stirred at ambient temperature for 18 hours. The solvent is evaporated off under vacuum by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge with an eluent of 100% dichloromethane to 85/15 dichloromethane/methanol. 72 mg of 1,1-diethyl-3-{3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea in the form of a trifluoroacetate salt are isolated in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm). For this batch, we observe a 60%-40% resolution of tautomers with: 1.23 (m, 6H); from 1.30 to 1.91 (broad m, 10H); 2.70 to 3.53 (very broad m, 6H); 3.41 (m, 4H); 4.12 (m, 2H); 7.11 (d, J=8.0 Hz, 0.6H); from 7.24 to 7.30 (m, 0.8H); 7.44 (d, J=11.0 Hz, 0.6H); 8.00 (s, 1H); 8.94 (broad m, 1H); 9.77 (s, 0.4H); 9.79 (s, 0.6H); 12.9 (broad s, 0.4H); 12.95 (broad s, 0.6H); 13.0 (broad s, 1H).
Reaction SMILES: [Al].II.[CH2:4](Br)[C:5]#[CH:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.[Hg](Cl)Cl>[C:18]([C:17]([OH:22])([CH:16]([N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:6][C:5]#[CH:4])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)C(Cc1ccc(Cl)cc1)n1cncn1
Reactant: C#CCBr
Agent: Cl[Hg]Cl
Agent: II
Agent: [Al]
Solvent: C1CCOC1
Product: C#CCC(O)(C(Cc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
3.7 g of aluminum (in the form of flakes), a pinch of mercury(II) chloride and an iodine crystal are stirred with 20 ml of absolute tetrahydrofuran for 12 hours. 24 g (0.2 mol) of propargyl bromide, dissolved in 25 ml of tetrahydrofuran, are then added dropwise at 50° to 60° C. The mixture is stirred for a further 30 minutes at 60° C. and cooled to -60° C., and 29.2 g (0.1 mol) of 5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one in 100 ml of tetrahydrofuran are slowly added dropwise. Thereafter, the reaction mixture is stirred for a further hour at 0° C. and for 2 hours at 20° C., 50 ml of saturated, aqueous ammonium chloride solution are added, while cooling, the mixture is filtered and the filtrate is evaporated down. The remaining crystalline residue is digested with water and recrystallized from 520 ml of cyclohexane. 24.6 g (74.2% of theory) of 4-tert.-butyl-6-(4-chlorophenyl)-5-(1,2,4 -triazol-1-yl)-hex-1-in-4-ol of melting point 121° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CN(C)C=O.Cl>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(Cl)nc2cc(C(F)(F)F)ccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Nc2c([N+](=O)[O-])c(Cl)nc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,4-dichloro-3-nitro-7-trifluoromethyl-quinoline (220 mg; 0.70 mmol; 1 eq) in dimethylformamide (3.5 mL), are added successively triethylamine (105 μL; 0.76 mmol; 1.08 eq) and 4-methoxyaniline (88 mg; 712 mmol; 1.01 eq.). The reaction mixture is allowed to stir for 1 hour at room temperature until the reaction is complete on TLC. The crude solution is diluted with a 1M aqueous solution of HCl (5 mL) and then extracted with ethyl acetate (40 mL). The organic layer is separated and washed 3 times with a 1M aqueous solution of HCl (3×40 mL), dried over sodium sulfate, filtrated and concentrated under vacuum to afford the title compound as a yellow powder (280 mg; 0.70 mmol; 100%) which is used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([N+:16]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.N.[S-][S-].[Na+].[Na+]>C(O)C>[C:1]1([CH2:7][CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(C=CCc2ccccc2)c1
Agent: N
Agent: [Na+]
Agent: [S-][S-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C=CCc2ccccc2)c1
Yield: 84.9 %

