Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[C:27](=[O:33])[CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[CH:17][C:7]2=1)=[O:3])[CH3:32]
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 80 above, with the compound from Example 60B, 6-acetyl-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and diethyl oxalate.
Reaction SMILES: Br[C:2]([F:14])([CH:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[F:14][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:9]2[CH:8]1[CH2:12][CH2:11][C:10]2=[O:13]
Reactant: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(F)C2CCC(=O)C21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2SR)ethyl 2-bromo-2-fluoro-2-[(1RS)-3-oxocyclopentyl]acetate in an amount of 1.00 g was dissolved in 5.0 mL of N,N-dimethylformamide, and 0.84 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by stirring for 5 hours at room temperature. The reaction mixture was poured into 1M hydrochloric acid, followed by extractions with ethyl acetate twice. The organic layers were combined, and the combined organic layer was subsequently dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=8:1), thereby yielding 0.68 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate.
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].CC(C)=O.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([NH:19][C:20]([NH:7][C:2]([CH2:5][OH:6])([CH2:3][OH:4])[CH2:1][OH:8])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(CO)(CO)CO
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)NC(CO)(CO)CO

Procedure:
66.6 g (0.55 mol) of tris(hydroxymethyl)aminomethane are dissolved in 200 ml of distilled water, and 400 ml of acetone are added. 59.6 g (0.5 mol) of phenyl isocyanate are added dropwise, while stirring, whereupon a heavy white precipitate forms. When the addition has ended, the mixture is stirred for a further 2 hours and the precipitate is filtered off with suction. It is then digested successively with in each case 150 ml of water, acetone and diethyl ether. Finally, the compound (11), which is obtained in virtually analytically pure form, is dried at 75° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([NH2:28])[C:24]1=[O:29])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.Cl.[O-:31][C:32]#[N:33].[Na+].C(=O)([O-])O.[Na+]>O.CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@:5]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11])([N:23]1[CH2:27][CH2:26][N:25]([NH:28][C:32]([NH2:33])=[O:31])[C:24]1=[O:29])[CH2:6]2
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N)C3=O)S[C@H]12
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)NN1CCN([C@]2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
In a mixed solvent consisting of 30 ml of water and 30 ml of methanol was suspended 5.00 g of (3R,5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. To suspension was added 2.96 ml of concentrated hydrochloric acid with water cooling. To the resulting solution was added 1.36 g of sodium cyanate in 10 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered. To the filtrate were added 50 ml of ethyl acetate and 50 ml of water. The aqueous layer was separated. The organic layer was extracted three times each with 30 ml of water. The extracts were combined with the aqueous layer obtained previously. The combined aqueous solution was adjusted to pH 6.9 with sodium hydrogencarbonate. The solvent was removed by distillation under reduced pressure. The residue was dehydrated by four times of azeotropy with ethanol. To the resulting residue was added a mixed solvent consisting of 50 ml of methylene chloride and 10 ml of methanol. The insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=10/1 to 5/1) to obtain 4.29 g (yield: 77.9%) of (3R,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: COC(=O)CCCCCCC(NC1SC=C(C2C=CC=C([N+]([O-])=O)C=2)N=1)=O.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)([O-:30])=[O:29].[CH2:43]([O:50][NH:51][C:52]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])=[O:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:38]=[C:39]([NH:42][C:60](=[O:61])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][C:52]([NH:51][O:50][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:53])[S:40][CH:41]=1)([O-:30])=[O:29]
Reactant: O=C(O)CCCCCCC(=O)NOCc1ccccc1
Reactant: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Agent: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Product: O=C(CCCCCCC(=O)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1)NOCc1ccccc1

