Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].C([O-])(O)=O.[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14].[Cl-].[Na+]>CO>[CH3:12][S:13]([NH:1][NH:2][C:3]([NH:5][NH:6][S:13]([CH3:12])(=[O:15])=[O:14])=[O:4])(=[O:15])=[O:14]
Reactant: NNC(=O)NN
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)NNC(=O)NNS(C)(=O)=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A mixture of 45 g (0.5 mole) carbohydrazide, 84 g NaHCO3 (1.0 mole) and 50 ml methanol was stirred as 114.5 g (1.0 mole) methane sulfonyl chloride was added over 30 minutes. The temperature rose from 25° to 40° C. The stirring was continued for 15 minutes (temp. 44° C). The mixture was then heated to 65° C for two hours, and was then cooled to 25° C and the solid product (including sodium chloride was filtered and washed with methanol and dried. Yield: 146 g. The material was first suspended in water to remove sodium chloride and then filtered, washed with water and dried. Yield: 81 g, m.p. = 207° C dec.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12])([O-:5])=[O:4].[CH2:17](I)[CH2:18][CH3:19].O>CN(C)C=O>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([CH:13]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[O:16][CH2:17][CH2:18][CH3:19])[CH:11]=[O:12]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (6.09 g, 152.3 mmole) in 20 mL of dry dimethylformamide (DMF) was cooled to 0° C. and then 5-nitrovanillin (25 g, 126.8 mmole) in 41 mL of DMF was added dropwise. After 30 minutes, propyl iodide (25.87 g, 152.0 mmole) was added dropwise at 0° C. When the addition was completed, the reaction was maintained at room temperature for 2 hours and then stirred overnight at 70° C. Water was added, and-the solution extracted with ethyl ether, washed with 10% NaOH, dried over MgSO4, filtered and then evaporated in vacuo to an oil (19 g, 62.7%).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][CH2:50][NH2:51]>CC(N(C)C)=O>[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][CH2:50][NH:51][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:12]
Reactant: NCCc1ccccn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-pyridin-2-yl-ethylamine (39 mg, 2 eq.). The mixture was stirred at rt for 3 days. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: C([O-])=O.[NH4+].[CH:5]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH:30]4[CH2:33][N:32](C(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:31]4)[N:21]=3)[N:18]=2)[N:13]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:12]=1)=[O:10])([CH3:7])[CH3:6]>CO.C1COCC1.[Pd]>[CH:5]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH:30]4[CH2:33][NH:32][CH2:31]4)[N:21]=3)[N:18]=2)[N:13]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:53])([CH3:52])[CH3:54])[CH:12]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)nc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CNC4)c4cc(F)ccc34)nc12
Temperature: 50 °C
Yield: 67.8 %

Procedure:
In a round-bottomed flask ammonium formate (135 mg, 2.15 mmol) was dissolved in MeOH (1.5 mL). This solution was added to a solution of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (74 mg, 0.107 mmol) in THF (1.5 mL) which caused a white precipitate to form. This slurry was transferred via pipet to a pressure tube containing 10% palladium on carbon (wet, 23 mg) in MeOH (1 mL). The tube was sealed and heated at 50° C. for 4 h then cooled to room temperature overnight. The mixture was filtered over Celite, rinsing with CH2Cl2. The filtrate was concentrated and the residue was absorbed onto SiO2 and chromatographed with 0% to 10% MeOH/CH2Cl2 (0.5% NH4OH) to afford 38 mg (68%) of 2-(1-azetidin-3-yl-6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a pale yellow foamy solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1)=[O:48])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(N)cnc3c2CCC3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of tert-butyl [1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3-methylpiperidin-3-yl]carbamate (8.0 mg, 0.023 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (9.1 mg, 0.025 mmol), HATU (21.9 mg, 0.058 mmol) in DMF (0.05 mL) and DIPEA (0.012 mL, 0.069 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (8.4 mg, 53%). LCMS calc. for C34H43F2N6O5S (M+H)+: m/z=685.3. Found: 685.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Cl:11][CH2:12][CH2:13]Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:13][CH2:12][Cl:11]
Reactant: ClCCCl
Reactant: COc1ccc(O)c(Br)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OCCCl)c(Br)c1

Procedure:
To a solution of 2-bromo-4methoxyphenol (20.00 g, 98.04 mmol) in 1,2-dichloroethane (50.00 mL, 0.63 mol) was added sodium hydroxide (12.00 g, 0.29 mol) and benzyltriethylammonium chloride (3.00 g) in water (150 mL). The mixture was stirred at reflux for 24 h and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue gave 14.20 g (66% over two steps) of the title compound as a yellow oil: 1H NMR (250 MHz, CDCl3) d 7.09 (d, 1H), 6.82-6.72 (m, 2H), 4.27 (t, 2H), 3.75 (t, 3H), 3.71 (s, 3H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1.