Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:28])[N:5]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:6]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:7]2.[CH3:29][N:30]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.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>[C:29]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:28])[N:5]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:6]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:7]2)#[N:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Br)c2c(=O)n1-c1cccnc1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C#N)c2c(=O)n1-c1cccnc1
Temperature: 80 °C
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl 1-(5-bromo-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate (255 mg, 0.58 mmol) in NMP (2 mL) was added zinc cyanide (74 mg, 0.63 mmol) and (PPh3)4Pd (66 mg, 0.06 mmol). The resulting suspension was degassed under Argon and heated to 80° C. for 5 hours. The reaction was poured into EtOAc, washed twice with aq. NaHCO3 and once with brine. Purification by flash chromatography (0-75% EtOAc/hexanes) provided (S)-tert-butyl 1-(5-cyano-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate 196 mg (87%). ES/MS 392.1 (M+H+).
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16].[CH2:17]([OH:20])[CH2:18][OH:19].CCOC(C)=O>CS(C)=O>[F:16][C:9]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:8]=1[O:19][CH2:18][CH2:17][OH:20]
Reactant: OCCO
Reactant: Fc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OCCOc1cc(F)c(F)cc1F
Temperature: 80 °C

Procedure:
t-BuOK (3.0 g, 27 mmol) was added to a mixture of 1,2,4,5-tetrafluorobenzene (2.0 g, 13.3 mmol) and ethylene glycol (7.5 mL, 133 mmol) in DMSO (50 mL) and heated at 80° C. for 1 h and then at 60° C. overnight. EtOAc was added and the resulting solution was washed several times with water. The organic layer was dried (Na2SO4) and concentrated carefully in vacuo at 30° C. to furnish 1.5 g (containing ˜14% EtOAc) of the title compound as a white semisolid. NMR analysis supports the stated structure. This material was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>CO>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCN1
Reaction time: 12 h

Procedure:
To a solution of Example 29B (140 mg, 0.28 mmol.) in methanol (2 mL) was added hydrogen chloride in dioxane (0.5 mL, 2.000 mmol) and stirred for 12 hr. The solvent was removed under reduced pressure and the residue recrystallized from methanol:diethyl ether to provide the title compound as a hydrogen chloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H) 1.68-1.79 (m, 1 H) 1.87-2.01 (m, 2 H) 2.03-2.12 (m, 1 H) 3.14-3.28 (m, 2 H) 3.81 (s, 3 H) 3.93-4.06 (m, 1 H) 4.47 (d, J=6.44 Hz, 2 H) 7.14 (d, J=9.16 Hz, 1 H) 7.45-7.50 (m, 2 H) 7.63 (d, J=2.71 Hz, 1 H) 9.29 (d, J=4.41 Hz, 2 H); MS (DCI) m/z 408 (M+H)+. Anal. calcd for C20H26ClN3O2S.2HCl.1.0H2O: C, 48.15; H, 6.06; N, 8.42. Found: C, 48.00; H, 6.04; N, 8.27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.I[CH3:10]>>[CH3:10][N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: CI
Product: Cn1cc(Br)cc1C=O
Yield: 53.2 %

