Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](Cl)=[O:39].[CH2:41]([CH2:43][NH2:44])[OH:42]>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:38](=[O:39])[CH2:37][NH:44][CH2:43][CH2:41][OH:42])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: NCCO
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(C(=O)CNCCO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
To a mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00013 mol) and potassium carbonate (0.036 g, 0.00026 mol) in anhydrous N,N-dimethylformamide (3 mL) was added chloroacetylchloride (0.028 g, 0.00026 mol) at room temperature. The mixture was stirred for 10 min. before ethanolamine (0.078 mL, 0.0013 mol) was added. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-[(2-hydroxyethyl)amino]-1-ethanone (0.022 g, 0.00005 mol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([F:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([F:22])=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2c(F)ccc(Cl)c2o1
Reactant: Brc1ccccn1
Product: Fc1ccc(Cl)c2oc(CCC#Cc3ccccn3)nc12
Yield: 12531.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (124 mg, 0.79 mmol) and 2-(but-3-ynyl)-7-chloro-4-fluoro-benzo[d]oxazole (176 mg, 0.79 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 30 mg (99 mmol, 13%) of 7-chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid (M.P.=102-103° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Reaction time: 24 h

Procedure:
To a solution of ethyl(RS)-1-(4-methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting suspension was stirred under an atmosphere of H2 for 1 d, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH3:37][Mg]I.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]([OH:18])[CH3:37])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
To a stirred solution of diphenylmethyl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate (1.556 g) in a mixture of tetrahydrofuran (30 ml) and toluene (30 ml) is added a solution of methylmagnesium iodide (1.853 mM/ml) in ether (13 ml) during 4 minutes at -40° C. After 15 minutes, the reaction mixture containig diphenylmethyl 7-(2-thienylacetamido)-3-(1-iodomagnesium oxyethyl)-2-cephem-4-carboxylate is poured into an aqueous saturated solution of ammonium chloride (30 ml), and is extracted with acetate. The extract solution is washed with saturated saline, dried over sodium sulfate, and evaporated under reduced pressure to give diphenylmethyl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate, IR: νmaxCHCl 3 3400, 3350, 1780, 1750, 1685, 1505 cm-1. The product is dissolved in pyridine (16 ml), and is mixed with acetyl chloride (0.47 ml) under ice cooling. After 35 minutes, the reaction mixture is decomposed with a small amount of ice, poured into water after 10 minutes, and is stirred with ethyl acetate under ice cooling. The solution is neutralized with 4N-hydrochloric acid to pH 2.5, and is extracted with ethyl acetate. The extract solution is washed with saturated saline, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the residue (1.66 g) by chromatography over silica gel (68 g) gives from fractions eluted with a mixture of benzene and ethyl acetate (6:1) diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-2-cephem-4-carboxylate (625 mg: a mixture of stereoisomers). Colorless amorphous powder. Yield: 36.3%. NMR: δCDCl 3 1.21d(7.3Hz)3H, 1.73s+1.83s3H, 3.80s2H, 5.0-5.6m4H, 6.38br-slH, 6.9-7.4ml4H. IR: νmaxCHCl 3 3400, 1782, 1746, 1690, 1502 cm-1.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.C(Cl)(Cl)Cl.CO>COCCOCCOC>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: COCCOCCOC
Product: COc1cc2nccc(Oc3ccc(C(=O)C4CCCCC4)cc3)c2cc1OC
Temperature: 160 °C
Yield: 33.1 %

Procedure:
Under argon, 4-cyclohexylcarbonyl-1-hydroxybenzene (273 mg) obtained in Example 142 and 4-chloro-6,7-dimethoxyquinoline (100 mg) were dissolved in diethylene glycol dimethyl ether (0.2 ml), and the solution was refluxed at 160° C. for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was washed with brine and then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/acetone and then with chloroform/methanol to obtain 58 mg of the title compound (yield: 33%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:10]2)=[C:4]([F:25])[CH:3]=1.[Cu][C:27]#[N:28].CN(C)C=O.[OH-].[NH4+]>O>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH:11]1[CH2:12][CH2:13][CH:9]([C:5]2[C:4]([F:25])=[CH:3][C:2]([C:27]#[N:28])=[C:7]([F:8])[CH:6]=2)[CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(C2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1F

