Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[C:17]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)[CH2:35][CH2:34]4)=[C:29]([CH3:46])[CH:28]=3)[C:18]([C:23]([NH2:25])=[O:24])=[N:19][C:20]=2[CH2:21][CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C>[OH-].[Pd+2].[OH-].C(O)(=O)C>[CH2:21]([C:20]1[N:19]=[C:18]([C:23]([NH2:25])=[O:24])[C:17]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)=[C:29]([CH3:46])[CH:28]=2)=[N:16][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:22]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
To a mixture of 5-[(1-benzylpiperidin-4-yl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (Example 507) (1.31 g), ethanol (26 mL) and acetic acid (13 mL), palladium hydroxide (0.65 g) was added and stirred under a hydrogen atmosphere at room temperature for 3 days. After the catalyst was separated by filtration, the solvent was concentrated and partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. The organic layer was concentrated to give 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide (0.73 g) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]#C.[F-].[Cs+].[CH2:15](OCC)C>CCN(C1C=CC=CC=1)CC>[Br:1][C:2]1[C:3]2[O:9][C:10]([CH3:11])=[CH:15][C:4]=2[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: C#CCOc1cc(F)ccc1Br
Reactant: CCOCC
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc2c(F)ccc(Br)c2o1
Yield: 89 %

Procedure:
A suspension of 57 g (250 mmol) of 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene and 53 g (350 mmol) of caesium fluoride in 400 ml of diethylaniline was heated at reflux in a metal bath for 4 hours. After cooling to room temperature 1500 ml of diethyl ether were added thereto and the insoluble constituents were filtered off. The diethyl ether phase was washed three times with 600 ml of 1N hydrochloric acid, dried over sodium sulfate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane). 51.4 g (89%) of 7-bromo-4-fluoro-2-methylbenzofuran were obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[CH:3]=[O:4].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].[Na]>>[C:13]([NH:1][C@H:2]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[CH2:3][OH:4])(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)Cl
Reactant: N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na]
Product: C=CC(=O)N[C@@H](CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
An attempt was done to prepare the same compound by reacting 2-amino-2-deoxy-D-glucose and acryloyl chloride, followed by reduction of the product with sodium boronhydride. However, it was not possible to get pure N-acryloyl-2-amino-2-deoxy-D-glucitol in this way.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N12CCCN=C1CCCCC2.[CH:47]1(/[CH:52]=[CH:53]/[C:54]#[N:55])[CH2:51][CH2:50][CH2:49][CH2:48]1>C(#N)C>[CH:47]1([CH:52]([N:25]2[CH:26]=[C:22]([C:20]3[NH:19][C:16]4=[N:17][CH:18]=[C:13]([CH2:12][CH2:11][C:5]5[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:14]=[C:15]4[CH:21]=3)[CH:23]=[N:24]2)[CH2:53][C:54]#[N:55])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: N#C/C=C/C1CCCC1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C(CC#N)C5CCCC5)c4)cc3n2)cc(OC)c1
Reaction time: 16 h
Yield: 17.5 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (25.0 mg, 51.1 μmol) in acetonitrile (1.0 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.2 μL, 61.5 μmol) and (2E)-3-cyclopentylacrylonitrile (from Adesis, cat#9-245, 6.8 μL, 61.7 μmol) were added sequentially at room temperature. After 16 hours, the volatiles were removed and the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (4.2 mg) as its TFA salt. LCMS calculated for C27H31N6O2 (M+H)+: m/z=471.2. Found: 471.2.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: Cc1ccccc1Nc1ncccc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1Nc1ncccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.05 mL, 7.53 mmol) was added to a mixture of N2-o-tolylpyridine-2,3-diamine (500 mg, 2.51 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (520 mg, 2.76 mmol), HOAt (380 mg, 2.76 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (530 mg, 2.76 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min and then slowly warmed to RT. Stirring at RT was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.19 min [M+H]+ 371.1.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].Cl>CC(O)C>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2cccnc12
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2ncnc3cccnc23)c1
Yield: 87 %