Procedure:
In a similar manner to Example 10(b), by reaction of 4 g (23 mmol) of 4-bromo-2-pyrrolecarboxaldehyde with 1.7 ml (27.6 mmol) of iodomethane, 2.3 g (50%) of the expected product are obtained, with a melting point of 123-4° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[CH:14]=1)=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([NH:39][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)=[CH:19][CH:18]=2)[CH:14]=1)=[O:7]
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(F)cc1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(NCCCN2CCOCC2)cc1
Yield: 3 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]4-fluorobenzamide was reacted with 3-morpholinopropylamine to give the title compound in 3% yield; NMR Spectrum: (DMSOd6) 1.77 (m, 2H), 2.24 (s, 3H), 2.46 (m, 6H), 3.02 (s, 6H), 3.16 (q, 2H), 3.65 (t, 4H), 6.33 (t, 1H), 6.67 (d, 2H), 6.97 (m, 1H), 7.28 (m, 2H), 7.36 (t, 1H), 7.62 (m, 1H), 7.83 (m, 3H), 9.45 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C2=CCC(C)(C)CC2)c(-c2ccccc2)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)c(C2=CCC(C)(C)CC2)c1C(OC(C)(C)C)C(=O)O
Yield: 86.2 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetate (1f) (121 mg, 0.29 mmol) and potassium hydroxide (144 mg, 1.18 mmol) in a mixture of ethanol (1.5 mL) and water (1.5 mL) was refluxed for 6 hours. The reaction mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2×2 mL), acidified with concentrated hydrochloric acid until pH 2 and extracted with diethyl ether (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetic acid (example 1) (101 mg, 0.25 mmol, 86%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 43 mg, 0.125 mmol) and morpholine (43 mg, 0.499 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with DMF and then purified by preparatory HPLC (20-35% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (22.4 mg, 45%). Melting point (242.8-242.9° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H), 2.38 (s, 3H), 3.69-3.78 (m, 4H), 3.80-3.88 (m, 4H), 6.18 (s, 1H), 7.34 (s, 1H), 7.60 (d, J=8.84 Hz, 2H), 7.99 (d, J=8.84 Hz, 2H), 10.87 (s, 1H); ESI-MS: m/z 396.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([S:34][CH:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)=[CH:24][C:6]=43)[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (210 mg, 0.541 mmol), 1-isopropylpiperidine-4-thiol (129 mg, 0.812 mmol), Pd2(dba)3 (25 mg, 5 mol %), XantPhos (31 mg, 10 mol %) and DIPEA (380 μl, 2.16 mmol) in dioxane (5 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was then diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 2-15% MeOH in DCM followed by C18, gradient 15-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid/gum (146 mg, 58%). LCMS: RT 2.20 min [M+H]+ 467.0
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(N(CC)CC)C.[S:18]1[C:22]2[C:23]([C:27](Cl)=[O:28])=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1>C(OCC)(=O)C>[S:18]1[C:22]2[C:23]([C:27]([O:8][C:6]3[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=3)=[O:28])=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(Cl)c1cccc2nnsc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)C=C(OC(=O)c2cccc3nnsc23)C1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
5.6 g (0.04 mol) of 5,5-dimethyl-1,3-cyclohexanedione are dissolved in a mixture of 4.4 g (0.044 mol) of triethylamine and 120 ml of ethyl acetate. 8.7 g (0.044 mol) of benzothiadiazole-7-carboxylic acid chloride are added dropwise at 15° to 20° C., and the mixture is subsequently stirred overnight at room temperature. The ethyl acetate solution is washed with H2O, dried and concentrated. Purification by column chromatography using ethyl acetate/hexane gives 10.5 g (87.5%) of the title compound, melting point 131°-133° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[CH:53]=[CH:52][C:50]([NH:51][C:14]([C@@H:9]3[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[CH:49][CH:48]=2)=[CH:44][CH:43]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step (a) A flask was charged with (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.1 mmol), HATU (3.80 g, 10.0 mmol), 4-(4-fluorophenoxy)aniline (1.85 g, 9.09 mmol), DIEA (4.8 mL, 27 mmol) and DMF (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with ethyl acetate (60 mL) and the extract was washed with deionized water (30 mL) and then brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate, which was carried forward without further purification.
Reaction SMILES: [CH2:1]([S:3]/[C:4](/[O:7][Si](C)(C)C)=[CH:5]/[CH3:6])[CH3:2].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[O:14].Cl.CO>C1(C)C=CC=CC=1>[CH2:1]([S:3][C:4](=[O:7])[CH:5]([CH3:6])[CH:13]([OH:14])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[CH3:2]
Reactant: C/C=C(\O[Si](C)(C)C)SCC
Reactant: CCCCOC(=O)C=O
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(O)C(C)C(=O)SCC
Temperature: 0 °C
Yield: 64 %

