Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14]([Cl:19])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21]OS([O-])=O.[K+].[OH2:27]>CO>[CH2:1]([S:8]([C:9]1[S:20][C:12]2=[N:13][C:14]([Cl:19])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)(=[O:21])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Cc1c(Cl)nc2sc(SCc3ccccc3)nn2c1=O
Reactant: O
Agent: [K+]
Solvent: CO
Product: Cc1c(Cl)nc2sc(S(=O)(=O)Cc3ccccc3)nn2c1=O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Four point nine (4.9) grams of 2-benzylthio-7-chloro-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved in methanol. To this solution, an aqueous suspension of 69.2 g of OXONE® in 240 ml of water was added, and the mixture was stirred at 60° C. for 1 hour and 45 minutes. After cooling, the reaction mixture was extracted with chloroform, the organic layer was washed with an aqueous sodium thiosulfate solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a toluene/ethanol (1:1) mixture. Thus 3.3 g of 2-benzylsulfonyl-7-chloro-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 211°-213° C. Yield 62%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH:17]=O)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:19][OH:20].CO.N1C=CC=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH:17]=[N:19][OH:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(O)cc2)c2occc2c1
Reactant: NO
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CO
Product: ON=Cc1cc(-c2ccc(O)cc2)c2occc2c1
Temperature: 68 °C