[CH2:32]([O:39][C:40]1[C:41]([O:49][CH3:50])=[CH:42][C:43]([CH3:48])=[C:44]([CH:47]=1)[CH:45]=[O:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1.CCCCCC>[CH2:32]([O:39][C:40]1[C:41]([O:49][CH3:50])=[CH:42][C:43]([CH3:48])=[C:44]([CH:45]([C:27]2[C:22]([Cl:21])=[N:23][CH:24]=[CH:25][C:26]=2[C:28]([F:29])([F:30])[F:31])[OH:46])[CH:47]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1cc(C)c(C=O)cc1OCc1ccccc1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c(C(O)c2c(C(F)(F)F)ccnc2Cl)cc1OCc1ccccc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A hexane solution (11.4 ml) of n-butyllithium was dropwise added to a tetrahydrofuran (45 ml) solution of diisopropylamine (2.81 g) at 0° C., followed by stirring for 1 hour to prepare a tetrahydrofuran solution of lithium diisopropylamide. The solution was cooled to −50° C., and a tetrahydrofuran (7.5 ml) solution of 2-chloro-4-trifluoromethylpyridine (2.81 g) was gradually added thereto, followed by stirring at the same temperature for 30 minutes. The solution was cooled to −78° C., and a tetrahydrofuran (37.5 ml) solution of 5-benzyloxy-4-methoxy-2-methylbenzaldehyde (3.97 g) was gradually added thereto, followed by stirring at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution (50 ml) was added thereto, the temperature was raised to room temperature, the mixture was poured into a saturated aqueous sodium bicarbonate solution (50 ml), and extraction with ethyl acetate (150 ml) was carried out twice. The ethyl acetate phase was washed with an aqueous sodium chloride solution (100 ml) and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6.48 g (yield 96%) of (5-benzyloxy-4-methoxy-2-methylphenyl)(2-chloro-4-trifluoromethyl-3-pyridyl)methanol as a red-yellow oily substance, and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][C:30](O)=[O:31]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc2ccccc2c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(naphthalen-2-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.33-8.29 (m, 1H), 8.03-8.01 (m, 1H), 8.01-7.96 (m, 1H), 7.95-7.88 (m, 5H), 7.58-7.49 (m, 3H), 3.85 (s, 2H), 3.84-3.79 (m, 4H), 3.13-3.06 (m, 4H); MS (ESI−) M/Z 413 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A 2.5 L 4-necked round-bottomed flask (suspension tank in the sketch) equipped with a mechanical stirrer was charged with 236.4 g of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione, (0.5 mol), 196.6 g of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-diethyl ester (0.75 mol) and 750 g of Dowtherm A (20 w %, apparent density 1.132 g/ml). This mixture was stirred for ca. 2 h at room temperature until a homogeneous suspension was formed. The temperature of the tube reactor was set to 230° C. and was controlled automatically. When the temperature was reached, pumping of the reactant suspension was started at a flow rate of 4.8 ml/min. The effluent was collected with stirring in the collection tank which contained 2300 ml of ethanol. After 2 h, 661 g (i.e. 584 ml) of product solution had passed through the reactor, which corresponds to 132.2 g (0.28 mol) of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione. Crystallization of the product in the collection tank took place almost immediately after the addition of the effluent to the ethanol had started. Finally, the suspension was stirred for additional 14 h at room temperature and in an ice bath at ca. 2° C. for 4 h. The precipitate was filtered with suction, the filter cake was washed twice with a total of 1500 ml of cold (0° C.) ethanol and dried to constant weight (60° C., 25 mbar, 17 h) to afford 124.9 g (yield: 95.9%, 99.9% purity based on HPLC assay) of 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione as a yellowish solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:11]([CH3:20])[CH:10]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][OH:28]>CC(C)=O>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][OH:28])(=[O:18])=[O:17])=[C:11]([CH3:20])[CH:10]=1
Reactant: OCC1CCCCN1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
K2CO3 (20.40 g, 147.6 mmol) and 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (19.05 g, 81.2 mmol) were added in succession to a suspension of piperidin-2-ylmethanol (8.50 g, 73.8 mmol) in acetone (350 ml). The reaction mixture was then stirred at 50° C. overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was employed in the next stage without further purification. The yield was 27.25 g (quantitative).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[C:7]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:36][CH2:35][N:34](C(C)C)[CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[CH:22]=2)[CH:6]=1)(C)C.C(N1CCN(C(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)CC1)(C)C.B(O)O>>[CH3:1][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[C:7]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:30])=[CH:27][CH:28]=3)[CH:22]=2)[CH:6]=1
Reactant: CC(C)Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)c2)cc(-c2ccccn2)n1
Agent: CC(C)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: OBO
Product: CNc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to [4-(6′-Isopropylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone (Example 2.46) by replacing (4-Isopropyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (Intermediate B4) with the appropriate boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]Cl.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:7]([I:12])[CH:8]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Yield: 14.2 %

Procedure:
A solution of 4-chloro-2-nitroaniline (34.5 g) in acetic acid (500 ml) was refluxed with iodine monochloride (65.0 g) for 7 h with stirring, then was cooled and added to excess water. The precipitate was filtered off, washed with aqueous sodium sulphite and after column chromatography yielded 4-chloro-2-iodo-6-nitroaniline (8.5 g). δ (360 MHz, DMSO-d6) 7.13 (2H, bs, NH2), 8.08 (1H, d, 3-H) and 8.13 (1H, d, 5-H).