Procedure:
Reaction of 4-chloropyrido[3,2-d]pyrimidine (prepared as described in a previous experimental) with 3-bromoaniline in propan-2-ol containing a trace of conc. HCl at 50° C. for 30 min, followed by chromatography of the product on silica gel, gives 4-(3-bromophenyl)aminopyrido[3,2-d]pyrimidine (87% yield). 1H NMR (CDCl3) δ 9.19 (1H, brs), 8.83 (1H, s), 8.80 (1H, dd, J=4.3, 1.5 Hz), 8.29 (1H, brs), 8.19 (1H, dd, J=8.5, 1.5 Hz), 7.83 (1H, m), 7.76 (1H, dd, J=8.5, 4.3 Hz), 7.29-7.27 (2H, m).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=O)=[CH:30][C:25]=2[O:24][CH2:23]1.O>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=[CH:9][C:10]#[N:11])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cccc(C(=O)c2ccc3c(c2)OCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=CC#N)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.1 mL, 13.6 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.6 mL, 13.6 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl)-methanone (1.74 g crude, 6.8 mmol) in THF (15 mL) and refluxed for one hour. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-benzo[1,3]dioxol-5-yl-3-(3-methoxy-phenyl)-acrylonitrile as an oil (0.87 g, 46% yield): 1H NMR (DMSO-d6) δ 3.77 and 3.78 (2s, 3H, OCH3), 6.10 and 6.13 (2s, 2H, CH2), 6.23 and 6.27 (2s, 1H, CH), 6.69-7.46 (m, 7H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.2, 94.4, 95.6, 101.6, 101.8, 107.4, 108.2, 108.3, 109.3, 113.7, 114.6, 115.0, 118.2, 120.9, 121.2, 123.7, 123.8, 129.7, 129.8, 130.6, 131.6, 138.6, 139.6, 147.3, 147.9, 148.5, 149.4, 159.1, 159.2, 160.9, 161.1. LC/MS showed desired peak at 280 for (M+1)+1 positive ion mass.
Reaction SMILES: [Br:1][CH2:2][CH:3](OC)OC.[CH2:8]([OH:13])[CH2:9][CH:10]([OH:12])[CH3:11].C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Br:1][CH2:2][CH:3]1[O:12][CH:10]([CH3:11])[CH2:9][CH2:8][O:13]1
Reactant: CC(O)CCO
Reactant: COC(CBr)OC
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC1CCOC(CBr)O1
Temperature: 25 °C

Procedure:
2-Bromo-1,1-dimethoxyethane (0.1 mole) and 1,3-butanediol (0.1 mole) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, Dean Stark trap and reflux condenser. Toluene sulfonic acid (0.1 grams) is added and the reaction mixture is heated and alcohol removed. When alcohol evolution ceases, the reaction mixture is then cooled to room temperature, treated with sodium carbonate (5 grams) and filtered. Volatiles are stripped from the filtrate using a rotary evaporator to yield the desired product 2-bromomethyl-4-methyl-1,3-dioxane as the residue.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=O)[CH2:26]Br.O>CN(C=O)C>[C:12]([CH:9]1[CH2:8][CH2:7][C:6]2[NH:5][C:4](=[O:17])[N:3]3[CH:26]=[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])[N:1]=[C:2]3[C:11]=2[CH2:10]1)([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCc2[nH]c(=O)nc(N)c2C1
Reactant: O=C(CBr)c1ccccc1F
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1