Procedure:
To a 25 ml round bottom flask was added 7-(4-hydroxyphenyl)-benzofuran-5-carbaldehyde (400 mg, 1.68 mmol), hydroxylamine hydrochlorode (234 mg, 3.36 mmol), anhydrous MeOH (10.4 ml), and anhydrous pyridine (0.272 ml, 3.36 mmol). The reaction was then heated to 68° C. and the reaction was brought to reflux for 1 h. The reaction was then cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 410 mg (96%) product as a yellow solid. The crude material was pure by 1H NMR (−4% cis isomer was detected) and LC-MS (one peak): mp 192–194° C. 1H NMR (300 MHz, DMSO-d6): δ 6.92 (2H, d, J=8.6 Hz), 7.05 (1H, d, J=2.2 Hz), 7.69–7.72 (3H, m), 7.79 (1H, d, J=1.4 Hz), 8.09 (1H, d, J=1.1 Hz), 8.27 (1H, s), 9.74 (1H, s), 11.14 (1H, s); MS (ESI) m/z 254 ([M+H]+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:22]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1.C(#N)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:22])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)O)c(NC(C)C)n1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC#N
Product: CSc1ncc(C(N)=O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (180 g, 0.792 mol) and HOBt (123 g, 0.911 mol) in anhydrous THF (6.9 L) was added drop-wise a mixture of EDC (174.6 g, 0.911 mol) in acetonitrile (3.7 L) at ambient temperature. The mixture was stirred for 1 h at ambient temperature and then an aqueous ammonium hydroxide solution (989 mL, 28-30% concentrated, 10 eq) was added drop-wise over 30 min. The resulting mixture was heated to gentle reflux for 3 h and then concentrated under reduced pressure. The remaining residue was diluted with a saturated aqueous sodium bicarbonate solution (5 L) and then extracted twice with ethyl acetate (9 L, and 2 L respectively). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (4 water (4 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(isopropylamino)-2-(methylthio)-pyrimidine-5-carboxamide (171.2 g, 95.5% yield) as a solid. MS (ESI) m/z 227.4 [MA-1]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>[Cl-].[Na+].O.O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH2:20]
Reactant: Cc1ccc(C=O)cn1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)OC)C(O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.8 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde, 97% (500 mg, 4.0 mmol, 1 eq), DABCO (458 mg, 1 eq) and methyl acrylate (1.80 ml, 5 eq) in a 1,4-dioxane (20 ml)/water (20 ml) solvent mixture was stirred at room temperature for 4 days. The resulting mixture was poured in 150 ml of brine and the organics were extracted with DCM (3×300 ml). The gathered DCM layers were dried, solvent was evaporated and the obtained crude was purified by chromatography on Biotage SP1 purification device using 25 g normal phase silica SNAP column and DCM/MeOH solvent system (gradient 1-6% of MeOH in 20 CV). Solvent from gathered fractions of appropriate composition was evaporated and the resulting crude was triturated with cyclohexane to obtain 2-[hydroxy-(6-methyl-pyridin-3-yl)-methyl]-acrylic acid methyl ester in form of white powder (375 mg, yield=43.8%, purity=95%). MS: [M+H]+=208.17 1H NMR (300 MHz; CDCl3) δ/ppm 2.55 (s, 3H), 3.11 (d, J=5.86 Hz, 1H), 3.74 (s, 3H), 5.58 (d, J=5.58 Hz, 1H), 5.87 (s, 1H), 6.38 (s, 1H), 7.15 (d, J=8.13 Hz, 1H), 7.61 (dd, J=8.13 Hz, J=2.45 Hz, 1H), 8.48 (d, J=2.45 Hz, 1H)
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]N)=[CH:13][CH:12]=1.O1C2C=CC=CC=2[N:22]=[C:21]1[C:29]1C=CC(CCCC#N)=CC=1.O1C2C=CC=CC=2N=C1C1C=CC(CCCCN)=CC=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH2:29][CH2:21][NH2:22])=[CH:15][CH:16]=1
Reactant: NCCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: N#CCCCc1ccc(-c2nc3ccccc3o2)cc1
Agent: Cl
Agent: NCCCCc1ccc(-c2nc3ccccc3o2)cc1
Product: CC(CCN)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
When 4-(benzoxazol-2-yl)benzyl cyanide of Example 42, Step D is replaced by 4-[4-(benzoxazol-2-yl)phenyl]butyronitrile, then the product prepared is 4-[4-(benzoxazol-2-yl)phenyl]butylamine (m.p. 220° C. dec.).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[NH:13][C:12]2=[O:22])[CH2:7][CH2:6]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[O:22]=[C:12]1[N:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:1]([Cl:4])=[O:2])[CH2:6][CH2:7]2)[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6 g (12.1 mmol) phosgene (20 percent by weight in toluene) were added to a solution of 2.5 g (10.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to 0° C. and the reaction mixture was stirred for 30 min at this temperature. It was allowed to come up to RT, evaporated down i.vac. to approx. 50 mL and filtered through silica gel, this washed with 200 mL DCM/EtOAc (1:1) and the combined filtrates were again evaporated down i.vac. The residue was stirred with diisopropylether, suction filtered and dried i.vac.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([O:15][CH3:23])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol (30 g) and potassium carbonate (13.8 g) were dissolved in acetone (300 ml) and, after addition of methyl iodide (28 g), the solution was stirred for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and water was added. The mixture was then subjected to extraction with ethyl acetate and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2-propenyl)anisole (31 g) quantitatively.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and m-anisoyl chloride (0.4 g, 2.5 mmol) in THF 30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (40 mL). The mixture was filtered, and the solid was slurried with hot ethanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-methoxy-benzamide (0.8 g, 93%) as a white solid: mp 244-246° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H), 2.36-2.65 (m, 2H), 2.86-3.00 (m, 1H), 3.80 (s, 3H, CH3), 4.41-4.61 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.1 and 13.2 Hz, 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.35-7.65 (m, 6H, Ar), 9.09 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.29, 51.59, 55.24, 112.41, 117.19, 119.44, 121.65, 128.31, 129.46, 130.67, 131.61, 134.68, 135.46, 140.12, 159.18, 166.08, 168.06, 171.00, 172.82; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.62; H, 5.06; N, 10.23.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:35][CH:34]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Phenyl chloroformate (0.42 mL, 3.34 mmol) was added dropwise to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-propan-2-ylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (1.4 g, 3.34 mmol) and sodium carbonate (0.421 g, 5.02 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give crude product which was triturated with diethyl ether to give the desired product (1.57 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH2:16]1.[CH:39]1([C:42](Cl)=O)[CH2:41][CH2:40]1>>[CH:39]1([CH2:42][N:6]([CH2:5][C:4]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:2]([F:1])[CH:3]=2)[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[CH2:16]2)[CH2:41][CH2:40]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(Cc1ccc(OCCN3CCCCC3)c(F)c1)CC1CC1)C2

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (450 mg) and cyclopropanecarbonyl chloride (0.47 ml) according to an analogous synthetic method to Example 152, the title compound (430 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)cc2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.25 g (6.28 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoic acid methyl ester using 1.32 g (31.4 mmoL) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.3 g of crude product are obtained which is used for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: BrCc1cccc(-c2ccsc2)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1cccc(-c2ccsc2)c1
Yield: 41.8 %

