Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl>[C:1]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CNc2ccccc2)C1
Solvent: ClCCl
Product: CCC(=O)N(CC1CN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of N-(1-Boc-Azetidine-3-ylmethyl)aniline 48 (218.6 mg, 0.791 mmol) and piperidinomethyl polystyrene resin (250 mg) in 2 mL of dry CH2Cl2 was added propionyl chloride (77 μL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2 Removal of CH2Cl2 afforded N-(1-Boc-azetidine-3-ylmethyl)-N-phenylpropionamide 49 (241 mg, 96%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>CN(C)C=O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)[S:6][N:5]=1
Reactant: Clc1nc(-c2ccccn2)ns1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 2-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine (3.96 g, 20.0 mmol) and 1-tert-butoxycarbonyl-piperazine (3.73 g, 20.0 mmol) in dimethylformamide (40 ml) was added triethylamine (11.2 ml, 80.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 6.35 g (91.2%) of tert-butyl 4-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44]O)[CH2:39][CH2:38]1>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][F:34])[CH2:38][CH2:39]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCN1CCN(CCF)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 67.6 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (146 mg, 0.69 mmol), (prepared as described for the starting material in Example 4), was suspended in dichloromethane (7.5 ml). Triphenylphosphine (254 mg, 0.97 mmol) and 2-[4-(2-fluoroethyl)piperazin-1-yl]ethanol (134 mg, 0.76 mmol) were added. Diisopropyl azadicarboxylate (165 μl, 0.83 mmol) was then added dropwise. The reaction mixture was stirred for 2.25 hours at ambient temperature and then loaded directly onto a silica column and eluted with methylene chloride/methanol (92/8) to give 4-chloro-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyquinazoline (172 mg, 67%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[C:11]3[CH2:19][N:18]([CH3:20])[CH2:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]3=[CH:13][CH:14]=2)[NH:9][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O.[OH-].[Na+]>O1CCCC1>[CH:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]3[CH2:19][N:18]([CH3:20])[CH2:17][CH:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:12]3=[CH:13][CH:14]=2)[NH:9][CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)NCCc1c[nH]c2c3c(ccc12)C(c1ccccc1)CN(C)C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)NCCC1CNc2c1ccc1c2CN(C)CC1c1ccccc1

Procedure:
2.1 g (0.00604 mol) of 3-(isopropylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indole are dissolved in 25 ml (0.3275 mol) of trifluoroacetic acid, with stirring and in the absence of moisture, and a solution of 1.76 g (0.0241 mol) of trimethylaminoborane in 10 ml of tetrahydrofuran is then added dropwise at a temperature of 0°-+2° C. The mixture is subsequently stirred at 0° C. for 1 hour, a solution of 1.76 g (0.0241 mol) of trimethylamonoborane in 10 ml of tetrahydrofuran is then again added and the mixture is subsequently stirred for 2.5 hours. 150 ml of H2O are now added to the reaction mixture, the mixture is brought to pH 13 with NaOH and the oily product which deposits is extracted with CH2Cl2. The CH2Cl2 phase is washed with H2O, dried over Na2SO4 and then freed from the solvent on a rotary evaporator. The residue is chromatographed twice on silica gel (silica gel 60 from E. Merck, Darmstadt). Eluent: initially CH2Cl2 /MeOH/N(C2H5)3 (15:4:0.25), then diethyl ether/MeOH/N(C2H5)3 (15:3:0.25).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C([O-])([O-])=O.[K+].[K+].[NH:25]1[C:29]2=[N:30][CH:31]=[C:32]([NH2:34])[CH:33]=[C:28]2[CH:27]=[CH:26]1>C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:34][C:32]1[CH:33]=[C:28]2[CH:27]=[CH:26][NH:25][C:29]2=[N:30][CH:31]=1)=[O:6]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: c1ccccc1
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrobenzoic acid from example d-2 (2 g, 9.1 mmol) in benzene (40 ml) was added thionyl chloride (2 ml) and refluxed for 3 h. The reaction mixture was concentrated, diluted with dry acetonitrile (20 ml). To this solution dry K2CO3, (2 g, 14 mmol) was added, followed by a solution of 1H-Pyrrolo[2,3-b]pyridin-5-ylamine (example c), 1.2 g, 9.1 mmol) in acetonitrile (20 ml) and the reaction mixture was stirred for 16 h at RT. Filtered the reaction mixture through cintered faunal. The residue was washed with dry acetonitrile several times. Solvent was removed under reduced pressure, 2.8 g of the crude title product. LC-MS: (m/z 335)
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:23]=[CH:24][C:25](=[O:32])[N:26]([CH2:28][C:29]([OH:31])=O)[CH:27]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:35][CH3:36].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:37]1([NH:40][C:29](=[O:31])[CH2:28][N:26]2[C:25](=[O:32])[CH:24]=[CH:23][C:22]([CH:20]3[O:19][N:18]=[C:17]([C:12]4[N:13]=[C:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]5[CH:33]=[CH:34][C:2]([F:1])=[C:3]([O:35][CH3:36])[CH:4]=5)=[O:9])[CH:11]=4)[CH2:21]3)=[CH:27]2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(=O)n(CC(=O)O)c4)C3)nc(C)n2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(=O)n(CC(=O)NC5CC5)c4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.7 %

