Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CS(C)=O.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([OH:18])=[N:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([O:18][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:26])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cccc(Cl)c2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A 2.2 g portion of sodium was dissolved in 75 ml of methanol and the solution was added to 100 ml of dimethylsulfoxide. To that was added 19.2 g of 1-(3-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole, and the mixture was stirred on the steam bath for 4 hours. To it was then added 17.7 g of ethyl 2-bromopropionate, and heating was continued for 2 hours more. The mixture was then cooled and poured over ice-water, and the solid was collected, dried and recrystallized from ethanol and then from toluene to obtain 8.5 g of the desired product, m.p. 70°-72°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) in dichloromethane (1.6 ml) was added at room temperature triethylamine (139 mg, 192 μl, 1.38 mmol) and methanesulfonyl chloride (43.0 mg, 29.2 μl, 375 μmol). The mixture was allowed to stir at room temperature for 4 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (0.1 g) was triturated with dichloromethane (1 ml) and heptane (5 mL) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (90 mg, 88%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.CC(C)=[O:28]>O>[OH:28][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]2
Reactant: CC(C)=O
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: O
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(O)cc2C1
Yield: 92 %

Procedure:
To a stirred solution of (R)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (6.21 mmol, 2.27 g) in acetone (20.00 mL), a solution of oxone monopersulfate compound (6.84 mmol, 4.20 g) in Water (20 mL) was added dropwise over 2 min. The resultant solution was stirred for a further 10 min before being quenched with NaHSO3 (aq). The solution was extracted with DCM (×3), dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a colourless oil which solidified to a white solid on standing. The solid was triturated with heptane to give the title compound as a white solid (1.46 g, 92%). MS (ESI): m/z [M−H]− 254.0
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Yield: 56.5 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.297 g, 0.000674 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.221 g, 0.000741 mol), sodium carbonate (0.179 g, 0.001684 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.185 g, 0.000381 mol): 1H NMR (DMSO-d6, 400 MHz) 8.79 (s, 2H), 8.24 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.81 (m, 1H), 1.55-2.56 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.23.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16]
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)[nH]c(=O)n2CCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
1185 mg (5.38 mmol) of 1-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (Intermediate 14) are suspended in 56 ml of dichloromethane. 2285 mg (6.89 mmol) of carbon tetrabromide and then 6890 mg of polymer-supported triphenyl phosphine (1 mmol/g; 6.89 mmol) are added. The mixture is shaken at rt for 24 hr. The polymer is filtered and sequentially washed with dichloromethane, EtOH and MeOH. The filtrates are concentrated and the residue (2.2 g) is chromatographically purified over silicagel eluting with chloroform/EtOH (100/0 to 90/10). 0.3 g of pure title compound are obtained (20% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:11]([C:13](O)=[O:14])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)=[N:8][C:7]=3[N:6]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:5]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl.O>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:13]([C:11]2[C:12]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[N:5][N:6]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:7]=3[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[CH:10]=2)=[O:14])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
To a suspension of 0.80 g of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 13 ml of DCM were added 1.4 ml of Hünig's base, 0.98 g of BEP and 0.47 g of tert-butyl-1-piperazine carboxylate. The reaction was stirred at r.t. for 4 h. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 0.79 g (68%) of the title compound.
Reaction SMILES: C(=O)([S:3][CH2:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)C.C[S-].[Na+]>C(Cl)(Cl)Cl.CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[O:6][C:5]([CH2:4][SH:3])=[CH:9][CH:8]=2)[CH:11]=1
Reactant: CC(=O)SCc1ccc(-c2cccnc2)o1
Agent: C[S-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: SCc1ccc(-c2cccnc2)o1
Yield: 62.7 %

Procedure:
(See FIG. 7.) To a solution of 13 (10 mg, 0.05 mmol) in CHCl3/CH3OH (1.5 mL, 2:1, v:v) was added sodium thiomethoxide (3 mg, 0.05 mmol) and the resultant solution was stirred under argon for 10 min. The solvent was removed with a stream of argon and the residue was applied directly to a TLC plate (20×20 cm, 250 μm silica gel), developed (EtOAc/Hex, 5/95, Rf=0.12), the product band was scraped, extracted with dichloromethane and the solvent was removed in vacuo to afford the title compound 14 (6 mg, 68% yield) as a white film: 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.19 (m, 1H), 7.96 (m, 1H), 7.28 (m, 1H), 6.66 (d, J=3.3 Hz, 1H), 6.07 (d, J=3.3 Hz, 1H), 3.59 (s, 2H), LRMS (ESI) m/z calcd for C10H10NOS [M+H]+ 192. found 192.
Reaction SMILES: [Li+].[BH4-].C[Si](Cl)(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@@H:16]1[C:19](O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].CO>C1COCC1.O>[OH:20][CH2:19][C@H:16]1[CH2:17][CH2:18][N:15]1[C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 2M LiBH4 (200 ml, 400 mmol) in THF at 0° C. was added TMSCl (101 ml, 800 mmol) slowly. The mixture was warmed up to r.t and stirred at r.t. for 30 min. To the mixture at 0° C. was added a solution of (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (40 g, 200 mmol) in 200 ml THF with an additional funnel over 1 hour. The mixture was warmed up to r.t and stirred at r.t. for 2 hours. The mixture was cooled down to 0° C. and then treated with 32 mL MeOH followed by 40 mL H2O. After removal of THF, the residue was extracted with 300 mL EtOAc and washed with 300 mL brine. The organic layer was dried and concentrated to give (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate as a colorless oil (32.5 g, 87%). LRMS (M−100+H+) m/z 132.1.
Reaction SMILES: O1CCCC1.C1(C)C=CC(S(O[CH2:16][CH:17]2[S:29][C:21]3=[N:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:20]3[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].[H-].[Na+]>O>[CH2:31]([N:33]([CH2:16][CH:17]1[S:29][C:21]2=[N:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:20]2[CH2:19][CH2:18]1)[CH2:34][CH3:35])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: CCNCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CC1CCn2c(nc3ccccc32)S1
Yield: 40 %