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[CH2:26]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([N+:49]([O-])=O)[C:39]=1[C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[C:34]([OH:36])=[O:35])[CH2:27][CH2:28][CH3:29]>>[NH2:49][C:38]1[C:39]([C:40](=[O:48])[C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])[CH:32]=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(C)cc1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccc(C)cc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 3-n-butoxy-4-(4'-methylbenzoyl)-5-nitrobenzoic acid and following the procedure described, 5-amino-3-n-butoxy-4-(4'-methylbenzoyl)benzoic acid is obtained with a melting point of 170°-172° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:30]3[N:31]=[N:32][C:28]([CH3:27])=[N:29]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3nnc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[I:13]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>COCCOC>[Cl:1][C:2]1[C:7]2[C:8]([I:13])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]ncc12
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1nccc2[nH]nc(I)c12
Temperature: 75 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
To a mixture of 4-chloro-1H-pyrazolo[4,3-c]pyridine (4.0 g) and potassium hydroxide (4.4 g) in DME (50 mL) was added iodine (13.3 g) at room temperature. The reaction mixture was stirred at 75° C. for 4 hr. The reaction mixture was added to aqueous sodium thiosulfate solution, and the mixture was left stand overnight, and the resulting solid was collected by filtration to give the title compound (6.3 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]#[C:12][N:13]3[C:21]4[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[C:15]4[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]3=4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([CH2:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][NH:2][CH2:1]4)[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: Cc1ccc2c(c1)c1c(n2C#Cc2cccc3cnccc23)CCN(C)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc3c2CCNC3)CCN(C)C1
Yield: 24.4 %

Procedure:
To a solution of 5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (80 mg, 0.228 mmol) in MeOH (5 mL) were added 10% dry Pd—C (80 mg) and ammonium formate (72 mg, 1.14 mmol). The reaction mixture was refluxed for 4 h and filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude product, which was purified by reverse phase HPLC to yield 20 mg of 2,8-dimethyl-5-[2-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.21 (d, 1H), 7.18 (m, 2H), 7.1 (d, 1H), 7.0 (d, 1H), 6.93 (d, 1H), 4.7 (d, 1H), 4.2-4.4 (m, 5H), 3.7 (m, 1H), 3.2 (m, 3H), 3.08 (t, 2H), 3.02 (s, 3H), 2.83 (m, 1H), 2.6-2.8 (m, 3H), 2.4 (s, 3H).
Reaction SMILES: O[CH:2]1[O:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]1=[O:17].[CH3:18][C:19]([C:22]1[CH:26]=[CH:25][NH:24][N:23]=1)([CH3:21])[CH3:20].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>O1CCCC1>[CH3:18][C:19]([C:22]1[CH:26]=[CH:25][N:24]([CH:2]2[O:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:3]2=[O:17])[N:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccn(C2OCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-hydroxy-3-[3-(trifluoromethyl)phenyl]-4-oxazolidinone (1 g, 4.05 mmol) in tetrahydrofuran (20 mL) under nitrogen at ˜0° C., were added 3-(1,1-dimethylethyl)-1H-pyrazole (0.5 g, 4.05 mmol), triphenylphosphine (1.23 g, 4.7 mmol) and diisopropyl azodicarboxylate (0.88 mL, 4.46 mmol). After the addition, the reaction mixture was allowed to warm up slowly to room temperature and stirred at room temperature overnight. The reaction mixture was then concentrated, and the residue was purified by column chromatography (silica gel, ˜20% ethylacetate/80% hexanes) to give a crude product. The crude product was further purified by column chromatography (silica gel, ˜20% ethyl acetate/˜80% hexanes) to give the title compound, a compound of this invention, as a white solid (14 mg) melting at 95–98° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20.3 mmol) in THF (140 mL) were triphenylphosphine (7.97 g, 30.4 mmol) and 3,3,3-trifluoropropan-1-ol (1.963 mL, 22.27 mmol) added. Diisopropyl azodicarboxylate (5.98 mL, 30.4 mmol) was added dropwise and the mixture was left stirring at r.t. overnight. Since there was starting material remaining, 3,3,3-trifluoro-1-propanol (0.892 mL, 10.1 mmol) was added dropwise and stirring was continued. After 30 min the mixture was heated to 40° C. and after 1 h the mixture was concentrated. The crude product was purified by flash chromatography (0-12% EtOAc in heptane as eluent) to afford 1.08 g (22% yield) of the title compound (containing some diisopropyl azodicarboxylate): 1H NMR (500 MHz, CDCl3) δ 2.65 (qt, 2H), 2.71-2.77 (m, 2H), 3.05-3.13 (m, 2H), 4.23 (t, 2H), 7.17-7.23 (m, 2H), 7.40 (d, 1H); MS (ES+) m/z 245 [M+H]