Procedure:
To a stirred solution 2-(5-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-2-oxopyridin-1(2H)-yl)acetic acid (0.2 g, 0.404 mmol, G.1.225) in DMF (5 mL) was added cyclopropanamine (0.046 g, 0.807 mmol, Sd Fine Chem), EDCI.HCl (0.093 g, 0.484 mmol, spectrochem), HOBT (0.093 g, 0.605 mmol, spectrochem) and DIPEA (0.157 g, 1.211 mmol, spectrochem). The reaction mixture was stirred at RT for about 12 h. The reaction mixture was diluted with ice cold water (20 mL) and the product extracted with EtOAc (2×15 mL), The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford a thick mass. Crude compound was purified by preparative TLC, eluting with 2-4% methanol in DCM to afford 6-(5-(1-(2-(cyclopropylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 21 mg (9.73%) as an off white solid. 1H NMR (400 MHz, DMSO): δ 9.519-9.487 (m, 1H), 8.282-8.273 (d, J=3.6 Hz, 1H), 8.190 (s, 1H), 7.768-7.762 (d, J=2.4 Hz, 1H), 7.558-7.529 (dd, J=9.2 Hz, 1H), 7.186-7.119 (m, 2H), 6.908-6.871 (m, 1H), 6.429-6.404 (d, J=10 Hz, 1H), 5.705-5.654 (m, 1H), 4.491-4.458 (m, 4H), 3.857-3.784 (m, 4H), 3.461-3.393 (m, 1H), 2.767 (s, 3H), 2.745-2.650 (m, 1H), 0.649-0.601 (m, 2H) 0.425-0.387 (m, 2H); MS m/z=533.3 (M−H)−.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2/[CH:19]=[CH:20]/[C@H:21]([C:23]2[S:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=2)[OH:22])=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C1COCC1>[S:27]1[C:23]([C@H:21]([OH:22])/[CH:20]=[CH:19]/[C@@H:11]2[C@@H:12]3[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]3)[CH2:18][C@H:10]2[OH:9])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A mixture consisting of (3aR,4R,5R,6aS)-4-((R,E)-3-(benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (intermediate 28, 0.343 g, 0.672 mmol) and potassium carbonate (0.046 g, 0.336 mmol), and 1:1 methanol-THF (12 mL) was stirred at room temperature for 18 hours. The reaction mixture turned from colorless to red-orange. After complete consumption of starting material, as judged by TLC, the reaction mixture was diluted with ethyl acetate (300 mL), washed with 1:1 saturated ammonium chloride-water (2×50 mL) and brine (50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a yellow solid. The material was triturated in 10% ethyl acetate in hexanes (200 mL) for three days. The product was collected to give an off-white solid which was rinsed with hexanes and dried to afford the title intermediate 29 (189 mg, 85% triturated yield) as an off-white solid; MS (ESI+) m/z 313 (m+H—H2O), (ESI−) m/z 389 (m+AcO−); 1H NMR (d6-DMSO) δ 7.83-7.93 (m, 1H), 7.72-7.83 (m, 1H), 7.24-7.38 (m, 2H), 7.19-7.24 (s, 1H), 5.94-6.01 (m, 1H), 5.65-5.82 (m, 2H), 5.31-5.38 (m, 1H), 4.94-5.01 (m, 1H), 4.84-4.93 (m, 1H), 3.80-3.91 (m, 1H), 2.74-2.88 (m, 1H), 2.56-2.69 (m, 1H), 2.22-2.37 (m, 3H), 1.64-1.80 (m, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[S:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH:21]=3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:8])=[O:9])[CH:18]=2)[C:14]([C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:21]=2)=[CH:15]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(-c5ccncc5)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc(-c3ccncc3)cc(C(F)(F)F)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
N-(2,4-dimethoxybenzyl)-1-methyl-3-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.050 g, 0.075 mmol) was dissolved in 0.5 mL of DCM and TFA (0.5 ml, 6.49 mmol) was added. The reaction was stirred for 15 minutes at room temperature. The reaction was concentrated, dissolved in acetonitrile, and passed through a PEAX ion exchange column (purchased from Biotage, LLC, Charlotte, N.C.). The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 1-methyl-3-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.029 g, 0.056 mmol, 75% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.94-8.84 (m, 2 H), 8.46 (s, 1 H), 8.41 (s, 1 H), 8.32 (s, 1 H), 8.30 (d, J=6.1 Hz, 2 H), 8.14-8.09 (m, 3 H), 8.05 (d, J=1.3 Hz, 1 H), 7.62 (dd, J=1.6, 8.6 Hz, 1 H), 3.98 (s, 3 H). m/z (ESI). 516.0 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25].[Cl-].[Li+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:24]([C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:26])[CH3:25]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C(C)=O)c1OC
Temperature: 150 °C