Procedure:
To a solution of 3-(3-phenyl-1-propenyl)nitrobenzene (10.5 g) in 200 ml of ethanol were added 70 ml of 35% ammonia water and 44 g of sodium disulfide. After heating under reflux for 2 hours, the solvent was removed under reduced pressure, followed by extraction with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure to give 7.8 g of 3-(3-phenyl-1-propenyl)aniline (yield, 85%). B.P. 128°-130° C./0.09 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>>[CH3:18][N:19]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: CNc1cccc(OC)c1
Product: COc1cccc(N(C)c2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (180 mg, 0.693 mmol) and N-methyl-3-methoxyaniline (112 mg, 0.816 mmol) in 3 mL of solvent (ethanol:water=2:1) was refluxed for 20 h. The solvent was removed under reduced pressure and the residue was dissolved in 25 mL of ethyl acetate. The ethyl acetate solution was washed with 25 mL of 1M NaOH, and the aqueous layer was reextracted with ethyl acetate (25 mL). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40–45% ethyl acetate/hexanes) to give the title compound as an oil (250 mg, 0.693 mmol, 100%). 1H NMR (CDCl3): 8.86 (dd, J=0.6, 4.5 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 7.85 (dt, J=1.8, 7.8 Hz, 1H), 7.42 (m, 2H), 6.95 (dd, J=1.8, 8.4 Hz, 1H), 6.86 (m, 1H), 6.82 (m. 1H), 3.85 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: C(O[CH:5]([C:20]1[N:21]=[CH:22][N:23]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]=1[CH3:25])[CH:6]1[C:18](=[O:19])[N:10]2[C:11]3[C:16]([CH:17]=[C:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH3:25][C:24]1[N:23]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:22]=[N:21][C:20]=1[CH:5]=[C:6]1[C:18](=[O:19])[N:10]2[C:11]3[C:16]([CH:17]=[C:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2cc3ccccc3n2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1c(C=C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one in toluene (30 ml) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (762 mg). After being stirred at 55° C. for 2 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue obtained was purified with silica gel column chromatography (eluent:chloroform) to give 8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.3 g).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Temperature: 155 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (240 mg, 0.621 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (373 mg, 1.86 mmol) in n-BuOH (3 mL) was stirred at 155° C. for 16 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Gilson) to provide (R)-tert-butyl 1-(5-bromo-3-(3-chloro-4-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (110 mg, 31% yield).
Reaction SMILES: [CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]([OH:20])=[O:19])=[C:12]([CH3:21])[N:11]=3)[NH:8][C:4]=2[CH:3]=1.[CH2:25](O)[CH3:26]>OS(O)(=O)=O>[CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]([O:20][CH2:25][CH3:26])=[O:19])=[C:12]([CH3:21])[N:11]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc(Nc3nc(C)c(CC(=O)O)c(O)n3)[nH]c2cc1C
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C)nc(Nc2nc3cc(C)c(C)cc3[nH]2)nc1O
Yield: 19 %

Procedure:
A solution of (2) (0.935 g, 2.86 mmol) in ethanol (20 mL) and concentrated H2SO4 (3.5 mL) was heated at reflux for 24 h. The ethanol was evaporated in vacuo, cold water (30 mL) was added and the solution was then neutralised with NaOH 10M. The mixture was extracted with CHCl3 (4×20 ml,) and the combined organic phases were dried (MgSO4) and evaporated in vacuo. The resulting residue was triturated with ethanol and filtered to give 0.190 g (19%) of 2-[(5,6-Dimetlhyl-2-benzoimidazolyl)amino]-4-hydroxy-6-methyl-5-pyrimidine acetic acid, ethyl ester (1). mp: >300° C. (CF3CO2H/C2H5OH). IR (KBr): υ=3254, 2968, 2922, 1737, 1623, 1560, 1344, 1294, 774 cm−1. Accurate mass: calculated: 355.1644. Found 327.1644. Analysis calculated for C18H21N5O3: C, 60.83; H, 5.96; N, 19.71. Found: C, 60.1; H, 5.7; N, 18.7.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[S:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1

Procedure:
A mixture in DMF (1 ml) of trans-4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A; 90 mg, 0.20 mmol), propionic acid (15 mg, 0.20), iPr2NEt (103 mg, 0.80 mmol) and TBTU (67 mg, 0.21 mmol) was stirred 18 h at room temperature. Sat. aq. NaHCO3 sol. was added and the product was extracted with EtOAc (3×). The organic layers were washed with water and brine, dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to yield the title compound as an off-white crystalline solid (66 mg, 83%), MS (ISP) m/z=401.3 [(M+H)+].