Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].C[C:8]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:9]1O.Br[CH:17](Br)[CH3:18]>CC(C)=O>[CH3:9][C:11]1[C:1]2[O:4][CH2:18][CH2:17][O:15][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CC1(O)C=CC=CC1O
Reactant: O=C([O-])[O-]
Reactant: CC(Br)Br
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc2c1OCCO2
Reaction time: 0.25 h

Procedure:
Dry potassium carbonate (0.93 eq.) is added to a solution of ortho-methylcatechol (10 g) dissolved in 150 ml of acetone under an argon atmosphere; the reaction mixture is heated to a gentle reflux and dibromoethane (0.4 eq.) is then added. Those operations are repeated twice at 15 minute intervals and in identical proportions (that is to say, in total 2.8 eq. of K2CO3 and 1.2 eq. of dibromoethane are added). After 12 hours' reflux, the latter is again introduced into the reaction mixture in an altogether identical amount (that is, 1.2 eq.). Heating is continued for 72 hours. The solution obtained is cooled, the salts are then filtered off over Celite and the filtrate is concentrated, hydrolysed with 60 ml of water and then extracted with dichloromethane. The recovered organic phase is washed with a 5% sodium hydroxide solution, dried over magnesium sulphate and evaporated. The cyclised product is purified over a flash silica column eluted with a 2:8 AcOEt/PE mixture (PE=petroleum ether). Yellow oil.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:2]=1.N[C:18](N)=[O:19]>>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][NH:15][C:18]2=[O:19])[CH:2]=1
Reactant: Cc1cccc(Nc2ncccc2CN)c1
Reactant: NC(N)=O
Product: Cc1cccc(N2C(=O)NCc3cccnc32)c1
Temperature: 180 °C
Yield: 53.9 %

Procedure:
To a mixture of 4.3 g 2-(m-toluidino)-3-aminomethylpyridine and 12 g of urea was heated at 180° C for 2 hours and further heated at 200° C for 30 minutes. After cooling, crude reaction product precipitated was collected by filtration and washed with sufficient amounts of warm water. This product was purified by recrystallization from methanol to give 2.6 g of 1-(m-tolyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 212° - 214° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O=[Si]=O.[F:15][C:16]1[CH:17]=[C:18]([CH:23]([OH:26])[CH2:24][CH3:25])[CH:19]=[CH:20][C:21]=1[F:22]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([C:23](=[O:26])[CH2:24][CH3:25])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCC(O)c1ccc(F)c(F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
In a round bottom flask containing pyridinium chlorochromate (12.5 g, 58.1 mmol) was added celite 545 (25 g) and with the help of a magnetic stirrer the solids were mixed together. 200 mL of CH2Cl2 was added followed by a solution of 1-(3,4-difluoro-phenyl)propan-1-ol (5.0 g, 29.1 mmol) in 10 mL of CH2Cl2 and the resulting brown suspension was stirred overnight at room temperature. The suspension was filtered through a sintered glass funnel and the solvent was removed in vacuo from the pale green colored filtrate. The green oil was then diluted with diethyl ether (200 mL) and it was filtered through a pad of celite to remove the metal impurities. The solvent was removed in vacuo to obtain 1-(3,4-difluorophenyl)propan-1-one as a pale yellow oil (3.4 g, 69% yield). It was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH3:10])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH3:10])=[C:4]([C:11]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:13])[CH:3]=1
Reactant: Cc1c(C(=O)O)cc(Br)c(=O)n1C
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCN(C)CC2)cc(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.284 mmol), 1-methylpiperazine (28.5 mg, 0.284 mmol), Et3N (0.1 mL) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (108 mg, 0.284 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was subsequently purified via preparative HPLC, eluting with a gradient of 20-70% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20](=O)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([O:29][CH3:30])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32].C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:47])=O>>[ClH:47].[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:27]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][C:14]=3[O:29][CH3:30])[N:19]=2)[CH2:35][CH2:34]1)[CH3:32]