Procedure:
Into 20 ml of tetrahydrofuran was dissolved 1.12 g (3 m mole) of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, followed by the addition of 5 ml of diethylamine. Then, a catalytic amount of sodium hydride was added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature andthen refluxed for eight hours. The reaction mixture was cooled and then condensed under reduced pressure. The reaction product was added with water and then extracted with chloroform. The chloroform layer was then dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and elutedwith chloroform to obtain 0.33 g (yield: 40%) of the intended product, m.p.93°-94° C.; IR νmaxKBr cm-1 : 3100-2800, 1420; Anal. Calcd. for C15H21N3S: C, 65.42; H, 7.68; N, 15.26; S, 11.64; Found: C, 65.33; H, 7.77; N, 15.49; S, 11.41.
Reaction SMILES: [C]=O.C=O.[C:5]([OH:9])(=[O:8])[CH2:6][CH3:7].C([O:14][CH2:15][C:16]([OH:18])=[O:17])(=O)CC>O>[C:16]([OH:18])(=[O:17])[CH2:15][OH:14].[C:5]([OH:9])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)OCC(=O)O
Agent: C=O
Agent: [C]=O
Solvent: O
Solvent: CCC(=O)O
Product: O=C(O)CO

Procedure:
FIGS. 1 and 2 present two, non-limiting embodiments or the instant invention described herein in detail. In a first embodiment of the invention as laid out in FIG. 1, Carbon Monoxide Stream 1, Aqueous Formaldehyde Stream 2, and Propionic Acid Stream 3 are fed to Hydrocarboxylation Reactor 50 which comprises a fixed bed, solid catalyst (not shown). The Effluent Stream 4 comprises the esters of glycolic and propionic acid including 2-propionoxyacetic acid and (2′-(propionyloxy)acetoxyacetic acid. Effluent Stream 4 and Water Stream 8 are fed to Hydrolyzer 55. Hydrolyzer 55 is operated at sufficient temperature, pressure, and residence time to produce Hydrolyzed Mixture Stream 9 comprising glycolic acid, propionic acid, and water. Hydrolyzed Mixture Stream 9 is extracted with Hydrophobic Solvent Stream 11, such as methyl tertiary-butyl ether, in Extractor 60, to produce Organic Extract Stream 10 and Aqueous Raffinate Stream 12. Organic Extract Stream 10 can be separated into Propionic Stream 3 and Hydrophobic Solvent Stream 11 in Separator 70. Separator 70 can be, for example a distillation column. Propionic Acid Stream 3 is recycled to Hydrocarboxylation Reactor 50 and Hydrophobic Solvent Stream 11 is recycled to Extractor 60.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3([CH3:15])[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:16])[O:3]1.[OH:17][CH2:18][C@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1>CCO>[OH:17][CH2:18][C@@H:19]1[N:24]([CH2:14][C:12]([OH:13])([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:16])[O:3][C@@H:2]([CH3:1])[CH2:11]3)[CH3:15])[CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1
Reactant: C[C@@H]1Cc2cc(C3(C)CO3)ccc2C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: C[C@H]1Cc2cc(C(C)(O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A solution of (3R)-3-methyl-6-(2-methyloxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (598 mg, 2.74 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (770 mg, 3.56 mmol dissolved in EtOH (15 mL) was heated in a sealed tube to 110° C. for 14 hours. The reaction was cooled and concentrated to give crude product which was purified via MPLC (30-80% EtOAc/Hexane) to give the title compound as a mixture of diastereomers: LC-MS: (M+1)+435;
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:28]2[C:27]3[C:22](=[CH:23][C:24]([OH:29])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][CH:17]=1>CS(C)=O.CCOC(C)=O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:28]2[C:27]3[C:22](=[CH:23][C:24]([O:29][CH3:1])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CI
Product: COc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 9.3 %