Procedure:
A solution of 4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone (262 mg) and 2'-fluoro-bromoacetophenone (217 mg) in dry DMF (10 mL) was refluxed under nitrogen for 1.5 h. The solution was cooled and 40 mL water is added. The precipitate was collected and washed successively with 10 mL of methanol and 20 mL hot ethyl acetate to yield 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 1), m.p. 257°-277° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[N+:15]([O-])([O-:17])=[O:16].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1ccccc1-c1ccccc1
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
2-Cyanobiphenyl (0.111 moles, 20.0 g) and ammonium nitrate (10.0 grams) were added to 250 ml chloroform. Trifluoroacetic anhydride (80 ml) was added. The reaction mixture was stirred until the ammonium nitrate was dissolved. The reaction mixture was added to 300 ml of ice water. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 23.5 g of 2-Cyano-4-nitrobiphenyl. (MS)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)[C@H]1CN2CCC1CC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
480 mg (3.50 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 490 mg (2.33 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 250 mg (1.17 mmol) of 4-amino-4′-nitrobiphenyl in 11 ml of a 10:1 mixture of dioxane and DMF. The reaction mixture is stirred at 100° C. for 18 h and then concentrated. The residue is suspended in methanol and filtered. The filtration residue is washed with water, mixed with 20 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. The above filtrate is purified by preparative HPLC. The product fractions are concentrated, taken up in 5 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 291 mg (61.7% of theory) of the title compound are obtained from the filtration residue, and a further 65 mg (12.4% of theory) are obtained from the filtrate, in this way.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][O:12][C:13](=[O:17])[CH2:14][CH2:15][SH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[CH2:14][CH2:15][S:16][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: COC(=O)CCS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
15.5 parts of chloroacetophenone are added to a solution, cooled to 0° C., of 12 parts of 3-mercapto-propionic acid methyl ester and 15.3 parts by volume of triethylamine in 100 parts by volume of chloroform. The mixture is stirred for 2 hours at 0° C. and is washed with water, and the organic phase is separated off, dried and concentrated. 21 parts (90% of theory) of 3-(benzoylmethylthio)-propionic acid methyl ester of boiling point 156°-160° C./0.3 mbar are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][C:21]1([O:24][CH2:23]1)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:20][C:21]([CH3:23])([OH:24])[CH3:22])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CC1(C)CO1
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 80 °C
Yield: 51.3 %

Procedure:
A 5 L pressure vessel fitted with a pressure relief valve, bursting disc, pressure gauge, and oil-filled thermometer well, and containing a 3″×½″ octagonal stir bar was charged with a solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (prepared according to Example 25, Steps A-D; 150 g, 0.46 mol) and isobutylene oxide (82 mL, 0.92 mol) in N,N-dimethylacetamide (1000 mL). The solution was magnetically stirred, and granular potassium carbonate (191 g, 1.38 mol) was added. The vessel was sealed and stirring was continued. The apparatus was placed behind a blast shield. The vessel was heated with a heating mantle connected to a J-Kem Model 150 temperature controller. The temperature setting was initially set to 55° C., and the temperature was increased to 80° C. over 6 hr. The temperature was maintained at 80° C. for a further 16 hr. The reaction mixture was then cooled to 28° C. and the vessel was opened. The thermometer well was removed and the reaction mixture was decanted from the inorganic salts and filtered through a coarse fritted sintered glass funnel. The salts that remained in the vessel were stirred with DMA (3×200 mL) and the solution decanted as before. The filtrates were combined and the solvent evaporated under reduced pressure to afford a dark brown oil. Meanwhile, the solid remaining in the vessel was partitioned between water (2000 mL) and diethyl ether (1000 mL), and the resulting mixture stirred for 16 hr. The water/ether mixture was transferred to a separatory funnel, and the organic layer was added to the brown oil. Additional ether (2000 mL) was added to completely dissolve the oil. The resulting solution was transferred to a separatory funnel and washed with a mixture of water (500 mL) and brine (500 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residual dark brown oil (an approximate 1:1 mixture of N-1 [less polar] and N-2 [more polar] regioisomers) was purified by chromatography on silica gel, using 70/30 EtOAc/hexanes as eluent. Fractions containing product were pooled and the solvent removed under reduced pressure to afford the title compound as a red-orange solid (93.8 g, 51%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH:13]=[C:14]([I:16])[S:15][C:3]=12.C1(C)C=CC=CC=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][C:14]([I:16])=[CH:13][C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(I)sc2c1O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)sc2c1O
Temperature: 190 °C