Reactant: CCN1CCNCC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OCCOCc2ccccc2)ccc1-c1cc2ccccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1CCN(c2nc(-c3ccc(OCCOCc4ccccc4)cc3OC)cc3ccccc23)CC1
Product: Cl

Procedure:
The resulting 3-[4-(2-benzyloxyethoxy)-2-methoxyphenyl]isoquinolin-1-one (0.47 g) was added to phosphorus oxychloride (10 ml), and the mixture was reacted at room temperature overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water, an aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting 1-chloro-3-[4-(2-benzyloxyethoxy)-2-methoxyphenyl]isoquinoline was reacted as it was with N-ethylpiperazine (5 ml) in the presence of potassium carbonate (1.2 g) at 120° C. for 24 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethoxy)-2-methoxyphenyl]isoquinolinehydrochloride (0.11 g) as a yellow powder.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH:27]([C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[F:45])[S:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OC(C)C)(C)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([CH:27]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])(=[O:30])=[O:29])=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](OCc1ccccc1CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccccc1CO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.9 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved 2-[2-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-1-[(4-chlorophenyl)sulfonyl]ethyl]-1,4-difluorobenzene (1.10 g, 1.66 mmol), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After addition of water (3 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diisopropyl ether, whereby the title compound (595 mg, 1.41 mmol, 85%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]2)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Product: C[C@@H]1CN(c2nc(Cl)nc3c2COC3c2ccc(F)cc2)C[C@H](C)O1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) was reacted as described in Preparation Xa with (2R,6S)-2,6-dimethylmorpholine to give 2-chloro-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation Mh). LC-MS (M+H)+=364.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.39 (dd, J=8.70, 5.34 Hz, 2H) 7.07 (t, J=8.70 Hz, 2H) 5.90 (br. s., 1H) 5.34-5.42 (m, 1H) 5.24-5.34 (m, 1H) 4.14 (q, J=7.02 Hz, 2H) 3.67 (ddd, J=10.38, 6.41, 2.44 Hz, 4H), 1.20 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[O:15]1[C:19]2[C:20]([CH2:24]O)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1>>[O:15]1[C:19]2[C:20]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: OCc1cccc2c1OCC2
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc3c2OCC3)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 2,3-dihydro-1-benzofuran-7-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.27 (2H, q, J=8.8 Hz), 4.68 (2H, q, J=8.8 Hz), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.86 (1H, q, J=7.6 Hz), 7.17 (1H, d, J=7.6 Hz), 7.22 (1H, d, J=7.2 Hz), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=2.0 Hz), 8.14 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H14N4O2, 319. Found, 319.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](=[S:17])[NH2:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](=O)[CH2:28]Br)=[CH:25][CH:24]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[S:17][CH:28]=[C:27]([C:26]4[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Solvent: CO
Product: COc1ccc(-c2csc(-c3cc4c(Nc5cccc(Cl)c5)ncnc4[nH]3)n2)cc1
Reaction time: 17 h

Procedure:
57.5 mg (0.19 mmol) of 4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine (see Example 10) in 3 ml of methanol and 57.3 mg (0.25 mmol) of 4-methoxyphenacyl bromide are heated to boiling for 17 h. Cooling of the pale yellow suspension, filtering and washing with isopropanol/diethyl ether yields 4-(3-chloroanilino)-6-[4-(4-methoxyphenyl)thiazol-2-yl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=15.4; TLC-Rf=0.33 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=434.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH2:20][CH3:21].C=CCC>C(CC(C)(C)C)(C)C>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: C=CCCC
Agent: C=CCC
Agent: O=S(=O)(O)O
Solvent: CC(C)CC(C)(C)C
Solvent: O=CO
Product: CCCCCOC(=O)CCC(C)=O