Procedure:
A suspension of 91.35 g (0.225 mol) of 2-[3-(4-bromo-2,5-difluorophenyl)cyclopentyl-1H-isoindole-1,3-(2H)-dione, 22.4 g (0.25 mol) of copper (I) cyanide and 250 ml of N,N-dimethylformamide was stirred and heated in a nitrogen atmosphere at 170° for 18 hours. The cooled mixture was poured into a solution of 100 ml of concentrated ammonium hydroxide in 1 L of water. The aqueous mixture was extracted with ether (4×350 ml) and the combined ether layers were washed with water (3×300 ml), dried (MgSO4), and evaporated in vacuo to give 71.2 g of the title compound which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=5)[C:26]([F:38])([F:37])[C:25]=4[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:40]([O:44][C:45]([N:47]1[CH:52]([C:53]2[NH:57][C:56]3[CH:58]=[C:59](B4OC(C)(C)C(C)(C)O4)[CH:60]=[CH:61][C:55]=3[N:54]=2)[CH:51]2[CH2:71][CH:48]1[CH2:49][CH2:50]2)=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]([O:44][C:45]([N:47]1[CH:52]([C:53]2[NH:57][C:56]3[CH:58]=[C:59]([C:29]4[CH:30]=[CH:31][C:32]5[C:33]6[C:25](=[CH:24][C:23]([C:20]7[NH:19][C:18]([CH:17]8[CH2:16][C:13]9([CH2:15][CH2:14]9)[CH2:12][N:11]8[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:39])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=7)=[CH:35][CH:34]=6)[C:26]([F:38])([F:37])[C:27]=5[CH:28]=4)[CH:60]=[CH:61][C:55]=3[N:54]=2)[CH:51]2[CH2:71][CH:48]1[CH2:49][CH2:50]2)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Temperature: 87.5 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
(1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (840 mg, 1.4 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (615 mg, 1.4 mmol), Pd(PPh3)4 (161 mg, 0.14 mmol), K2CO3 (579 mg, 4.2 mmol), were dissolved in DME (15 mL)/water (3 mL) under an argon atmosphere. The mixture was heated for 120 minutes at 85-90° C. (oil bath). After 120 minutes additional boronate ester (61 mg, 0.14 mmol) was added and heating was continued. After 3 hours, the reaction was cooled to room temperature. Most of the DME was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with brine and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (878 mg). LCMS-ESI+: calc'd for C47H51F2N7O5: 831.9 (M+). Found: 832.7 (M+H+).
Reaction SMILES: COC1C=C(C([O:11][CH2:12][C:13]2[C:14]([C:19]3[N:23](C)[N:22]=[CH:21][CH:20]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=CN=1)C=O.Cl.[CH:26]([NH:29][NH2:30])([CH3:28])[CH3:27].Cl.[CH3:32][CH2:33][OH:34]>>[CH:26]([N:29]1[C:19]([C:14]2[C:13]([CH2:12][OH:11])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:20][CH:21]=[N:30]1)([CH3:28])[CH3:27].[CH:26]([N:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:13]=[CH:18][C:32]([CH2:33][OH:34])=[CH:16][N:15]=2)=[N:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)NN
Reactant: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C)cn1
Reactant: CCO
Agent: Cl
Product: CC(C)n1ccc(-c2ccc(CO)cn2)n1
Product: CC(C)n1nccc1-c1ncccc1CO
Temperature: 80 °C
Yield: 25 %
Yield: 71 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 1.03 g, 3.22 mmol, 1 eq.; refer to Example 46) in EtOH (10 mL) was added isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). The mixture was heated at 80° C. for 2 h, cooled, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHCO3(sat) (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) as pale yellow oils. Data for 2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: 1H NMR (400 MHz, CDCl3) δ 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 4.67 (s, 2H), 4.55 (sep, J=6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 218.1 Data for (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: 1H NMR (400 MHz, CDCl3) δ 8.62 (dd, J=4.8, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.23 (dd, J=7.6, 4.8 Hz, 1H), 6.99 (dd, J=8.0, 6.5 Hz, 1H), 6.07 (t, J=7.6 Hz, 1H), 4.67 (d, J=7.6 Hz, 2H), 4.58 (sep, J=6.7 Hz, 1H), 1.60 (d, J=6.7 Hz, 1H). LRMS (M+H+) m/z 218.1
Reaction SMILES: C(O)C1C=CC=CC=1.[Si:9]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:38])[CH2:29][CH2:30]2)[CH:25]=[C:24]3[CH3:39])[CH2:21][CH2:20]1)[CH3:18])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>[Pd].CCCCCCC>[Si:9]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][C@@H:24]3[CH3:39])[CH2:21][CH2:20]1)[CH3:18])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:11])[CH3:10]
Reactant: CC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: OCc1ccccc1
Solvent: CCCCCCC
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C