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65, 1.0 g), 1-ethoxyvinyl tributyl stannane (0.9 ml), tetrakis-(triphenylphosphine) palladium (0.29 g) and lithium chloride (1.0 g) in dioxane (15 ml) was stirred and heated in the microwave at 150° C. for 15 minutes. The solution was filtered and the filtrate was diluted with 1M hydrochloric acid and then stirred at room temperature for 5 hours. The resultant mixture was extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-75% to give methyl 3-acetyl-6-(benzenesulphonylmethyl)-2-methoxybenzoate (0.965 g) as an oil.
Reaction SMILES: COC1C=CC(C[O:10][C:11]([CH2:13][C:14]([O:16][C:17]2[CH:18]=[C:19]([C:23]3[N:24]=[C:25]4[N:29]([CH:30]=3)[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[S:26]4)[CH:20]=[CH:21][CH:22]=2)=[O:15])=[O:12])=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(O)C.[ClH:53]>ClCCl.O1CCCC1>[ClH:53].[C:11]([CH2:13][C:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]3[N:29]([CH:30]=2)[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[S:26]3)[CH:20]=[CH:21][CH:22]=1)=[O:15])([OH:12])=[O:10]
Reactant: COc1ccc(COC(=O)CC(=O)Oc2cccc(-c3cn4c(n3)sc3ccccc34)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)CC(=O)Oc1cccc(-c2cn3c(n2)sc2ccccc23)c1
Temperature: 0 °C

Procedure:
In 5 ml of anhydrous dichloromethane was dissolved 1.146 g of 2-[m-(p-methoxyphenylmethoxycarbonylacetoxy)phenyl]imidazo[2,1-b]benzothiazole and after adding thereto 0.4 ml of anisole, the mixture was cooled with ice-water. Then, 5 ml of trifluoroacetic acid was added dropwise to the mixture and the resultant mixture was stirred for one hour. The reaction mixture thus formed was concentrated under reduced pressure and the oily product thus obtained was dissolved in 10 ml of anhydrous tetrahydrofuran. Then, while stirring the mixture under ice-cooling, 2 ml of 2N hydrogen chloride ethanol solution was added to the solution and white crystals thus precipitated were recovered by filtration to provide 911 mg of 2-(m-carboxyacetoxyphenyl)imidazo[2,1-b]benzothiazole hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20]([NH2:21])=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[N:18][CH:17]=[CH:16][CH:15]=4)[C:20]=3[NH:21][S:24](=[O:26])(=[O:25])[N:23]2[CH3:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)c(F)c2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)c(F)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 49 %

