Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:15]=2[C@H:14]([CH3:34])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O.O>[CH3:34][C@H:14]1[C:15]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:18]=[N:17][C:16]=2[C:12](=[O:11])[CH2:13]1
Reactant: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 82.3 %

Procedure:
A solution of DMSO (5.45 ml, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a −78° C. solution of oxalyl chloride (3.35 ml, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at −78° C., after which neat triethylamine (18.0 ml, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H2O was added. The mixture was extracted with DCM (3×200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1:4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3×) from DCM/hexanes, which gave a very light brown foam. HPLC>95% area. LC/MS (APCI+) m/z 333 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCNCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
0.3 g (3.4 mmol) of piperazine in 10 ml of DMF was added to a solution of 0.6 g (1.7 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and the mixture was stirred at 60° C. for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 8:1) and crystallization from EtOH yielded 0.35 g (51%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 201-202°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][B-](F)(F)F.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:24]([N:31]1[CH2:36][CH:35]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=2)[O:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:24]([N:31]1[CH2:32][CH2:33][O:34][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([CH2:10][CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[CH:39][CH:38]=2)[CH2:36]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: F[B-](F)(F)CCc1c(Cl)cccc1Cl
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cccc(Cl)c1CCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
To a degassed solution of potassium[2-(2,6-dichlorophenyl)ethyl]trifluoroborate (0.28 g; 1 mmol) and potassium phosphate tribasic (0.58 g; 2.7 mmol) in toluene (20 mL) and water (4 mL) was added 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.30 g; 0.90 mmol), palladium(II) acetate (6.1 mg; 0.03 mmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (25.3 mg; 0.05 mmol). The resulting mixture was heated under reflux, overnight. After cooling to RT, the mixture was concentrated in vacuo and partitioned between EtOAc and 5% aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-benzyl-2-{4-[2-(2,6-dichloro-phenyl)-ethyl]-phenyl}-morpholine (0.21 g).
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(F)c1F
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(-c2csc(Br)n2)c1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (40 ml) solution was added to a solution of 2-(2,3-difluorophenyl)-2-oxoethyl thiocyanate (5.67 g, 26.6 mmol) in acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.74 g (91.8%) of the desired product as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:4]=12.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:15]1[CH2:14][CH2:13][C:5]2=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:7][C:3]([S:2][CH3:1])=[C:4]2[C:16]1=[O:17]
Reactant: BrBr
Reactant: CCOC(=O)c1oc(SC)c2c1CCCC2=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(SC)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]furan-1-carboxylate (4.26 g) was dissolved in chloroform (75 ml); a solution of bromine (2.73 g) in chloroform (5 ml) was added dropwise at room temperature over a period of 10 minutes. After the reaction mixture was stirred at room temperature for 30 minutes, it was washed with a 2% aqueous solution of sodium sulfite (100 ml), water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]furan-1-carboxylate (5.01 g, 89.8%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 130-131° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH:12]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:26]=[O:27])C>>[CH:26]([C:21]1[CH:20]=[N:19][N:18]([CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:22]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(c1ccccc1)n1cccn1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(c1ccccc1)n1cc(C=O)cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Phosphorous oxychloride (7.0 mL, 75 mmol) was added dropwise to 14 mL DMF at 0° C. under an atmosphere of N2. The resulting solution was stirred for 0.5 hour and then a solution of ethyl (±)-α-phenyl-1H-pyrazole-1-acetate (5.76 g, 25 mmol) in 5 mL DMF was added dropwise. The resulting orange solution was warmed to 70° C. for 16 hours. The reaction mixture was cooled to 0° C. and carefully quenched with saturated Na2CO3 solution. The reaction mixture was partitioned between water and ether and the ether layer was dried over MgSO4, filtered, and concentrated to give an orange oil. Chromatography (15% EtOAc/hexanes on silica) gave 5.73 g (89%) of the title compound as a yellow/green oil which solidified upon standing; mp 68°-70° C.
Reaction SMILES: [CH:1]1([S:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10]C)=[O:9])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1>[CH:1]1([S:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([OH:10])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1SC1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To 2A (7.20 g, 28.3 mmol) in THF (190 mL) was added 1 N LiOH (94 mL). The reaction was stirred for 1 h at rt, then was heated gradually to 65° C. After cooling to rt, the THF was removed under reduced pressure. The remaining solution was cooled to 0° C. and acidified to pH 1 with 1N HCl. The product was extracted with CH2Cl2, and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to provide 2B as a clear oil (6.30 g). LC-MS: 241.08 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:2]#[CH:3].[OH-].[Na+].[I:13]I.O>CO>[I:13][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: C#CCOc1cccnc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: IC#CCOc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
In 300 ml methanol was dissolved 39.0 g (0.27 mole) 3-(2-propynyloxy)pyridine. This solution was cooled to 0° C. and 54.0 g (1.35 moles) sodium hydroxide was added slowly while maintaining the temperature at 0°-5° C. Iodine (82.0 g, 0.32 mole) was added portionwise followed by the addition of 400 ml methanol. After stirring for 2 hours at room temperature, the reaction mixture was poured into cold water. The resulting precipitate was filtered and dried. This crude product was recrystallized from 350 ml methanol and 75 ml toluene to give 60.0 g (86% yield) 3-(3-iodo-2-propynyloxy)pyridine, mp 130° C. with decomposition.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>CN(C=O)C.O>[Si:27]([O:8][CH:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5]1)([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 18 h