Procedure:
A stirred solution of 8.7 g (0.034 mol) of 3-(3-bromomethylphenyl)thiophene and 5.1 g (0.051 mol) of potassium acetate in 65 mL of glacial acetic acid was heated under reflux for three hours. The reaction mixture was cooled and transferred to a separatory funnel, and 150 mL of water was added. The mixture was extracted with two portions of 120 mL each of methylene chloride. The combined extracts were washed with 150 mL of a saturated solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally 100 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give an oil residue. The residue was subjected to column chromatography on silica gel, eluting with hexane:methylene chloride (3:2). The appropriate fractions were combined to give 3.3 g of 3-(3-thienyl)phenylmethyl acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[CH:34](OC(=O)C)=[O:35]>>[CH:34]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:35]
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC=O
Product: O=CN1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[C:14](Cl)[C:13](C(F)(F)F)=[CH:12][C:11]=1[N+:21]([O-:23])=[O:22].CO[C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1N.ClC1C=C(Cl)C(C(F)(F)F)=CC=1[N+]([O-])=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:27]=2)[CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccccc1Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COc1ccccc1N
Agent: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Product: COc1cc(-c2ccccc2)ccc1Nc1ccccc1[N+](=O)[O-]

Procedure:
N-(2-methoxyphenyl)-2-nitro-4-trifluoromethyl-5-chloroaniline, M.p. 142°-145° C., by reaction between 2-methoxyaniline and 2-chloro-4-chloro-5-trifluoromethyl-nitrobenzene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].IC.[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C)c(Cl)c1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Heat a solution of 3-chloro-4-methylphenol (15 g, 0.11 mol), iodomethane (9.8 mL, 0.16 mol), and potassium carbonate (22 g, 0.16 mol) in DMF (200 mL) to 50° C. and stir for 2 hr. Cool the reaction to room temperature and quench with 1N aqueous HCl. Extract the aqueous with diethyl ether (Et2O). Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 16.4 g (100%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[N:2].OO.NC(N)=[O:20].[OH-].[Na+]>CO>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)(=[O:20])[NH2:2]
Reactant: COC(=O)c1ccc2c(C#N)n[nH]c2c1
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1n[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of methyl 3-cyano-1H-indazole-6-carboxylate (254 mg, 1.26 mmol) in methanol (12 mL) at 0° C. was added a cold solution of urea hydrogen peroxide (1.22 g, 12.6 mmol) in sodium hydroxide (12.6 mL 1M in water, 12.6 mmol). The yellow solution was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove methanol. The pH of the resulting residue was adjusted to ˜4 with 1N hydrochloric acid. A precipitate formed. The mixture was filtered and the solid was dried to afford 3-carbamoyl-1H-indazole-6-carboxylic acid as a brown solid (82 mg, 32%). 1H NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1 H), 13.04 (br. s., 1 H), 8.20 (d, J=8.4 Hz, 1 H), 8.13-8.16 (m, 1 H), 7.77 (br. s., 1 H), 7.74 (dd, J=8.6, 1.4 Hz, 1 H), 7.38 (br. s., 1 H).
Reaction SMILES: [C:1]([C:3]([C:24]#[N:25])=[C:4]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:5]1([C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:3]([C:1]#[N:2])[C:24]#[N:25])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=C(C#N)C#N)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC(C#N)=C(c1ccccc1)N1CCNCC1
Reaction time: 16 h
Yield: 71 %

Procedure:
tert-Butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate (2 g) was dissolved in a 33.3% solution of TFA in methylene chloride (20 ml). After 16 hour at room temperature, solvents were removed under vacuum to offer a residue which was purified using silica gel chromatography to give 2-(phenyl(piperazin-1-yl)methylene)malononitrile (1 g). 1H NMR (500 MHz, CD3OD) □7.62 (m, 5H), 3.70 (b, 4H), 3.47 (b, 4H); 13C NMR (125 MHz, CD3OD) □172.9, 132.7, 132.5, 129.6, 116.6, 116.0, 55.2, 43.4. MS m/z: (M+H)+ calcd for C14H15N4 239.13, found 239.13. Retention time 0.56 min (column A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:9])[CH2:7][NH:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCc1cccs1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNCc1cccs1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
t-Butylbromoacetate (1.45 mL, 10 mmol) was added to 2-aminomethyl thiophene (1.13 g. 10.0 mmol) and DIEA (2.0 ml) in THF (20 mL). The mixture was warmed to room temperature (4 h), diluted with ether (100 mL) and washed with water (20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated in vacuum. The product was purified by column chromatography eluting with 10-25% EtOAc in hexane to give [(thiophen-2-ylmethyl)-amino]-acetic acid tert-butyl ester (1.2 g). LCMS m/z: 229 (M+1)+.