Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]([NH:12]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 3-methoxy-1-phenylpropylcarbamate (Intermediate 61, 78 mg, 0.294 mmol) was dissolved in DCM (4.5 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred for 1 h at room temperature when LCMS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo, and the crude product was taken onto next step without further purification (0.294 mmol). LCMS [M+H]=166
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](SC)=[N:7][C:6]=2[CH:12]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].N1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:19]3[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]3)=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(Br)ccc2s1
Reactant: CC(C)N1CCNCC1
Solvent: c1ccncc1
Product: CC(C)N1CCN(c2nc3cc(Br)ccc3s2)CC1
Temperature: 160 °C
Yield: 76.3 %

Procedure:
A mixture of 5-bromo-2-(methylthio)benzothiazole (200 mg, 0.77 mmol), 1-isopropyl-piperazine (985 mg, 7.7 mmol) and pyridine (610 mg, 7.7 mmol) was heated at 160° C. for 36 h. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluent: 2% EtOAc in Petroleum ether) to give 200 mg (77%) of 5-bromo-2-(4-isopropylpiperazin-1-yl)benzothiazole.
Reaction SMILES: Br[C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C:7](=[O:14])[CH2:6][CH2:5][C:4]=2[C:3]=1Br.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[CH2:13]1[CH2:12][O:11][C:10]2[CH:2]=[CH:3][C:4]3[CH2:5][CH2:6][C:7](=[O:14])[C:8]=3[C:9]1=2
Reactant: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2ccc3c(c21)CCO3
Reaction time: 8 h
Yield: 86.5 %

Procedure:
4,5-Dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (280 kg, 843 mol), anhydrous sodium acetate (173 kg, 2109 mol), methanol (6384 L) were mixed, and the reaction system was replaced with nitrogen. Then, to the reaction mixture was added 10% Pd/C (30.8 kg, as dry weight), and pressurized with hydrogen to 0.29 to 0.49 MPa, and catalytically reduced at about 40° C. for 8 hrs with stirring at such a stirring rate that the gas-liquid overall mass transfer coefficient KLa(1/hr) is about 15. The catalyst was filtered, and the filtrate was concentrated under reduced pressure, and further water was added to the residue, followed by concentrating under reduced pressure to substitute the solvent, cooling and stirring for 1 hr to mature. The crystallization solution was filtered to give wet crystals of title compound (amount 127 kg as dry weight, yield 86.6%). The content of dimer in the wet crystals was less than 0.1% by weight. (2) Purification Step
Reaction SMILES: [Mg].[CH3:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:10](Br)[C:11]#[CH:12].C(OC(C)C)(C)C>[Cl-].[Zn+2].[Cl-].C(Br)C#C.O1CCCC1>[OH:8][CH:7]([C:6]1[O:9][C:3]([CH3:2])=[CH:4][CH:5]=1)[CH2:12][C:11]#[CH:10]
Reactant: C#CCBr
Reactant: Cc1ccc(C=O)o1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: C#CCC(O)c1ccc(C)o1
Temperature: 10 °C
Yield: 80.6 %

Procedure:
In the same flask as in Example 1, there were charged granular magnesium (14.6 g), dry zinc chloride (6.8 g) and dry tetrahydrofuran (110 g). Propargyl bromide (0.88 g) was added thereto at 10° C. while stirring. The resultant mixture was kept in an adiabatic condition, whereupon the reaction proceeded. When the heat generation stopped, a mixture of 5-methylfurfural (55.06 g), propargyl bromide (64.5 g), tetrahydrofuran (55 g) and isopropyl ether (55 g) was dropwise added to the reaction mixture at 50° C. in 1.5 hours while stirring under cooling. The resultant mixture was kept at room temperature for 30 minutes while stirring. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to give 2-(1-hydroxy-3-butynyl)-5-methylfuran (60.5 g) in a yield of 81% (based on the starting 5-methylfurfural).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O.CO>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([C:1]#[N:2])([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCNCC1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC1(N2CCCCC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.4 %