Procedure:
Potassium carbonate (25.1 mg, 0.182 mmol) and iodomethane (4.9 μL, 0.079 mmol) were added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 19.4 mg, 0.061 mmol) in DMSO (1 mL) and the mixture was stirred at rt. After 17 h, the mixture was diluted with EtOAc (30 mL), washed with saturated aqueous ammonium chloride (5 mL), water (2×5 mL), and brine (5 mL), dried and concentrated. The residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-methoxy-9H-carbazole-1-carboxamide (1.9 mg, 9%). 1H NMR (400 MHz, chloroform-d) δ 10.39 (1H, br. s.), 7.58 (1H, d, J=7.70 Hz), 7.44-7.55 (2H, m), 7.28-7.39 (2H, m), 7.07-7.22 (2H, m), 7.00 (1H, d, J=2.20 Hz), 6.65 (1H, dd, J=8.80, 2.42 Hz), 6.57 (2H, br. s.), 3.88 (3H, s). Mass spectrum m/z 335.0 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15](O)=[O:16])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].O.[NH2:21][NH2:22]>C(O)C>[C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH:12]3[CH:13]([C:15](=[O:16])[NH:21][N:22]=2)[CH2:14]3)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 81.8 %

Procedure:
1.0 g (3.8 millimoles) of cis-2-(p-propionylaminobenzoyl)-cyclopropanecarboxylic acid, 0.22 g (4.4 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 5 hours. After filtering off the product at 25° C. and drying it under reduced pressure at 50° C., 0.8 g (81% of theory) of 2-(p-propionylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 268°-270° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=C(C(O)=O)[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([O-:3])=[O:2].[C:16](Cl)(=O)[C:17]([Cl:19])=[O:18].C(Cl)[Cl:23]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:16]([C:17]([Cl:19])=[O:18])[CH:7]=[C:8]([CH:12]=1)[C:9]([Cl:23])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-nitroisopthalic acid (10 grams) in methylene chloride (943 mL) was added oxalyl chloride (12.3 mL) and N,N-dimethylforamide (1 drop). The reaction mixture was stirred at room temperature overnight. Removal of the solvent in vacuo afforded 10.63 grams of the title compound. 1H NMR δ 9.17 (s, 2), 9.07 (s, 1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1.[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(O)C>[CH2:17]([N:24]([CH3:25])[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(Cl)nc2C1
Reactant: CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CN(Cc1ccccc1)c1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 48.3 %

Procedure:
A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.22 g, 0.94 mmol), benzyl(methyl)amine (0.17 g, 1.4 mmol) and triethylamine (0.14 ml, 0.1 g, 1.0 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (20 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-hexane, 1:1). The product obtained was recrystallized from ethyl alcohol to give the title compound (0.145 g, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][C:9]1[N:14]=[C:13]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[F:28])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[N:14]=[C:13]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[F:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1nc(CC(NC(=O)OC(C)(C)C)C(=O)O)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1nc(CC(NC(=O)OC(C)(C)C)C(=O)O)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(6-(3-tert-Butoxy-3-oxopropyl)-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid. To a solution of 139C (0.68 g, 1.551 mmol) in THF (10 mL) and water (3 mL) was added LiOH (0.074 g, 3.10 mmol) at 0° C. The reaction was stirred under argon at 0° C. for 2 hrs. 1.0 N HCl (3.1 mL) was added to neutralize the reaction. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give a tan solid of (E)-3-(6-(3-tert-butoxy-3-oxoprop-1-enyl)-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid. MS (ESI) m/z: 411.1 (M+H)+. To the above obtained intermediate were added catalytic amount of 10% Pd/C and MeOH (15 mL). The reaction mixture was stirred under a hydrogen balloon at rt for 1 h. Catalyst was filtered off and solvent was removed to give 139D as a tan solid. MS (ESI) m/z: 413.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[C:21]([O:27][CH2:28][CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])(=[O:26])[CH2:22][C:23]([CH3:25])=O>CC(O)C>[CH3:25][C:23]1[NH:13][C:14]([CH3:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=2[N+:10]([O-:12])=[O:11])[C:22]=1[C:21]([O:27][CH2:28][CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])=[O:26]
Reactant: O=Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc(Cl)c1[N+](=O)[O-]
Yield: 58.4 %

Procedure:
A mixture of 556 mg of 3-chloro-2-nitrobenzaldehyde, 362 mg of methyl 3-aminocrotonate and 820 mg of 2-(N-benzyl-N-methylamino)ethyl acetoacetate in 4 ml of 2-propanol was refluxed for 6 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by a method of column chromatography onon silica gel to yield 900 mg of the desired compound (108).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:51]>O1CCCC1.CO>[ClH:51].[ClH:51].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
185 mg 4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}-1-benzene sulfonamide obtained in Example 11 was dissolved in 3.5 mL solvent mixture of tetrahydrofuran and methanol (1:1), then 3.5 mL of 5 N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with 4 mL diethyl ether, and the aqueous layer was evaporated into dryness under reduced pressure (azeotropic evaporation with ethanol). The residue was recrystallized from ethanol and diethyl ether to give 123 mg of the title compound as colorless crystals.