Procedure:
To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) in DMF (0.5 M) was added imidazole (4.0 equiv.) and TBDMSCl (2.5 equiv.). After stirring for 18 hours the solution was portioned between EtOAc and H2O and separated. After washing further with H2O (3×) and NaCl(sat.), drying over MgSO4, filtering and removal of solvents, 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)-3-nitropyridine was obtained (85%). LC/MS=349.2 (M+H), LC=5.99 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)=[C:6]3[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(N)cc1
Product: O=C(O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-(4-amino-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and benzenesulfonyl chloride followed the procedure of Example 3 Step 2 as a light brown solid: 1H NMR (DMSO-d6) δ 5.67 (s, 2H), 6.95-7.05 (m, 4H), 7.14-7.23 (m, 3H), 7.30-7.35 (m, 1H), 7.49-7.75 (m, 8H), 10.26 (br s, 1H), 13.24 (br s, 1H); MS (ESI) m/z 489 (MH+); HRMS calcd for C26H21N2O4S2: 489.0940; found (ESI+): 489.0935.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[N+:11]([O-])([OH:13])=[O:12].C(OCC)C>C(O)(=O)CC>[N+:11]([C:7]1[C:2]([OH:1])=[C:3]2[S:10][CH:9]=[CH:8][C:4]2=[N:5][CH:6]=1)([O-:13])=[O:12]
Reactant: Oc1ccnc2ccsc12
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2ccsc2c1O
Temperature: 110 °C

Procedure:
Commercially available 7-hydroxythieno[3,2-b]pyridine (9.9 g, 65.5 mmol) was dissolved in propionic acid (200 mL) and heated to 110° C., behind a bomb shield. 4.85 mL of fuming nitric acid (90%) was added over 2 minutes, during which time a copius precipitate formed. The thick suspension was brought to reflux (oil bath temperature ˜150° C.) for 1 h during which time an orange gas evolved (Caution: procedure should only be performed in a well ventilated hood). The reaction mixture was allowed to cool to room temperature and 200 mL of diethyl ether was added. The product was collected by filtration, washed with ˜400 mL of water, 300 mL of 1:1 diethyl ether/methanol, and dried to yield 9.5 g, (74%) of A2.1 as a tan powder. M.S. 197 (M+H)+ 100%.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:31][CH3:32])[CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([N:31]([C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])[CH3:32])[CH:23]=1
Reactant: CNc1cc(Cl)ccc1C(=O)O
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(c1cc(Cl)ccc1C(=O)O)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 2 h
Yield: 58.4 %

Procedure:
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (800 mg, 2.16 mmol), 4-Chloro-2-methylamino-benzoic acid (400 mg, 2.16 mmol) and K2CO3 (298 mg, 2.16 mmol) were dissolved in about 8 ml DMSO. After stirred for about 2 h, the solution was poured into water to obtain the crude product. The crude product was purified by chromatography to obtain 600 mg solid rac-4-Chloro-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-benzoic acid
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[O:28][CH:27]=[N:26][CH:25]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:29]C(=O)C)[CH:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[O:28][CH:27]=[N:26][CH:25]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:29])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnco4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnco4)ccc32)c1
Temperature: 85 °C
Yield: 69 %

Procedure:
To a solution of the compound of Example 22 (800 mg, 1.86 mmol) in ethanol (10 ml) was added aqueous solution of NaOH (640 mg, 16 mmol, 8.6 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 69% yield (0.5 g). LC-MS (ESI): Calculated mass: 388.37; Observed mass: 389.1 [M+H]+ (rt: 1.517 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13]
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: O=C1CC(c2ccco2)CC(=O)C1Br
Temperature: 85 °C
Yield: 69.5 %

Procedure:
To a stirred solution of 5-(2-furyl)cyclohexane-1,3-dione (1 g, 5.6 mmol) in THF (50 mL) was added N-bromosuccinimide (1 g, 5.6 mmol). The reaction mixture was heated to 85° C. for 12 h and on completion was filtered. The filtrate was concentrated in vacuo to give the title compound (1.0 g, 69%) as a white solid. LCMS (ES+) 256.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])=[CH:6][C:5]=1[OH:15].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])=[CH:6][C:5]=1[OH:15]
Reactant: CCCC(O)c1ccc(C(=O)OC)c(O)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCC(=O)c1ccc(C(=O)OC)c(O)c1
Reaction time: 8 h