Procedure:
0.5 ml (0.1 mmol) of (R)-1 solution prepared in the same manner as in Example 1 were cooled to 0° C., and 190 mg (1 mmol) of (E)-1-ethylthio-1-trimethylsilyloxy-1-propene (77% E) and subsequently 130 mg (1 mmol) of freshly distilled butyl glyoxylate and 0.5 ml of toluene were added thereto, followed by allowing the mixture to react at 0° C. for 0.5 hour. The resulting mixture was poured into 10% hydrochloric acid-methanol cooled at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/1 by volume) to obtain 158 mg (yield 64%) of n-butyl 4-ethylthio-2-hydroxy-3-methyl-4-oxobutyrate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[OH-].[K+].[I:13]I.[OH-].[NH4+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:13]
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Into a round-bottom flask was dissolved 5-bromo-1H-indazole (1.99 g, 0.0101 mol) in N,N-dimethylformamide (10.0 mL). To this stirred solution was added potassium hydroxide (2.03 g, 0.0362 mol) then a cold solution of iodine (2.82 g, 0.0111 mol) in N,N-dimethylformamide (12.0 mL, 0.155 mol) was added dropwise. The mixture was stirred at room temperature for 2 hours before being added dropwise to an ammonium hydroxide (150 mL, 3.8 mol) solution in water (2.0 L) to give a precipate. The precipitate was collected and dried under vacuum for 18 hours to yield 3.00 g (92%) of 5-bromo-3-iodo-1H-indazole.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:19]2[C:14](=[CH:15][C:16]([S:20]([N:23](CC3C=CC(OC)=CC=3OC)[C:24]3[S:28][N:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:17][CH:18]=2)[N:13]([CH3:40])[CH:12]=1>>[CH3:40][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([S:20]([NH:23][C:24]3[S:28][N:27]=[CH:26][N:25]=3)(=[O:21])=[O:22])[CH:15]=2)[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12]1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2ccccc2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using phenylboronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-phenyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H) 7.15-7.30 (m, 1 H) 7.43 (t, J=7.73 Hz, 2 H) 7.48-7.55 (m, 1 H) 7.61-7.68 (m, 2 H) 7.81 (d, J=4.47 Hz, 2 H) 7.85-7.89 (m, 2 H). m/z (ESI) 370.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:16][CH2:17][CH3:18])(=[O:15])C>>[CH2:17]([O:16][C:13]([NH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])=[O:15])[CH3:18]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: CCOC(C)=O
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 (Method A) from 2-amino-5-nitrobenzonitrile. tlc: Rf=0.4 (33% ethyl acetate in hexanes)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:21][O:20][C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:19][CH:18]=1
Reactant: COc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(N2CCNCC2)nc1

Procedure:
953 mg 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 16 mL 4 mol/L HCl solution in dioxane for 45 min The precipitate was filtered, washed with dioxane and dried to yield 723 mg of the desired compound. Rt: 0.46 min (method F), (M+H)+: 195
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH3:17])[CH:12]=1.CO.O>O>[CH2:15]([NH:14][C:13]([C:11]1[CH:12]=[C:7]([CH2:6][C:5]([OH:25])=[O:4])[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)=[O:18])[CH2:16][CH3:17]
Reactant: CCCNC(=O)c1cc(CC(=O)OC)cc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCNC(=O)c1cc(CC(=O)O)cc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of LiOH (800 μL of a 2 M solution in H2O) was added to a solution of 68G (50 mg, 0.16 mmol) in 4 mL of a 3:1 mixture MeOH/H2O. After 1 hour, the reaction was complete as shown by TLC. The reaction mixture was then concentrated and the residue was dissolved in water and HCl 10% was then added. As no product precipitated, the aqueous solution was extracted 3 times with AcOEt. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. A white foamy solid was obtained and used in the next step without further purification (47 mg, quantitative). NMR 1H (ppm, DMSO-d6): 7.86 (s, 1H), 7.61-7.60 (m, 3H), 7.57 (s, 1H), 7.46-7.33 (m, 3H), 6.16 (br, s, 1H), 3.72 (s, 2H), 3.70 (s, 3H), 3.46-3.39 (m, 2H), 1.64 (sext., J3=7.43 Hz, 2H), 0.98 (t., J3=7.50 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[N:9])=[N:6][S:5][N:4]=1)#[N:2].[OH-:10].[K+]>O>[C:1]([C:3]1[C:7]([C:8](=[O:10])[NH2:9])=[N:6][S:5][N:4]=1)#[N:2]
Reactant: [OH-]
Reactant: N#Cc1nsnc1C#N
Agent: [K+]
Solvent: O
Product: N#Cc1nsnc1C(N)=O