Procedure:
A stirring mixture of ethyl 7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxylate (1.5 g, 4.29 mmol) in 4-chlorobenzylamine (15 mL) was heated at 190° C. for 1 hour. The resulting dark solution was cooled to ambient temperature and 100 mL toluene added. The resulting solid was collected by filtration and dried at 50° C. for 16 h to afford 0.875 g title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([N+:20]([O-:22])=[O:21])[C:13]=1[F:23])[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:27].S(Cl)(Cl)=O.[CH2:34](O)[CH3:35]>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([N+:20]([O-:22])=[O:21])[C:13]=1[F:23])[CH:9]=[C:8]([C:24]([O:26][CH2:34][CH3:35])=[O:25])[C:7]2=[O:27]
Reactant: CCO
Reactant: O=C(O)c1cn(-c2c(F)cc(F)c([N+](=O)[O-])c2F)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(-c2c(F)cc(F)c([N+](=O)[O-])c2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 830 mg of 8-chloro-6,7-difluoro-1-(2,4,6-trifluoro-3-nitrophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added 2 ml of thionyl chloride. The solution was stirred at 80° C. overnight. With ice cooling, 4 ml of ethanol was slowly added dropwise to the reaction solution. The reaction solution was distilled of the solvent whereupon the precipitated solid was collected by filtration to give 310 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([CH2:2][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 50.8 %

Procedure:
10 g (36 mmol) of 2-bromomethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 6 g (36 mmol) of ethyl 4-hydroxybenzoate and 7.2 g (52 mmol) of anhydrous potassium carbonate in 60 ml of dimethylformamide were refluxed for 5.25 h. The mixture was then poured into water and extracted several times with ether, and the organic phase was washed with water, dried over Na2 SO4 and concentrated. Recrystallization from methanol resulted in 6.7 g of the title compound of melting point 109°-111° C.
Reaction SMILES: Br[CH:2]([C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(C)C>[NH2:19][C:17]1[S:18][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:16]=1
Reactant: NC(N)=S
Reactant: O=C(O)CC(Br)C(=O)c1ccc(F)cc1
Solvent: CC(C)O
Product: Nc1nc(-c2ccc(F)cc2)c(CC(=O)O)s1

Procedure:
A mixture of 10 grams of β-bromo-β-p-fluorobenzoyl-propionic acid and 2.77 grams of thio-urea in 60 c.c. of isopropyl alcohol is refluxed for 1 hour. After cooling, the precipitated solid is filtered off and recrystallised from isopropyl alcohol, m.p. 267°-268°C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 3.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (110 mg, 0.34 mmol) and 3-amino-butyric acid (354 mg, 3.4 mmol) (Sigma-Aldrich Corp., St. Louis Mo.) in 0.5 M NaOMe/MeOH solution (5.4 mL<2.72 mmol) was refluxed overnight and then microwaved at 120° C. for 2 h. Reaction mixture was concentrated and residue was dissolved in water (60 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. The crude product was purified by silica gel chromatography, eluting with 5-100% EtOAc (with 0.075% acetic acid)/hexane (with 0.1% acetic acid). White solid was crystallized from fractions containing the desired produce. Solid was collected and rinsed with EtOAc and dried in vacuo to provide the title compound 5.1 mg (0.013 mmol) in 3.8% yield. LC-MS ESI−: 390.01 (M−1)−.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[C:5](#[N:8])[CH2:6][CH3:7]>>[NH2:8][C:5]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH2:6][CH3:7]
Reactant: CCC#N
Reactant: OP(O)O
Product: CCC(N)(P(=O)(O)O)P(=O)(O)O
Reaction time: 10 h
Yield: 71 %

Procedure:
Into a reactor like the above was charged 261 g phosphorous acid. 44.3 g propionitrile was introduced slowly for 70 minutes at 135°-143° C. into the agitated phosphorous acid. The reactant mixture was held for additional 10 hours at 150°-155° C. The 1-aminopropane-1, 1-diphosphonic acid produced was isolated from the reaction mixture in the manner described in Example 1.