Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:20])=[O:21])=[O:24])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: COc1nc(N)nc(OC)n1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc(OC)n1

Procedure:
To 15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 300 ml of dry methylene chloride containing 0.1 g 1,4-diazabicyclo[2,2,2]octane was added 21 g 2-chlorobenzenesulfonyl isocyanate with stirring. The mixture was stirred for 16 hours and the resultant solid was removed by filtration. After washing the solid with 1-chlorobutane, the resulting product, N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)-aminocarbonyl]-2-chlorobenzenesulfonamide melted at 188°-189° C. Infrared absorption analysis showed absorption peaks at 1740 cm-1, 1630 cm-1 and 1595 cm-1 which are typical for this type of compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].N([O-])=O.[Na+].[C-:22]#[N:23].[Na+]>O.Cl>[C:22]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17])#[N:23]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1nnc2ccc(C#N)cc2c1O
Temperature: 0 °C

Procedure:
A suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1.164 g.) in water (10 ml.) and concentrated hydrochloric acid (1.0 ml.) was stirred at 0° C. in an ice-salt bath, and a solution of sodium nitrite (0.5 g.) in water (3 ml.) was added during 5 minutes, maintaining the temperature at 0°-5° C. The mixture was stirred at 0° C. for 10 minutes, and this mixture was then added dropwise to a stirred solution of cuprous cyanide (0.54 g.) and sodium cyanide (0.6 g.) in water (4 ml.), heated at 60°-70° C. on a steam bath. The mixture was heated under reflux for 30 minutes. The brown solid which was precipitated was filtered off, washed thoroughly with water and dried as much as possible on the filter. The crude product was extracted with boiling ethanol (2 × 100 ml.), and the combined extracts were filtered and the filtrate evaporated under reduced pressure. The residue was applied to a column of silica (30 g., Kieselgel 60). Elution with a mixture containing 15% v/v of ethanol and 85% v/v of chloroform yielded ethyl 6-cyano-4-hydroxycinnolin-3-yl carboxylate, m.p. 259°-261° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC1(c2ccc(F)c(Cl)c2)CCNC1
Yield: 53.2 %

Procedure:
Preparation according to Example 1: (−)-1-benzyl-3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidine (0.39 g, 1.22 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.69 g, 4.88 mmol). Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound 0.149 g (53%). [a]D=−3.4° (methanol). MS m/z (relative intensity, 70 eV) 229 (M+, 1), 199 (79), 187 (bp), 157 (42), 133 (41).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]3[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cccc(NC(=O)OC3CN4CCC3CC4)c2)c1
Yield: 71 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromophenylcarbamate, 3-methoxyphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (100 mg, 71%). 1H NMR (500 MHz, CDCl3) δ 7.63 (br s, 1H), 7.40-7.27 (m, 4H), 7.17 (d, J=8.0 Hz, 1H), 7.11 (m, 1H), 7.07 (br s, 1H), 6.89 (dd, J=8.0, 2.0 Hz, 1H), 4.85 (m, 1H), 3.85 (s, 3H), 3.30 (m, 1H), 2.99-2.70 (m, 5H), 2.12 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.68 (m, 1H), 1.62-1.55 (m, 1H), 1.48-1.40 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 159.9, 153.4, 142.3, 142.1, 138.4, 129.8, 129.4, 122.3, 119.7, 117.7, 112.9, 112.8, 72.0, 55.4, 55.3, 47.4, 46.5, 25.4, 24.5, 19.5 ppm. Purity: >97% LCMS (214 nm & 254 nm); retention time 1.52 min; (M+1) 353
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:20](OCC)[CH:21]([CH3:29])[CH:22](OCC)OCC)C>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:22]=[C:21]([CH3:29])[CH:20]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc2c3c(nn2c1)CN(C(=O)OC(C)(C)C)C3
Temperature: 50 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (5 g; 22.3 mmol; 1 eq.) and 1,1,3,3-tetraethoxy-2-methylpropane (4.32 mL; 22.3 mmol; 1 eq.) in AcOH (50 mL) was stirred at 50° C. for 20 hours then diluted with water (250 mL). The precipitate was filtered off and dried to afford the title compound (3.5 g, 57%) as a pale beige solid. 1H NMR (DMSO-d6) δ 8.98-8.95 (m, 1H), 8.43 (d, J=2.1 Hz, 1H), 4.61-4.54 (m, 4H), 2.31 (s, 3H), 1.47 (s, 9H). HPLC (max plot) 99.7%; Rt 3.27 min. UPLC/MS: (MS+) 275.0 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH2:3](O)[CH:4]=C.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH:3]=[CH2:4])=[O:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CCO
Reactant: COC(=O)/C=C/c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)/C=C/c1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
17.45 g of a 55% w/w suspension of sodium hydride in mineral oil were suspended in 400 ml of toluene; to the resulting suspension were added 400 ml of allyl alcohol, whilst ice-cooling and under a nitrogen atmosphere. 122.93 g of methyl (E)-3-(5-benzyloxy-1H-indol-3-yl)acrylate were added thereto, and the mixture was heated under reflux for 10 minutes. The reaction mixture was then washed, in turn, with a saturated aqueous solution of citric acid, with a saturated aqueous solution of sodium hydrogen carbonate, with water and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. It was then condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography using 20% v/v ethyl acetate in hexane as eluent, to give 100.12 g of the title compound as crystals melting at 73°-77° C.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].B(F)(F)F>C(O)(CC)C.CCOCC>[C:1]([O:16][CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC#CCCCCCC(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCC(C)O
Product: CCCCCCC#CCCCCCC(=O)OC(C)CC
Yield: 170.5 %