Procedure:
A solution of 5.3 g of sodium cyanide in 20 ml of water is added dropwise at RT to a solution of 18.9 g of 1-benzylpiperid-4-one and 12.16 g of piperidine hydrochloride in 25 ml of MeOH and 25 ml of water and the mixture is stirred for 48 hours at RT. The precipitate formed is wrung, washed with water and dried under vacuum to give 27 g of the expected product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S-:11][C:12]#[N:13].[NH4+].[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>S(Cl)(Cl)=O>[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:12]2[S:11][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:13]=2)[CH2:17]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: OC1CCCNC1
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: O=c1nc(N2CCCC(O)C2)sc2ncccc12
Yield: 17.1 %

Procedure:
The reaction procedure of Example 106 was followed except that 1.0 g of 2-chloronicotinic acid, 10 ml of thionyl chloride, 531 mg of ammonium thiocyanate and 642 mg of 3-hydroxypiperidine were used. The product was subjected to separation through silica gel column chromatography (eluant: 50:1:0.1 mixture of chloroform, methanol and aqueous ammonia), and then recrystallized from a mixture of isopropyl ether and isopropanol to obtain 285 mg of 2-(3-hydroxypiperidino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30].Cl.[N:39]1([CH2:45][CH2:46][SH:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.C(OCC)(=O)C>[CH3:37][O:36][C:34]1[CH:33]=[CH:32][C:26]2[S:27][C:28]([C:29]([NH2:31])=[O:30])=[C:24]([S:47][CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:25]=2[CH:35]=1
Reactant: SCCN1CCOCC1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SCCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Diazabicycloundecene (DBU) (990 μL, 6.62 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.83 mmol) and 4-morpholineethanethiol hydrochloride (608 mg, 3.31 mmol) in 4 mL of DMF. The mixture is stirred at room temperature for 3 hours then diluted with ethyl acetate and washed with water followed by aqueous citric acid. NaHCO3 is added to the acidic extracts and the precipitated solids are collected and washed with water. Recrystallization from methanol:water provides 5-methoxy-3-[[2-(4-morpholinyl)ethyl]thio]benzo[b]thiophene-2-carboxamide in 83% yield; mp=158.5°-159.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:33]1[CH2:35][C@@H:34]1[CH2:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][N:16]([CH2:35][C@@H:34]([OH:33])[CH2:36][O:37][C:38]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:39]=3[CH:40]=[CH:41][CH:42]=[N:43]4)[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCc1ccccc1)[C@@H]1CCNC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CC(C)O
Product: O=C(NCCCCc1ccccc1)[C@@H]1CCN(C[C@@H](O)COc2cccc3ncccc23)C[C@H]1C(=O)NCCCCc1ccccc1
Temperature: 70 °C
Yield: 61.1 %

Procedure:
trans-Piperidine-3,4-dicarboxylic acid bis[(4-phenyl-butyl)-amide] (8) (78.1 mg; 0.179 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (36.1 mg; 0.179 mmol) is added then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→50% methanol in methylene chloride) affording the desired product (69.6 mg) as a solid. ESMS: MH+ 637.4 (base).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][N:15]=[CH:14][C:13]=3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2].ClCCl.F[B-](F)(F)F.[CH2:36]([O+](CC)CC)[CH3:37].CO>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][N:15]=[N:16][C:17]=3[O:19][CH2:36][CH3:37])[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2]
Reactant: CC[O+](CC)CC
Reactant: CCOC(=O)C1=C(C)Nc2cn[nH]c(=O)c2C1c1ccc(C#N)cc1OC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)Nc2cnnc(OCC)c2C1c1ccc(C#N)cc1OC
Reaction time: 1 h

Procedure:
50 mg (0.136 mmol) of ethyl 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate are mixed under an argon atmosphere with 5 ml of abs. dichloromethane and 51.8 mg (0.273 mmol) of triethyloxonium tetrafluoroborate. After a reaction time of 2 hours at room temperature, the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 1 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent:acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 15 mg (27.8% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:29]([C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH:27]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCCN4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.05 g, 4.73 mmol), 3-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.67 g) and xylenes (7 ml) was heated to 160° C. overnight. Additional aldehyde (0.4 g) was added and the mixture was heated at 160° C. until the reaction was complete. The reaction mixture was cooled to room temperature and a solid formed which was collected by filtration and washed with ether. The filtrate was concentrated to dryness and the residue was combined with the solid and was purified by column chromatography on silica gel eluting with ethyl acetate/ethanol (60/40). The solid product thus obtained was washed with ether, recrystallized from ethyl acetate and then washed with ether again to afford 1-cyclopentyl-3-ethyl-6-[3-[2-(4-morpholinyl)ethoxy]phenyl]-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 173-176° C.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4].[H-].[Na+].[H][H].I[CH2:19][CH3:20]>O1CCCC1.ClCCl>[CH2:19]([N:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH3:20]
Reactant: CC(C)CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CCC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.7 %