Procedure:
Compound 15 was prepared using the methodology described for the preparation of compound 14, by substituting 4-(3-nitrophenyl)-thiazol-2-ylamine with 4-(2-nitrophenyl)-2-thiazolamine (12) and using of compound 5 instead of compound 13. 1H NMR (400 MHz, DMSO-d6) δ (ppm). 12.14 (1H, s), 10.93 (1H, s); 7:88 (1H; d, J=7.4 Hz), 7.77 (1H, t, J=7.0 Hz), 7.72 (1H, d, J=7.4 Hz), 7.60 (1H, t, J=7.0 Hz), 7.51 (1H, s), 7.38-7.33 (5H, m), 4.78 (2H, s), 2.44 (2H, t, J=7.3 Hz), 1.94 (2H, t, J=7.3), 1.58 (2H, m), 1.49 (2H, m), 1.30-1.18 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:16]2[CH3:19])=[C:12]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:11]=1.[C:37](O)(=O)[CH2:38][CH3:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(O)(=O)C>[CH2:38]([C:39]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([CH2:20][N:21]4[CH2:22][CH2:23][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:25][CH2:26]4)[N:16]3[CH3:19])=[C:12]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:11]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[N:1]=1)[CH3:37]
Reactant: CCC(=O)O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3cccc(F)c3N)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(F)cccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
To a solution of 2-{1-[2-(2-amino-3-fluorophenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (65 mg, 0.13 mmol), propionic acid (78 uL, 0.14 mmol) and DIPEA (49 uL, 0.29 mmol) in DMF (3 mL) was added HATU (59 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 18 hours. Propionic acid (78 uL, 0.14 mmol), DIPEA (49 uL, 0.29 mmol) and HATU (59 mg, 0.16 mmol) were added and the reaction mixture was stirred at room temperature for 2 days, then diluted with water and extracted with EtOAc. The organic layer was separated and washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated to give a red oil dissolved in acetic acid (2 mL). The mixture was stirred at 90° C. for 18 hours then concentrated under reduced pressure. The residue was azeotroped with toluene, then taken up in MeOH. The resulting solution was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give 485 (36 mg, 52%). LCMS (Method I): RT 3.18 min; [M+H]+ 537. 1H NMR (400 MHz, CHCl3-d): δ 7.78-7.75 (m, 1 H); 7.21-7.12 (m, 1 H); 6.97 (dd, J=10.3, 8.0 Hz, 1 H); 4.34 (m, 4 H); 3.90-3.84 (m, 7 H); 3.73 (s, 2 H); 3.35 (q, 7.5 Hz, 2 H); 2.97 (d, J=11.4 Hz, 2 H); 2.12 (m, 2 H); 1.77 (m, 2 H); 1.44 (t, J=7.5 Hz, 3 H); 1.44-1.28 (m, 4 H); 1.24-1.15 (m, 6 H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[C:11]([CH2:16][CH3:17])[N:12]=[C:13]1[CH3:15]
Reactant: CI
Reactant: CCc1nc(C)[nH]c1Sc1cc(C)cc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)n(C)c1Sc1cc(C)cc(C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
In dry dimethylformamide (4 ml)was dissolved 200 mg (0.8 mmol)of 5-(3,5-dimethylphenylthio)-4-ethyl-2-methylimidazole (5c), followed by addition of 49 mg (1.2 mmol)of 60% sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 138 mg (1.00 mmol)of methyl iodide was added and stirred for 30 minutes. The reaction mixture was poured in ice-water and extracted with diethyl ether, and the organic layer was dried over sodium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:1). From the first fraction, 40 mg (yield 19%)of positional isomer (6e')of the target compound was obtained as oil. From the latter fraction, 140 mg of 1,2-dimethyl-5-(3,5-dimethylphenylthio)-4-ethylimidazole (Compound I-5)was obtained as oil (yield 66%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:23]([C:21]2[N:22]=[C:18]([CH3:17])[O:19][C:20]=2[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[O:24])=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)CCCCn1ccc(NC(=O)c2nc(C)oc2-c2cccc(C)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[O:4].[BH4-].[Na+]>C(O)C.O.ClCCl>[Cl:1][CH2:2][CH:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)[OH:4]
Reactant: O=C(CCl)C1CCc2cc(F)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: OC(CCl)C1CCc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution under stirring of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanone (0.33 g, 1.28 mmol, 88.4 A %) in ethanol (2.5 ml) was cooled to 0° C. under nitrogen. NaBH4 (60.1 mg, 1.59 mmol) was added to the solution and the reaction mixture stirred for 2 hours. After checking that the starting product had disappeared by GC, the mixture was diluted with demi water (7 ml) and dichloromethane (7 ml) and the phases separated. The organic stratum was dried under anhydrous sodium sulphate, filtered and concentrated under vacuum to give raw 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) ethanol as a mixture of diastereoisomers 54:46 (0.30 g, 70% yield, 67.9 A %).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6](=[O:28])[C:7](=[CH:13][C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[NH4+].[OH-]>C1COCC1.[Cu]I>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH:13]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[CH:18][CH:19]=1)[CH3:2])[C:6]([O:5][CH2:3][CH3:4])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: [Li]C
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
MeLi (6.5 mL, 10.4 mmol, 1.6 M in diethyl ether) was added dropwise to a slurry of CuI (0.9 g, 4.73 mmol) in THF (28 mL) at −78° C. under argon. The reaction mixture was stirred for 30 min. A solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (0.84 g, 2.3 mmol) in THF (7 mL) was added dropwise and the reaction was stirred for 180 min at −78° C. Saturated aqueous NH4OH was added dropwise and the mixture was extracted with EtOAc. The organic phase was washed with saturated aqueous NH4OH and NaCl, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 3:1→1:6) gave 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid diethyl ester (0.723 g, 82.4%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[N:19]=[CH:18]3)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][CH2:26][OH:27])[N:19]=[CH:18]3)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCCO)c1
Yield: 88 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridine-2(1H)-one (200 mg, 0.63 mmol) in DMSO (5 mL) was added Cs2CO3 (1.03 g, 3.15 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (0.15 mL, 0.66 mmol). After stirring overnight at ambient temperature under argon, the reaction mixture was filtered through a layer of Celite and concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one (90 mg, 29%). To a solution of 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one in THF (3 mL) was added TBAF (0.75 mL, 0.75 mmol, 1.0 M). After the reaction was complete, the mixture was treated with H2O, extracted with CH2Cl2, and the combined organics were concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-hydroxypropyl)-1H-indazol-5-yl)pyridin-2(1H)-one (50 mg, 88%) as a white solid. In accordance with the procedure of Example 1, the HCl salt was made to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.73-7.71 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.33 (dd, J=9.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.50 (t, J=7.0 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H), 2.01-1.96 (m, 2H); ESI MS m/z 376 [M+H]+.
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:23]([O:25][C:26](C1C=CC(C2C=CC(CBr)=CC=2)=CC=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].SCCO>CN(C=O)C>[CH2:23]([O:25][C:26]([C:11]1[CH:6]=[CH:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(CSCCO)cc2)cc1