Procedure:
To the solution of 2-hydroxy-4-(1-hydroxy-butyl)-benzoic acid methyl ester (132 mg, 0.59 mmol) in DCM (6 mL), is added PDC (245 mg, 1.1 mmol) in one portion. The reaction is stirred overnight. The reaction mixture is filtered through a silica gel plug using DCM as eluent. The filtrate is concentrated to give 4-butyryl-2-hydroxy-benzoic acid methyl ester as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 7.92 (d, 1H, J=8.4 Hz), 7.52 (d, 1H, J=1.6 Hz), 7.44 (dd, 1H, J=1.6, 8 Hz), 3.99 (s, 3H), 2.93 (t, 2H, J=7.2 Hz), 1.76 (qt, 2H, J=7.6 Hz), 1.00 (t, 3H, J=7.6 Hz).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(4-chloro-phenyl)-propylamine (0.102 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-chloro-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.031 g, 23%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.96 (m, 2H), 2.69 (t, 2H), 3.64 (t, 2H), 4.36 (s, 2H), 7.14-7.58 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 285 (M)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][N:14]([CH3:16])[NH2:15]>C(O)C>[CH3:13][N:14]([CH3:16])[NH:15][C:2](=[O:3])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN(C)N
Solvent: CCO
Product: CN(C)NC(=O)c1ccccc1N
Yield: 29.2 %

Procedure:
Isatoic anhydride (5.0 g, 30.6 mmol), 35 mL of absolute ethanol and anhydrous 1,1-dimethylhydrazine (2.56 mL, 33.6 mmol) were refluxed for 2 hours. The volatiles were removed in vacuo. The residue was purified by silica gel flash chromatography using 5-10% methanol in dichloromethane. Concentration in vacuo produced 1.60 g of 2-aminobenzoic acid N′,N′-dimethylhydrazide.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[K+]>[CH2:9]([O:16][C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
10 g of L-valine (85 mmol) are dissolved in 4 M KOH (40 ml) and the mixture is cooled in ice. 21.9 g of benzyloxycarbonyl chloride (128 mmol) are added thereto over 5 minutes and a white solid forms. The mixture is stirred at 0° C. for one hour, the temperature is then allowed to rise and stirring is continued for another hour at room temperature. The reaction mixture is then diluted with 4 M KOH (200 ml) and is extracted with ether (2×100 ml). The aqueous phase is then brought to an acidic pH<1 with concentrated hydrochloric acid and is then extracted with ethyl acetate (3×200 ml). The extracts are combined and dried (Na2SO4) and the solvent is evaporated off. A clear oil is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].O(CC)[C:13]([S-])=[S:14].[K+]>C(O)C>[SH:14][C:13]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(S)nc2c1
Yield: 76.1 %

Procedure:
A mixture of 2-amino-4-nitrophenol (12.5 g, 71 mmol) and potassium ethyl xanthate (13 g, 81 mmol) were dissolved in ethanol (200 mL). The reaction was heated at reflux overnight. After cooling, solvent in the reaction mixture was evaporated under reduced pressure. The resultant residue was dissolved in water and adjusted to pH 2-3 with 2N HCl, resulting in the formation of a red solid. The red solid was filtered giving 2-mercapto-5-nitrobenzoxazole (10.6 g, 76%).
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:35])([CH3:34])[CH2:22][C:23]1[N:27]([CH2:28][CH2:29][CH3:30])[N:26]=[C:25]([C:31](O)=[O:32])[CH:24]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C=O)C.O>[NH2:3][C:31]([C:25]1[CH:24]=[C:23]([CH2:22][C:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:35])[CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[N:26]=1)=[O:32]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCn1nc(C(=O)O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(C(N)=O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 93.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.68 g, 29.6 mmol) was added to a solution of 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylic acid (8.77 g, 27.0 mmol) and 1-hydroxybenzotriazole (4.00 g, 29.6 mmol) in DMF (44 mL) at ambient temperature. The mixture was stirred for 5.5 hours until a solution formed, then was cooled in an ice bath. Concentrated ammonium hydroxide (5.5 mL) was added and the cloudy solution was stirred for 10 minutes, then was allowed to warm to ambient temperature and stir overnight. Water (150 mL) was added and the mixture was extracted with chloroform (4×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was concentrated twice from xylene under reduced pressure to afford an oil that was purified on chromatography on a HORIZON HPFC system (silica gel, elution with ethyl acetate) to yield 8.21 g of tert-butyl 2-[3-(aminocarbonyl)-1-propyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[Br:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([Br:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Brc1cn[nH]c1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(Br)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-bromopyrazole and cesium carbonate in NMP. EI-MS m/e (%): 313 (M{81Br}+H+, 95). 311 (M{79Br}+H+, 100).