Procedure:
To a stirred solution of tert-butyl iso-pentylcarbamate (1.87 g, 9.99 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 0° C. was added sodium hydride (600 mg, 25.00 mmol, 1.20 equiv). When the evolution of hydrogen subsided, iodoethane (1.7 g, 10.90 mmol, 1.10 equiv) was then added dropwise to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. It was then diluted with 50 mL of dichloromethane and washed with 4×20 mL of brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-13% of ethyl acetate in petroleum ether to give 0.51 g (24%) of tert-butyl ethyl(iso-pentyl)carbamate as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ 3.25-3.14 (m, 4H), 1.57-1.46 (m, 1H), 1.46 (s, 9H), 1.40-1.36 (m, 2H), 1.09 (t, J=7.2 Hz, 3H), 0.92 (d, J=8.8 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.81 min, m/z=216.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:7]=O)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1.Cl>C(O)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Agent: Cl
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Br)cc32)cc(C(C)C)c1OCCN1CCOCC1
Reaction time: 12 h
Yield: 12.4 %

Procedure:
A mixture of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.4 g), 5-bromo-2-oxindole (0.27 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was then added to 1N hydrochloric acid (100 ml) and the solids removed by filtration and washed with more water (50 ml). The solids were then dissolved in ethyl acetate (200 ml), the solution washed with 1N hydrochloric acid (75 ml) and brine (75 ml), dried with magnesium sulfate and concentrated. The crude solid was chromatographed (silica, 4:4:1 dichloromethane: hexanes: methanol) to give 80 mg (13%) of 5-bromo-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a reddish-brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=O.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]=[C:20]1[S:16][C:17](=[O:22])[NH:18][C:19]1=[O:21]
Reactant: O=Cc1ccccc1-c1ccccc1Cl
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccccc2-c2ccccc2Cl)S1

Procedure:
To a solution of 2-formyl-(2′-chloro-1,1′-biphenyl) (0.12 g, 0.55 mmol) and 2,4-thiazolidinedione (0.08 g, 0.65 mmol) in toluene (10 mL) were added piperidine (0.008 mL, 0.073 mMol) and benzoic acid (0.011 mg, 0.08 mmol), and the reaction was refluxed for 4 h with continuous removal of water. The solvent was then distilled off and the oily residue obtained was purified by chromatography on silica-gel using hexane: ethyl acetate (3:1) as the eluent to yield titled product.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14]>>[NH2:5]/[C:10](/[CH2:9][CH2:8][CH2:7][CH:6]([CH3:12])[CH3:11])=[CH:14]\[C:13]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCOC(=O)/C=C(\N)CCCC(C)C
Reaction time: 8 h

Procedure:
To a mixture of β-ketoester (ethyl 7-methyl-3-oxooctanoate) in 100 mL of toluene ammonium acetate (5.34 g, 69.3 mmol) was added. The mixture was allowed to stir overnight at reflux. The reaction mixture was dissolved in ethyl acetate and the organics washed with H2O (3×) and brine. The organics were then dried over sodium sulfate, filtered and concentrated to yield a yellow oil: TLC (EtOAc/hexanes (1:4)): Rf=0.39
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:31]1[CH:35]=[C:34]([CH:36]2[CH2:41][CH2:40]NC[CH2:37]2)[N:33]=[CH:32]1.C1C=[N:46][C:45]2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:37][CH:36]([C:34]4[N:33]=[CH:32][S:31][CH:35]=4)[CH2:41][CH2:40][CH2:45]3)=[O:28])=[CH:24][CH:23]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: c1nc(C2CCNCC2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCCC(c4cscn4)C3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 4-{((2s,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl}benzoic acid (82 mg, 0.2 mmol) and 4-(1,3-thiazol-4-yl)piperidine (30 mg, 0.2 mmol) in 1.5 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.4 mL, 0.2 mmol) followed by EDC (78 mg, 0.4 mmol) and DIEA (70 μL, 0.4 mmol). The resulting mixture was stirred at RT under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (1000 uM) eluting with 5% MeOH in dichloromethane to afford the product (91 mg, 88%). ESI-MS calculated for C32H39N3O4S: Exact Mass: 561.27. Found 562.28 (MH)+ and 584.28 (MNa)+.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)C(C)c1ccc(-c2cn3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 55.3 %