Temperature: 75 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of iso-octane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-pentene and heated to 75° C. for 5 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of pentyl formate and pentyl levulinate is formed as product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)[C:5]([CH3:22])=[CH:4][C:3]=1[OH:23].CN.[I:26]I>CCO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=2)[C:5]([CH3:22])=[C:4]([I:26])[C:3]=1[OH:23]
Reactant: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C
Reactant: II
Agent: CN
Solvent: O
Solvent: CCO
Product: COCOc1ccc(Cc2cc(C)c(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 2,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (intermediate for the synthesis of compound 7-17; 0.35 g, 1.11 mmol) in EtOH (5.0 mL) and CH3NH2 40% in water (2.5 mL) was added iodine (0.34 g, 1.33 mmol) and KI (0.27 g 1.66 mmol) in H2O (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h, quenched with brine (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:3) to afford 2,5-dimethyl-6-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as a colorless oil (0.32 g, 64%): 1H NMR (300 MHz, CDCl3): δ 7.02 (d, J=2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.88 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 5.20 (s, 2H), 3.95 (s, 2H), 3.51 (s, 3H), 3.35-3.30 (m, 1H), 2.39 (s, 3H), 2.30 (s, 3H), 1.22 (d, J=6.9 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethylacetate (9:1); Rf=0.6.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][N:12]=1)=[O:16])[CH3:50]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(Nc2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a stirred solution of 5-phenylamino-pyridine-2-carboxylic acid (0.26 g, 0.00121 mol) in DMF (2 mL) was added DIPEA (0.471 g, 0.00364 mol), HOBt (0.196 g, 0.00145 mol) and EDCI.HCl (0.278 g, 0.00145 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.203 g, 0.00146 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.32 g (88%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 300.13 (M+1)+, 97%. To a stirred solution [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00107 mol) in a mixture of THF (5 mL), methanol (10 mL) and H2O (2 mL) was added LiOH.H2O (0.134 g, 0.00321 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.26 g (90%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]([C:9]1[C:10]2[N:11]([N:20]=[N:21][N:22]=2)[C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7]>CN(C)C=O>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]2[N:20]=[N:21][N:22]=[C:10]2[C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)c2ccccc2n2nnnc12
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, POCl3 (16.42 ml, 0.17 mol) was slowly added to a chilled (0° C.) flask containing N,N-dimethylformamide (100 ml). The resulting solution was slowly warmed to room temperature and then added dropwise to a suspension of 4-nitro-tetrazolo[1,5-a]quinolin-5-ol in N,N-dimethylformamide (300 ml). The reaction was heated to 100° C. for 30 minutes. The orange/red solution was quenched by pouring over 1 liter of ice water. A yellow precipitate formed and was collected by filtration, redissolved in chloroform (approx. 750 ml), dried (Na2SO4), filtered, and concentrated in vacuo to yield 33.74 g of 5-chloro-4-nitrotetrazolo[1,5-a]quinoline as a yellow solid.
Reaction SMILES: [CH2:1]1[O:25][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=4)=[N:11][NH:10][C:9](=[O:23])[CH2:8][C:7]=3[CH:24]=[C:3]2[O:2]1.O>C(O)C.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:25][CH2:1][O:2][C:3]4=[CH:24][C:7]=3[CH2:8][C:9](=[O:23])[NH:10][N:11]=2)=[CH:14][C:15]=1[CH3:22]
Reactant: Cc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(3-methyl-4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (147 mg, 0.433 mmol) in ethanol (5 mL) was added water (2.5 mL), 5% Pd/C (42 mg), and HCO2NH4 (320 mg, 5.07 mmol). The mixture was stirred at room temperature for 4 h. The catalyst was filtered out. The filtrate was concentrated in vacuo and water (25 mL) was then added to the residue. The resulting solid was collected by filtration, washed with water, and dried in vacuo to afford the title compound as a light yellow solid (65 mg, 0.21 mmol, 49%), mp: 164°-166° C. 1H NMR (CDCl3) 8.23 (s, 1H), 7.35-7.22 (m, 2H), 6.82 (s, 1H), 6.71-6.65 (m, 2H), 6.03 (s, 2H), 3.87 (s, 2H), 3.42 (s, 2H), 2.19 (s, 2H). Anal. calcd. for C17H15N3O3.H2O: C, 62.38; H, 5.23; N, 12.84. Found: C, 62.50; H, 5.19; N, 12.86.