Procedure:
A solution of 7-tetradecynoic acid (1.22 g) and BF3 -etherate (1 ml) in 20 ml of sec-butyl alcohol was refluxed for 18 hours. The solution was diluted with ether and washed with saturated Na2CO3 solution, water, 2N NaOH, water, and saturated NH4Cl solution. The ether layer was dried (MgSO4) and the solvent removed under reduced pressure to give 1.30 g of sec-butyl 7-tetradecynoate as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:20])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([O:34][C:35]([F:38])([F:37])[F:36])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:20])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=3[O:34][C:35]([F:36])([F:37])[F:38])(=[O:32])=[O:31])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(O)C(=O)Nc2ncc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Cl)cnc32)c(OC(F)(F)F)c1
Yield: 26.1 %

Procedure:
With 1.18 g of the compound obtained in Step 118-5 and 1.24 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 565 mg of the title compound (brown gummy substance) was obtained by a similar method to Example 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[Cl:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2nc3cccc(Cl)c3n2)n1
Yield: 34 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (30 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol, Example 146(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 16 mg (51 μmol, 35%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:16]=[N:15][N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Clc1cc2c(-c3cn[nH]c3)cccc2cn1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2cccc3cnc(Cl)cc23)cn1
Temperature: 190 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 28 mg, 0.122 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (35.1 mg, 0.244 mmol) and K2CO3 (50.5 mg, 0.366 mmol) in DMF (4 mL) was stirred at 190° C. under microwave irradiation for 90 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]([C:10]([CH:13](Br)Br)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)(O)[O-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[Na+]>CC(N(C)C)=O.O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:13][C:10]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:16][CH3:17])[C:2]([Br:1])=[CH:12][CH:11]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1c(C(Br)Br)ccc(Br)c1OC
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(Cl)cc2)ccc(Br)c1OC
Temperature: 90 °C
Yield: 57.7 %

Procedure:
A mixture of ethyl 3-bromo-6-(dibromomethyl)-2-methoxybenzoate (Intermediate 88, 0.25 g), sodium bicarbonate (0.122 g) and sodium 4-chlorobenzenesulphinate (0.29 g) in dimethylacetamide (4 ml) and water (1 ml) was stirred and heated at 90° C. for 5 hours. After cooling, the mixture was diluted with water and loaded onto a water washed C-18 column which was then flushed with water and eluted with DCM and ethyl acetate. The organic eluent was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give ethyl 6-(4-chlorobenzenesulphonylmethyl)-3-bromo-2-methoxy-benzoate (0.15 g) as a gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:44][O:45][C:46]([CH3:62])([CH3:61])[C:47]([NH:49][NH:50][C:51](=[O:60])[C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[C:54]([OH:59])[CH:53]=1)=[O:48]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45][C:46]([C:47](=[O:48])[NH:49][NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[C:54]([OH:59])[CH:53]=2)([CH3:61])[CH3:62])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(-c4ccc(O)c(O)c4)nc4ccnn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 24 h
Yield: 91.3 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (625 mg) and 500 mg of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 10 ml of dimethylacetamide and left at room temperature for 24 hours. Thereafter, the solvent is evaporated at 30° C. in a vacuum. The residue is triturated with 30 ml of water, whereby it becomes solid. It is filtered off under suction, washed with water and dried at 0.1 mmHg/40° C. and there are obtained 800 mg of beige (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]-acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)([Cl:15])=O>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:15])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)nc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)nc1Cl
Yield: 151.6 %

Procedure:
A mixture of 6-chloro-5-methoxypicolinic acid (1.5 g, 8.0 mmol), thionyl chloride (5 g, 8.0×5.25 mmol), a catalytic amount (35 mg) of N,N-dimethylformamide and 5 ml of benzene was refluxed for 1 hour. Then, thionyl chloride and benzene were distilled off, and the residue was distributed with water and dichloromethane. A dichloromethane layer was separated and dried with sodium sulfate. The solvent was then distilled off to obtain 1.64 g of 6-chloro-5-methoxypicolinic acid chloride. It was dissolved again in 5 ml of dichloromethane and the resultant solution was added dropwise to a solution of phenol (0.79 g, 8×1.05 mmol) and triethyl amine (0.89 g, 8×1.1 mmol) in 30 ml of dichloromethane under cooling with ice. After conclusion of the addition, the reaction solution was stirred at room temperature for 2 hours, followed by adding water to separate an organic layer. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with sodium sulfate. The organic solvent was distilled off to obtain a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][N:7]([OH:9])[CH:8]=1.Cl[CH2:11][S:12][C:13]#[N:14].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[N:6][N:7]([O:9][CH2:11][S:12][C:13]#[N:14])[CH:8]=1
Reactant: On1cc(Cl)cn1
Reactant: N#CSCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CSCOn1cc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.6 %