Procedure:
A mixture of 8 g of ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]-propionate, 50 ml of ethanol, 1.4 g of sodium hydroxide and 10 ml of water is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and the residue is dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off, washed with water, and recrystallized from methanol to give 4 g of 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionic acid as colorless crystals melting at 244°-246°C with decomposition. The corresponding hydrochloride melts at 210°-211°C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: OB(O)c1cccs1
Product: O=C1NC(=O)c2c1c(-c1cccs1)cc1[nH]c3ccc(O)cc3c21
Yield: 69 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in example 7 with 2-thiopheneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(2-thienyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (505) (1; Ar=2-thienyl) in a 69% yield; mp (THF/CH2Cl2/hexane) 179–184° C. (dec). 1H NMR [(CD3)2SO] δ 11.75 (br s, 1H), 11.11 (br s, 1H), 9.26 (br s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.73 (dd, J=3.6, 1.0 Hz, 1H), 7.68 (dd, J=5.1, 1.3 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.20 (dd, J=5.1, 3.6 Hz, 1H), 7.07 (dd, J=8.7, 2.5 Hz, 1H). Found: C, 62.38; H, 3.11; N, 7.74. C18H10N2O3S.3/4H2O requires C, 62.15; H, 3.33; N, 8.05.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[I-].[Na+].CN(C=O)C>[ClH:2].[Cl-:1].[CH3:10][C:7]1[N:8]=[CH:9][C:4]([CH2:3][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: [Cl-]
Temperature: 90 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
5-(Chloromethyl)-2-methylpyridine hydrochloride (1.13 g) and DMF (9 ml) were mixed, and triphenylphosphine (1.67 g) and sodium iodide (5 mg) were added thereto, followed by stirring at 90° C. for 6 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with toluene to obtain [(6-methylpyridin-3-yl)methyl](triphenyl)phosphonium chloride hydrochloride (2.18 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C[CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)(=O)C.C=O>[NH:1]1[C:5]2[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:3]=[CH:2]1
Reactant: C1CCNCC1
Reactant: C1CCNC1
Agent: C=O
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1

Procedure:
Nitroindole AA1 was alkylated with an appropriately substituted alkyl or arylalkyl halide in the presence of a base such as cesium carbonate, potassium carbonate and the like also in the presence of a solvent such as DMF to provide a 1-substututed indole intermediate. The resulting intermediate was reacted with an amine such as pyrrolidine, piperidine and the like while dissolved in an organic acid such as glacial acetic acid in the presence of formaldehyde also in glacial acetic acid to provide a 3-substututed indole intermediate. The nitro group of the resulting intermediate was then reduced to an amino group by reaction with 1,1-dimethylhydrazine in the presence of an alcohol solvent such as MeOH and charcoal and ferric chloride hexahydrate which provided intermediate AA2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cc(Cl)cc(Cl)c1
Temperature: 80 °C

Procedure:
To 1,3-dichloro-5-iodobenzene (300 mg, 1.099 mmol) and methyl acrylate (0.099 ml, 1.099 mmol) in DMF (10 ml) under nitrogen was added [Pd(t-BuP)]2 (56.1 mg, 0.110 mmol) and triethylamine (0.306 ml, 2.199 mmol). The reaction mixture was heated to 80° C. for 2 h. The reaction mixture was diluted with EtOAc and filtered through a silica cartridge (2 g). The organic solution was washed with water, saturated sodium bicarbonate solution, water and brine. The organic portion was dried using a phase separating column and the solvent was removed under reduced pressure to afford the title compound;