Procedure:
A slurry of 5% palladium on carbon (7.12 gm) and benzyl alcohol (213 mL) in heptane (356 mL) was refluxed for 20 min. The mixture was cooled to 80° C. and a solution of 20-tert-butyldimethyl-silyloxy-7-methyl-pregn-4,6-dien-3-one (71.2 gm, 0.16 mol, product of Step 5) in heptane (427 mL) was added. The slurry was refluxed for 9.5 h. The reaction was cooled to room temperature and filtered through SOLKA FLOK filter aid which was subsequently washed with hexane. The filtrate was extracted with acetonitrile which was subsequently back-extracted with hexane. The heptane and hexane extracts were combined, washed with saturated sodium sulfate and saturated salt solutions, and dried over anhydrous magnesium sulfate. The solution was filtered through a pad of anhydrous sodium sulfate and the solvent removed by rotoevaporation. The title compound was purified by column chromatography on silica gel eluted with 7% ethyl acetate in hexanes.
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].Cl.Cl.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][C@@H:32]([NH2:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C.C[O-].[Na+].CO>>[CH3:27][O:29][C:30](=[O:40])[CH2:31][C@@H:32]([NH:39][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:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)C[C@@H](N)c1cccnc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Temperature: 140 °C
Yield: 67 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in a CEM microwave tube (10 mL) with (R)-3-amino-3-pyridin-3-yl-propionic acid ethyl ester dihydrochloride (134 mg, 0.5 mmol) (commercially available from AstaTech 46345) and a solution of sodium methoxide in methanol (2 mL, 0.5M, 1 mmol) was added with stirring. The reaction was heated to 140° C. in the CEM microwave apparatus for approximately 90 minutes. The reaction was cooled, concentrated under vacuum and filtered through silica to provide 49 mg of the desired product which was used without additional purification.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Cl:26][C:10]1[C:11]2[C:16](=[CH:15][C:14]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Sc3ccccc3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2ccc(Sc3ccccc3)cc2c1O

Procedure:
194 mg of 1-chloro-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 155 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.19 (t, 1H), 8.18 (d, 1H), 7.52 to 7.79 (m, 7H), 4.00 (d, 2H).
Reaction SMILES: [Na+].[CH2:2]([C:6]1[S:10][C:9](OB(O)[O-])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[F:35].C(=O)([O-])O.[Na+]>C1COCC1.O.CC(OC)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:2]([C:6]1[S:10][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=3)=[CH:18][C:17]=2[F:35])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(OB([O-])O)s1
Reactant: CCCCCCOc1ccc(-c2ccc(Br)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(CCCC)s3)c(F)c2)cc1

Procedure:
A mixture of 4.48 g (20.0 mmol) of 5-butylthiophen-2-ylhydroxyboronic acid sodium salt, 7.0 g (19.9 mmol) of 4-bromo-3-fluoro-4′-hexyloxybiphenyl, 3.36 g (40.0 mmol) of sodium hydrogencarbonate and 1.1 g (0.95 mmol) of tetrakis(triphenylphosphine)palladium(0) in 90 ml of THF/water (2:1) is heated under reflux for 19 h. The mixture is diluted with MTBE, and the organic phase is separated off. The aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol. 2-Butyl-5-(3-fluoro-4′-hexyloxybiphenyl-4-yl)thiophene is obtained as a colourless wax having an m.p. of 66° C.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH:26]=O)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:31][CH2:30][CH2:29][NH:28][CH2:26][CH2:25][CH:22]1[S:21][C:20]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:2]([CH3:1])[S:3]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)(=[O:5])=[O:4])=[N:24][CH2:23]1
Reactant: CN(c1cccc2cc(C3=NCC(CC=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of N-methyl-N-{2-[5-(2-oxoethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (300 mg) in methanol (5 mL) was added 2-aminoethanol (70 μL), and the mixture was stirred with heating under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature, sodium borohydride (55 mg) was added, and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (220 mg, yield 67%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio). MS: 465 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2.[OH-].[Na+]>COCC(O)=O.O.ClCCl>[CH3:1][O:2][CH2:3][C:4]1[S:18][C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1S
Agent: COCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COCc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
Methoxyacetyl chloride (1.8 mL) was added to a mixture of 3-aminoquinoline-4-thiol (2.8 g) in methoxyacetic acid (15 mL). The reaction was heated at about 140° C. for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was diluted with a small amount of water, made basic with 10% sodium hydroxide and then extracted with dichloromethane (300 mL). The extract was washed with sodium bicarbonate, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide crude product as a dark oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel. The silica gel was eluted with 1:1 hexane:ethyl acetate. The eluant was concentrated under vacuum to provide 2.3 g of 2-(methoxymethyl)thiazolo[4,5-c]quinoline as an orange solid.