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1([C:12]#N)[CH2:11][CH2:10]1.C[OH:15]>>[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1([C:12]([OH:15])=[O:1])[CH2:11][CH2:10]1
Reactant: [OH-]
Reactant: CO
Reactant: N#CC1(c2cnccn2)CC1
Agent: [Na+]
Product: O=C(O)C1(c2cnccn2)CC1

Procedure:
A 20% aqueous sodium hydroxide solution (1 mL) was added to a solution of 1-(pyrazin-2-yl)cyclopropanecarbonitrile (0.2 g, 1.37 mmol) in methanol (10 mL) at room temperature. The reaction mixture was heated at reflux for 36 h. The mixture was cooled, and then the solvent was removed under reduced pressure. The resulting residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with aqueous hydrochloric acid (3N) and the water was removed under reduced pressure. To the residue was added methanol and dichloromethane. The mixture was filtered to remove the insoluble solids and the filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (100 mg). MS (ES−) (M−1) 162.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13](Cl)[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:31][NH2:32].[CH2:33](O)[CH3:34]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([NH:31][N:32]=[CH:8][C:5]4[CH:4]=[CH:3][CH:2]=[C:33]([CH3:34])[CH:6]=4)[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc(Br)cc4)cc3n2)c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 2-(4-bromo-phenyl)-5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (59.3 mg, 0.179 mM) and then potassium carbonate (27.2 mg, 0.197 mM) and hydrazine monohydrate (86.8 μL, 1.79 mM) were added to the suspension. This suspension was stirred at 150° C. for 20 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined together, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (21.1 μL, 0.179 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (30.7 mg, overall yield of these two steps: 35%).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].S(=O)(=O)(O)O.[NH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=[O:13].[CH2:19]=O>O>[P:1]([CH2:19][N:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=[O:13])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CNCC(=O)O
Reactant: OP(O)O
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 115 °C
Yield: 92.1 %

Procedure:
Water (11.2 g, 0.623 moles) was charged to a 500 ml three neck flask fitted with thermometer, condenser, dropping funnel and stirrer. The stirrer was started and phosphorous acid (42.6 g, at 99%; 0.514 moles) was added whereupon the temperature dropped from 20° C. to 12° C. Sulphuric acid (49.8 g at 98%, 0.498 moles) was then added over 10 minutes whilst maintaining the temperature below 50° C. with a water bath. Iminodiacetic acid (66.5 g at 95.4% strength, 0.479 moles) was then added to the reaction flask. The reaction mixture was heated to 115° C. and formaldehyde (48.2 g at 37.0% strength, 0.594 moles) was added over two hours. The temperature was maintained between 110° and 120° C. during addition. On complete addition, the reaction mixture was held at 115° C. for a furthre hour and then allowed to cool to 90° C. A second water charge (92.0 g) was added over 1 hour maintaining the temperature at approximately 90° C. during the addition. The reaction mixture was allowed to self-cool overnight. The slurry was filtered, washed with cold water (57.0 g) and the resulting product was dried at 60° C. in a vacuum oven overnight to give 100.2 g of N-phosphonomethyliminodiacetic acid at 95.7% strength, equivalent to an isolated yield of 88.1%. The filtrates (172.8 g) and the water wash (71.7 g) contained 4.8% and 1.2% N-phosphonomethyliminodiacetic acid respectively. This gave a total conversion yield of 93.5% N-phosphonomethyliminodiacetic acid.