Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=[C:13]3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2].ClCCl.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=[C:13]3[N:12]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)[C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-2-(methoxymethyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (35 mg, 114 μmol) was stirred in abs. dichloromethane (30 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (65 mg, 343 μmol, 3 eq.), anhydrous copper(II) acetate (62.3 mg, 343 μmol, 3 eq.), abs. pyridine (25 μl) and triethylamine (35 mg, 343 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (22 mg, 114 μmol, 1 eq.), anhydrous copper(II) acetate (21 mg, 114 μmol, 1 eq.) and abs. pyridine (829 μl) were then added, and the mixture was stirred at RT for a further 3 d. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and pyridine and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (4.4 mg, 9% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:17](=[O:18])[C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:5]=3[C:4]=2[C:3]1=[O:26].[H-].[Na+].[Cl-].[CH2:30]([N+:32]1([CH2:37][CH3:38])[CH2:35][CH:34]([OH:36])[CH2:33]1)[CH3:31].C(OC(C)C)(C)C>CN(C)C=O>[CH2:30]([N:32]([CH2:37][CH3:38])[CH2:33][CH:34]([OH:36])[CH2:35][N:19]1[C:6]2[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]3[C:17](=[O:18])[N:2]([CH3:1])[C:3](=[O:26])[C:4]=3[C:5]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:31]
Reactant: CC[N+]1(CC)CC(O)C1
Reactant: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)N(C)C3=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
The starting material is prepared in the following manner: 1 g (2.95 mmol) 6,7,12,13-Tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole (precursor for Example 5) is dissolved in 15 ml dry dimethylformamide and added dropwise, under an atmosphere of argon, to a suspension of 100 mg (3.3 mmol) sodium hydride (80% in paraffin oil) in 25 ml dimethyl formamide. After stirring for 1 hour at 20° C., 915 mg (5.9 mmol) 1,1-diethyl-3-hydroxyazetidinium chloride are added thereto and the reaction mixture is stirred for 3 days at 20° C. The reaction mixture is evaporated in a vacuum, the residue is taken up in 150 ml of water and 500 ml ethyl acetate and the organic phase is separated off and dried over anhydrous sodium sulphate. After filtration, the filtrate is evaporated and the residue is chromatographed on silica gel with dichloro-methane/methanol (99:1 v/v). The fraction with the Rf 0.2 in dichloromethane/methanol (95:5 v/v) is isolated, stirred with 20 ml diisopropyl ether and the crystals obtained are filtered off. (±)-12-(3-Diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole is obtained in the form of yellow crystals; decomposition point 220°-228° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:8]([OH:10])=[O:9])=[O:5])#[N:2]>N.CO.[Rh]>[CH:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:11][C@H:7]([NH:6][C:4]([CH2:3][CH2:1][NH2:2])=[O:5])[C:8]([OH:10])=[O:9]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Rh]
Agent: N
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a 1-liter pressure autoclave, a solution of 10.00 g (45.0 mmol) of (S)-2-(cyanoacetylamino)-3-(1H-imidazol-4-yl)propionic acid (prepared according to Example 3) in a mixture of 157 g of conc. NH3/methanol (m/m=3:2) was added to 0.88 g of Rh/C (0.4 mol % pure Rh, based on reactant used). The autoclave was closed and flushed twice with 40 bar of nitrogen and once with hydrogen. The mixture was heated to 90° C. and the autoclave was pressurized with 40 bar of hydrogen. After 3 h at 90° C., the reaction mixture was cooled to room temperature, the autoclave was depressurized and the catalyst was filtered off by filtration. An in-process analysis (HPLC) showed that the reaction solution (147.2 g) contained 6.38% (m/m) carnosine, corresponding to a selectivity of 92% for complete conversion. The reaction mixture was then concentrated in a rotary evaporator to 41.2 g. 124 g of ethanol were added dropwise at room temperature and the flask was stored in a refrigerator overnight. On the next day, the precipitate was filtered off, washed with ethanol and dried in a drying oven at 40° C./20 mbar. 7.96 g (78%) of a slightly greenish solid with a content (HPLC) of 98% (m/m) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10]O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][C@@H:9]([CH3:12])[CH2:10][N:13]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Br)cnc2N[C@@H](C)CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3ncc(Br)cc32)cc1
Reaction time: 0.08 h