Procedure:
4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was prepared as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.2 g, 13.16 mmol, 1 eq.) in anhydrous DMF (100 mL) was treated with potassium carbonate (5.46 g, 39.48 mmol, 3 eq.) and 2-mercaptoethanol (1.23 g, 15.79 mmol, 1.2 eq.). When the reaction was complete, the reaction was worked up as described leaving a yellow oil upon removal of the solvent.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14]CC(C)=C)[CH:10]=[CH:9][C:8]=2[CH3:19])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:14][C:11]1[C:10]([CH2:3][C:1]([CH3:4])=[CH2:2])=[CH:9][C:8]([CH3:19])=[C:7]2[C:12]=1[CH:13]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:20])[NH:6]2
Reactant: C=C(C)COc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(C)Cc1cc(C)c2[nH]c(=O)c(C(C)C)cc2c1O
Yield: 185.3 %

Procedure:
Using 3-isopropyl-8-methyl-5-(2-methylallyl)oxycarbostyril (1.0 g, 3.7 mmol), the procedure of Reference Example 65 was followed (reaction, post-treatment, recrystallization from ethyl acetate-hexane). 930 mg of the title compound was obtained as colorless needles (92.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, followed the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 9.05 (s, 1H), 8.89 (s, 2H), 8.79 (dd, 1H), 8.06 (m, 1H), 7.65 (m, 1H), 7.44 (m, 2H), 7.24 (m, 2H), 7.12 (t, 1H), 6.74 (dd, 1H), 6.66 (m, 2H), 4.42 (s, 2H), 4.39 (s, 2H), 4.34 (s, 2H), 1.47 (s, 9H); MS 547 (M+1).
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30].O>O1CCCC1>[CH2:1]([C:8]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of diethyl 2-(6-heptenyl)malonate (3.83 g, 14.92 mmol) in anhydrous tetrahydrofuran (50 ml) was slowly added dropwise to a suspension of 60% sodium hydride (0.52 g, 12.94 mmol) in anhydrous tetrahydrofuran (150 ml) at 0° C., and the resulting mixture was stirred for 1 hour. The 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane prepared in Example 2 (4.0 g, 9.95 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) and then slowly added dropwise to the mixture, followed by stirring for 2 days at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(6-heptenyl)-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)malonate (4.7 g, Yield 89%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH:13]([CH3:17])[C:14](=O)[CH3:15]>CC(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[N:11]([C:13]([CH3:17])=[C:14]([CH3:15])[CH:1]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1cccnc1C
Reactant: CC(=O)C(C)Br
Solvent: CC(C)=O
Product: COC(=O)c1cccn2c(C)c(C)cc12
Temperature: 25 °C

Procedure:
A solution of methyl 2-methylnicotinate (4.9 g, 32.1 mmol) and 3-bromo-2-butanone (4.8 g, 32.1 mmol) in acetone (40 ml) were warmed to reflux for 3 d. Cooled to RT and partially purified the remaining residue via column chromatography (silica gel, 5-10% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([NH2:13])=O)[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:13])[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2cc(C(N)=O)sc12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(F)c2cc(C#N)sc12

Procedure:
A solution of 4-fluoro-7-methoxy-1-benzothiophene-2-carboxamide (0.756 g, 3.3 mmol) in phosphorus oxychloride (6.2 mL, 6.6 mmol) was refluxed for 3 h then cooled and the solvent evaporated in vacuo to give the title compound. Purified by flash chromatography with a gradient of 0–30% ethyl acetate in iso-hexane to give a colourless solid (0.635 g, 91%); δH (300 MHz, CDCl3) 7.95 (1H, s, 3-ArH), 7.10–7.01 (1H, m, ArH), 6.85–6.77 (1H, m, ArH) and 3.98 (3H, s, OCH3).