Procedure:
First, one mole of solid 3,4-dicyano-1,2,5-thiadiazole (II) is suspended in a quantity of water sufficient to obtain an easily stirrable mixture. Then, under stirring, there are admixed from 0.01 to 0.8 mole of KOH in the form of an aqueous solution. There occurs an exothermic reaction which is controlled by cooling so as to maintain a temperature of about 20° to 50° C. At this stage the 3,4-dicyano-1,2,5-thiadizole (II) passes into solution, hydrating to form 3-cyano-4-carbamoyl-1,2,5-thiadiazole (III), which may be separated as a solid if one operates at 20° to 35° C, or which will remain in solution if one operates at higher temperatures up to 50° C. This ends the first stage of the reaction.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:33])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2NC(OC(C)(C)C)=O)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][Cl:8].[Li+].[OH-:36].Cl>CO.O>[C:4]([O:36][C:17]([NH:18][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:17](/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][C:9]([CH:4]([CH2:5][CH2:6][CH2:7][Cl:8])[C:3]([OH:2])=[O:34])=[CH:10][CH:11]=1)=[O:33])=[O:33])([CH3:9])([CH3:5])[CH3:3]
Reactant: [OH-]
Reactant: COC(=O)C(CCCCl)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NN(C(=O)/C=C/c1ccc(C(CCCCl)C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-5-chloro-pentanoic acid methyl ester (48.7 mg, 10 mmol) in MeOH/H2O (4:1) (2 mL), LiOH (24 mg, 100 mmol) was added. After the solution was stirred at room temperature for 5 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (10 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain of a yellow solid product without further purification. MS: calc'd 473 (MH+), exp 473 (MH+). 1H NMR (400 MHz, DMSO-d6) 12.50 (s, 1H), 9.73 (s, 1H), 8.50 (s, 1H), 6.89-7.64 (m, 10H), 3.61 (m, 3H), 1.55-2.10 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]([CH2:12][O:13]C(=O)C)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[OH-].[K+]>CCO>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccnc1COC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1cccnc1CO
Yield: 52.8 %

Procedure:
To a stirred solution of ethyl-2-[2-(acetoxymethyl)-pyridin-3-yl]-acetate (prepared from 2-methylnicotinic acid as described by Y. Sato et al., Chem. Pharm. Bull.; EN. 1960, 8, 427) (2.37 g, 10 mmol) in EtOH (50 mL) was added KOH (3 g, 53 mmol) and the mixture stirred at reflux overnight. The mixture was cooled, concentrated under reduced pressure and diluted with brine (5 mL) and CH2Cl2 (25 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL), the phases separated and the combined organic extacts dried (Na2SO4), filtered and concentrated to afford ethyl-2-[2-(hydroxymethyl)-pyridin-3-yl]-acetate (1.03 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=1[C:4]([O:6]C)=O.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:6][C:4]1[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])[N:1]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(N)cccc1OC
Reactant: COC(=O)C#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(OC)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of methyl 2-amino-6-methoxybenzoate ((1.30 g, 7.17 mM) and dimethyl acetylenedicarboxylate (1.17 g, 8.23 mM) in t-butanol (11 mL) was refluxed under a nitrogen atmosphere for 4 hr. The reaction mixture was cooled to room temperature, potassium t-butoxide (0.92 g, 8.23 mM) was added, and the resulting mixture was heated to 90° C. for 1.5 hr during which solids precipitated out of solution. The mixture was cooled to room temperature, filtered and the collected solids were dissolved in water. The resulting solution was acidified with 1N H2SO4 to form a light tan precipitate. The solids were collected, filtered, washed with water and air dried to provide the desired compound (1.35 g, 65%) as a tan solid. A 0.28 g portion of this material was recrystallized from ethyl acetate to provide an analytical sample (0.24 g) of the title compound as a white solid, mp 184°-186° C.; MS(CI): 292 (M+H). Analysis for C14H13NO6 ·0.2 H2O: Calculated: C, 57.03; H, 4.58; N, 4.75 Found: C, 56.99; H, 4.40; N, 4.70