Procedure:
A solution of (S)-N-(5-bromo-2-(1-hydroxypropan-2-ylamino)pyridin-3-yl)-4-methylbenzenesulfonamide (6.39 g, 15.96 mmol) and triphenylphosphine (5.02 g, 19.16 mmol) in THF (160 ml) was heated to 60° C. whereupon diisopropyl azodicarboxylate (3.72 mL, 19.16 mmol) was added dropwise to the warm solution over a 5 minute period. Heating was discontinued after 5 minutes, and after cooling briefly, the solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and purified by column chromatography on silica gel (eluting with 6:1 dichloromethane-ethyl acetate followed by 5:1 dichloromethane-ethyl acetate) to afford (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazine a tan, waxy solid (3.12 g) which was used without further purification. MS (ESI, pos. ion) m/z 382, 384 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([N+]([O-])=NC#N)[CH:2]=1.CO.[Si](O)(O)(O)[OH:18]>Cl>[OH:18][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:1][CH:2]=1
Reactant: N#CN=[N+]([O-])c1ccc(C(=O)O)cc1
Reactant: O[Si](O)(O)O
Agent: Cl
Solvent: CO
Product: O=C(O)c1ccc(O)cc1

Procedure:
Degradation of calvatic acid in 1 N HCl containing 10% of methanol under reflux for 15 hours followed by silicic acid chromatography gave p-hydroxy-benzoic acid, melting at 210°-211° C., which was identified by comparison with the infrared spectrum of an authentic sample. Elemental analysis: found: C, 61.03; H, 4.76; N, 0.0, m/e 138; calcd. for C7H6O3 : C, 60.87; H, 4.38, m.w., 138. The data on high resolution mass spectrum of calvatic acid methyl ester is as follows:
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].Cl.C[O:7][C:8]1[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2>C1(C)C=CC=CC=1>[ClH:2].[OH:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC1CCc2c(ccc(O)c2O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41.4 g of dry AlCl3 (310.4 moles), 230 ml of toluene and 20.0 g of 5,6-dimethoxy-2-methylaminotetralin HCl (77.6 moles) are placed into a 4-necked round-bottomed flask, with stirring, under a slight stream of dry nitrogen. Temperature is brought to 80° C. to obtain a stirrable brown mixture, is left at 80° C. for 4 hours, then cooled to room temperature and poured into ice-water (about 1000 ml total). The aqueous phase is separated and evaporated under vacuum (T about 80° C.). The whitish solid is triturated at room temperature in 750 ml of absolute ethanol, then dried at 60° C.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[CH3:30][N:31]([CH3:35])[C:32]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[CH:21][CH:20]=3)=[O:23])[CH2:25][CH2:26]1)=[O:33]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)N(C)C)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and N,N-dimethylcarbamoyl chloride. Off-white solid. MS (m/z): 442.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([O:21]C)=[O:20])[CH2:15]1>O1CCOCC1.C(#N)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([OH:21])=[O:20])[CH2:15]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(C/C=C/c2cc(F)ccc2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(C/C=C/c4cc(F)ccc4F)C3)c2c1
Yield: 48.6 %

Procedure:
14.2 cm3 of a 5 N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 1.25 g (2.336 mmol) of methyl (±)-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate in solution in 25 cm3 of dioxane. After stirring under reflux for 16 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 40 cm3 of acetonitrile. After stirring for 0.5 hour at a temperature in the region of 0° C., the orange solid in suspension is filtered, rinsed with twice 7 cm3 of acetonitrile and then dissolved in 55 cm3 of water. The aqueous phase is then acidified with 1 N hydrochloric acid to a pH value in the region of 6–7 and then extracted with twice 20 cm3 of dichloromethane. The organic phases are combined, washed with twice 10 cm3 of water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.55 g of (±)-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid, in the form of a yellow solid melting at 77° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)c(Cl)nn2CCN1CCCC1
Temperature: 50 °C

Procedure:
A mixture of 3-chloro-5-nitro-1H-indazole (1.5 g, 7.6 mmol) was treated with potassium carbonate (3.1 g, 23 mmol) in DMF (20 mL) for 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine (1.9 g, 11 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.60 (m, 4H), 2.45 (m, 4H), 2.89 (t, J=6.44, 2H), 4.58 (t, J=6.44, 2H), 8.00 (m, 1H), 8.30 (m, 1H), 8.60 (m, 1H); MS (DCI/NH3) m/z 295 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[N:20][CH:19]=3)[C:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C:10]=3[C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[CH3:15][N+:12]1([O-:33])[CH2:13][CH2:14][C:9]2[N:8]([CH2:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[C:10]=2[CH2:11]1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC[N+](C)([O-])C1
Reaction time: 24 h
Yield: 41.9 %