Procedure:
50 ml of a 5% strength aqueous sodium hydroxide solution were added to 5 g (42 mMol) of 4-chloro-1-hydroxypyrazole, 13.5 g (126 mMol) of chloromethyl thiocyanate and 50 ml of methylene chloride. After the addition of 1 g (4 mMol) of tetra-n-butylammonium hydroxide, the mixture was stirred at room temperature for 24 hours. Thereafter, the organic phase was separated off, dried and evaporated down. Distillation of the residue under reduced pressure (airbath at 140° C./3 mbar) gave 5.7 g (71% of theory) of 4-chloro-1-[(thiocyanato)-methoxy]-pyrazole (compound No. 1), which was recrystallized from ether/petroleum ether (mp. 60° C.).
Reaction SMILES: O1CCCC1.C[O:7][C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:11]=1)=[O:9].[OH-].[Li+].Cl>O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:12]2[N:11]=[C:10]([C:8]([OH:9])=[O:7])[CH:15]=[N:14][C:13]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a tetrahydrofuran (5 ml) solution of 6-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester (0.48 g, 1.52 mmol, 1.0 eq) was added a solution of lithium hydroxide (1M, 1.52 ml, 1.52 mmol, 1.0 eq) in water. The mixture was stirred overnight at room temperature after which time the resulting solution was acidified with hydrochloric acid (pH˜5) and aqueous phase extracted with ethyl acetate (2×10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid as white crystals. Yield=0.42 g (91%). 1H NMR (400 MHz, DMSO): δ 1.46-1.53 (6H, m), 3.22-3.25 (4H, m), 7.32 (2H, t, J=8.87 Hz), 7.82-7.86 (2H, m), 8.62 (1H, s).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][C:11]([C:13]1[O:14][C:15]([CH3:36])=[C:16]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:17]=1)=[O:12]>CN(C)C=O>[CH3:9][O:10][C:11]([C:13]1[O:14][C:15]([CH3:36])=[C:16]([CH2:18][N:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH3:3])[CH:17]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 36 h
Yield: 63.8 %

Procedure:
Iodomethane (91 mg, 0.64 mmoles) and potassium carbonate (88 mg, 0.64 mmoles) were added to a solution of 4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (170) (62 mg, 0.16 mmoles) in N,N-dimethylformamide (10 ml) and the mixture stirred at room temperature for 36 hours under an argon atmosphere. The mixture was then heated at 35° C. for 21 hours. The mixture was partitioned between dichloromethane and water, the organic phase separated and dried (MgSO4). After evaporation of the solvent, the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 99:1 v/v as eluent, to afford compound 175 (41 mg) as a brown oil. This was used directly in part (b).
Reaction SMILES: B.C1COCC1.[N:7]([CH2:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)=[O:12])=[N+:8]=[N-:9].Cl>C1(C)C=CC=CC=1.C1COCC1>[N:7]([CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12])=[N+:8]=[N-:9]
Reactant: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Agent: B
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
R-(+)-2-Methyl-CBS-oxazaborolidine solution in toluene (1M, 7.5 ml) was added to THF (75 ml) and the solution was diluted to 0° C. Borane-THF complex (1M solution in THF, 125 ml) was added and the mixture was stirred under nitrogen for 15 min. A solution of 2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g) in THF (250 ml) was added dropwise over 1.5 h at 5° C. The mixture was stirred for a further 1 h and then cautiously treated with 2M HCl (100 ml). The reaction mixture was extracted with ether and the organic layer was washed with 2M HCl, NaHCO3, brine, dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with diethyl ether-petrol (40–60° C.) (1:9; 1:1) to give the title compound (16.99 g). ES+ve 250 (MH)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[CH2:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH2:33]([N:40]1[CH2:45][CH2:44][N:43]([C:29](=[O:31])[CH2:28][O:27][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=2)=[O:32])[CH2:42][CH2:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(Cc5ccccc5)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (103.5 mg, 0.22 mmol) in 8 ml of methylene chloride was added 1.0 equivalent of N-benzylpiperazine, 1.05 equivalent of HBTU and 4 equivalent of triethylamine. The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic phase was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 1-{3-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid as a fluffy solid (43 mg, 35%). ES-MS calcd for C32H31N3O7 (m/e) 569.6, obsd 570.3 (M+H).