Procedure:
In a similar fashion using route 27 general procedure 70, 7-[(3, 4difluorophenyl)carbonyl]-8-aminoquinoline (Intermediate 377) (100 mg, 0.35 mmol), N-methylsulfamoyl chloride (Intermediate 213) (105 mg, 1.0 mmol) and NaBH4 (14 mg, 0.34 mmol) in pyridine (4 ml) gave the title compound (62 mg, 47%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([CH2:4][OH:5])=[C:2]([C:15]2([OH:18])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:9]=1
Reactant: OCc1ccc(Cl)cc1Br
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(O)(c2cc(Cl)ccc2CO)CC1

Procedure:
Reaction of 2-bromo-4-chlorobenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-(4-chloro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2.[CH2:23]([N:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28](=[O:34])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:26]1=[O:42])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([C:29]3[C:28](=[O:34])[N:27]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:26](=[O:42])[N:25]([CH2:23][CH3:24])[CH:30]=3)=[O:32])=[CH:20][CH:21]=1)=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc2nccc(Oc3ccc(N)cc3)c2c1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4ccc(OC)c(OC)c34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(5,6-dimethoxy-quinolin-4-yloxy)-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp>250° C.; LCMS m/z=557 (M+1); 1H NMR (DMSO) δ: 10.92 (s, 1H), 8.86 (s, 1H), 8.48 (m, 1H), 7.79 (m, 2H), 7.49 (s, 1H), 7.35-7.42 (m, 5H), 7.24-7.27 (m, 2H), 6.49 (m, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.29 (m, 3H).
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:10][CH:9]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[O:25]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:26])[N:7]1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:12][CH:13]=1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2ccc(N3C(=O)c4ccccc4C3=O)cc2)S1
Yield: 92.3 %

Procedure:
Into 30 ml of dioxane were dissolved 1,00 g of 5-(4-amino-phenyl)thiazolidine-2,4-dione and 0.74 g of phthalic anhydride, and the solution was refluxed for 2 hours. Thereafter, 30 ml of acetic acid and 0.5 g of sodium acetate were added and the mixture was refluxed for 2 hours. The reaction liquor was poured into 400 ml of water, and the crystals deposited were collected by filtration. These were recrystalized from ethanol to obtain 1.50 g of title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2)([O-])=O.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][NH:1][C:4]1[CH:5]=[C:6]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)cc2cc(-c3ccccc3)[nH]c12
Product: COC(=O)CNc1cc(Oc2ccccc2)cc2cc(-c3ccccc3)[nH]c12

Procedure:
7-Nitro-5-phenoxy-2-phenyl-1H-indole prepared in Preparation 27 and methyl bromoacetate were reacted according to the same procedures as Step A of Example 1 and Example 22 sequentially to give the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:18]([CH3:30])[CH:17]=3)=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[C:35]([CH3:37])[N:36]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[C:18]([CH3:30])[CH:17]=3)=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[C:35]([CH3:37])[N:36]=[C:9]23)[CH2:4][CH2:3]1)[CH3:45]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2nc(C)nn12
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile (1.01 g), rhodium(I) acetate (0.30 g) and toluene (20 mL) was added dropwise a solution of ethyl diazoacetate (1.20 g) in toluene (10 mL) at 70° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.71 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:12].[CH2:13](OS([O-])(=O)=O)[CH2:14]CCCCCCCCCC.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][C:14]1[S:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[N:1]=1
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: Nc1c(S)ccc2ccccc12
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc2c(ccc3ccccc32)s1
Yield: 70 %

Procedure:
5 mmol of 1-aminonaphthalene-2-thiol was added to 20 ml of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of acetic anhydride was added for 5 minutes. A precipitation product was obtained in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain 2-methyl naphtothiazole at a yield of 70%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1[Cl:20]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:5][C:4]=1[Cl:20]
Reactant: N#Cc1cc(C(=O)CNC2CCCC2)cc(Cl)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCCC2)cc(Cl)c1N

Procedure:
m.p. of the hydrochloride: 138°-144° C., was prepared from 4'-amino-3'-chloro-5'-cyano-2-cyclopentylamino-acetophenone analogous to Example 48.