Procedure:
Dimebon (500 mg) was dissolved in 10 mL dichloromethane. To this was added a solution of mCPBA (65%, 536 mg) in 5 mL dichloromethane drop wise at 25 deg C. The reaction mixture was stirred at 25 deg C. for 24 h at which point it was found complete (by TLC and LCMS). The solvent was removed under reduced pressure (below 30 deg C.) and the residue was purified by column chromatography on neutral alumina eluting with methanol-dichloromethane gradient to obtain 220 mg of product as light brown oil. TLC Rf 0.5 in 5% MeOH-DCM. This compound also exhibited the following inhibition profile:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:34]=[CH:35][C:36]([C:18]3[N:13]4[C:14]([S:15][C:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:12]4)=[N:16][CH:17]=3)=[CH:37][N:38]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc3s2)cc1OC
Temperature: 110 °C
Yield: 102.5 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.3 g, 0.775 mmol, 1 eq), PdCl2(Ph3P)2 (0.11 g, 0.155 mmol, 0.2 eq), 2-(4-boc-piperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (0.454 g, 1.16 mmol, 1.5 eq) and Na2CO3 (2M aqueous solution, 1.5 mL) in dioxane (4.5 mL) was heated at 110° C. for 2.5 h. The reaction was cooled down to it and solvents were removed under reduced pressure. The residue was treated with water, sonicated and filtered. The solid was washed with water, Et2O and dried to give the desired product (416 mg, 100%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=6.48 min, [M+H]+ m/z 524.2; 1H NMR (300 MHz, DMSO) δ 8.99 (s, 2H), 7.70 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.80 (m, 4H), 3.43 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[OH:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=3[C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[N:29][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(O)nc2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (124 mg, 0.562 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-ol. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.59-7.68 (m, 3H), 7.4 (s, 1H), 7.3 (s, 1H), 6.98-7.18 (m, 3H), 6.82 (d, 1H), 6.23 (d, 1H), 4.7 (d, 1H), 4.37 (d, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:16][CH:17]=1)=[C:10]=S.N=C=N.CO>C1COCC1.ClCCl>[CH3:32][NH:31][C:27]1[N:26]=[C:25]([C:24]2[C:19]([O:18][C:15]3[N:16]=[CH:17][C:12]([NH:9][C:10]4[NH:8][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=5[N:7]=4)=[CH:13][CH:14]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N=C=S)cn2)n1
Reactant: Nc1ccccc1N
Agent: N=C=N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cn2)n1

Procedure:
A mixture of benzene-1,2-diamine (0.091 g, 0.85 mmol), 4-(2-(5-isothiocyanatopyridin-2-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.237 g, 0.70 mmol), and polymer-supported carbodiimide (Argonaut technologies, 1.6 mmol/g, 1.3 g, 2.1 mmol) was heated for 14 h in anhydrous THF in a sealed vial. The reaction was cooled and was filtered, rinsing with 100 mL DCM. The filtrate was concentrated in vacuo to give an off-white solid. Sonication in dichloromethane gave a fluffy precipitate, which was filtered and collected to give an off-white solid. This material was adsorbed onto 0.8 g SiO2 from MeOH/MC, and purified by silica gel chromatography, 40 g, 0-10% MeOH/MC to give N-(6-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-3-yl)-1H-benzo[d]imidazol-2-amine as a white solid MS m/z=411 [M+H]+. Calc'd for C22H18N8O: 410.4.
Reaction SMILES: [CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[NH:3]1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:16])[N:8]=2)[NH:3]1
Reactant: CC1(C(=O)O)C=CN(c2ccccn2)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C(=O)O)C=CN(c2cccc(Br)n2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
A mixture of 3-methyl-1-(pyridin-2-yl)-1H-pyrazolecarboxylic acid (7.0483 mmol, 1.63 g) and N-bromosuccinimide (2.51 g, 2.0 eq.) in carbon tetrachloride (40 mL) was stirred at ambient temperature for 18 h. The reaction mixture was filtered through celite to remove solid impurity and washed with carbon tetrachloride (30 mL). The filtrate was evaporated and purified by flash chromatography on a silica gel column (200 g) eluted with 3:1 hexane:ethyl acetate to give 0.258 g of pure 3-methyl-1-(6-bromopyridin-2-yl)-1H-pyrazolecarboxylic acid (12%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: CSc1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution containing 3-thiophenemethanol (0.56 g, 0.0041×1.2 mol) and sodium hydride (0.17 g, (ca.60% in mineral oil), 0.0041×1.05 mol) in tetrahydrofuran, 2,6- dichloro-4-methylmercaptopyridine (0.80 g, 0. 0041 mol) was added, and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [CH2:1]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>O>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:16][CH2:15][CH:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:17])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCOC(C)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 9 h

Procedure:
6.6 g of 2-dodecyloxypropanol and 20 ml of dry pyridine were mixed and cooled with NaCl-ice. 8.0 g of p-toluenesulfonic acid chloride was added little by little, and the reaction was continued for 9 hours. The reaction mixture returned to room temperature was mixed with a mixture of 30 ml of conc. hydrochloric acid added to 110 g of water, and the mixture was extracted with benzene and dried over anhydrous Na2SO4. Evaporation of benzene gave (2-dodecyloxypropyl) p-toluenesulfonate as an oily product. Yield: 10.7 g.