Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.Br[CH2:24][C:25]1[N:26]=[C:27]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:24][C:25]5[N:26]=[C:27]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:28][CH:29]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: COCCOCc1nc(CBr)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOCc1nc(COc2cc(OC)cc3oc(-c4cn5nc(OC)sc5n4)cc23)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.10 g, 0.315 mmol) and 4-(bromomethyl)-2-((2-methoxyethoxy)methyl)thiazole (Example 6E, 0.10 g, 0.376 mmol) in DMF (5 mL) was purged under vacuum and nitrogen for 10 minutes. The mixture was then treated with potassium carbonate (0.10 g, 0.724 mmol) and the reaction was stirred at RT for 2.5 hours. The reaction was then diluted with dichloromethane, washed with water (1×), brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 50% ethyl acetate/CH2Cl2) to give the title material which was crystallized in ethyl acetate and provided the desired title material (0.055 g, 35%) along with non-crystallized material (9 mgs, 6%). LC (Method F): 2.476 min. HRMS (ESI) calcd for C22H23N4O6S2 [M+H]+ m/z 503.1054, found 503.1066. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.82 (s, 1H), 7.35 (s, 1H), 7.05 (s, 1H), 6.68 (broad s, 1H), 6.39 (d, J=1.9 Hz, 1H), 5.28 (s, 2H), 4.86 (s, 2H), 4.19 (s, 3H), 3.82 (s, 3H), 3.74-3.77 (m, 2H), 3.58-3.61 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:11]2[CH:12]([CH3:15])[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O.O1CCCC1.CO.[OH-].[Li+]>O>[CH3:15][CH:12]1[C:11]2=[C:6]([NH2:5])[CH:7]=[CH:8][CH:9]=[C:10]2[O:14][CH2:13]1
Reactant: CC1COc2cccc(NC(=O)C(F)(F)F)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1COc2cccc(N)c21
Temperature: 25 °C
Reaction time: 47 h
Yield: 92.6 %

Procedure:
To a stirred solution of Intermediate 24 (0.087 g) in 2:2:1 tetrahydrofuran:methanol:water (5 ml) was added lithium hyroxide (0.149 g) and the mixture stirred at room temperature for 47 h, then at 60° C. for 2.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was re-extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give the title compound as a colourless oil (0.049 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([Mg]Br)[CH3:33].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:32][CH3:33])=[C:11]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Oc3cc(OCc4ccccc4)ccc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added thereto at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12][CH2:13][NH2:14])=[CH:3][CH:2]=1>[Pd].CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:3][CH:2]=1
Reactant: NCC=Cc1ccnc2ccccc12
Agent: [Pd]
Solvent: CO
Product: NCCCc1ccnc2ccccc12
Reaction time: 8 h
Yield: 76.3 %

Procedure:
Under a nitrogen atmosphere, 10% palladium on carbon (catalytic amount) was added to a solution of 3-(4-quinolyl)-2-propenylamine (Intermediate No. 2-4) (188 mg, 1.02 mmol) in methanol (3 ml) at room temperature, and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered with Celite, the solvent was evaporated under reduced pressure, and the obtained residue was distributed between ethyl acetate (30 ml) and a saturated aqueous ammonium chloride solution (30 ml). A 4 N aqueous sodium hydroxide solution (30 ml) was added to the aqueous layer, the whole was extracted with chloroform (100 ml), and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the target compound (145 mg, 76.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[Si:30]([O:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: C[C@]12CC[C@H](OCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 93 %

Procedure:
To a solution of 2.0 g of 3β-(2-hydroxyethoxy)-androst-5-en-17-one (Julia S. et al., Bull. Soc. Chim. France, 1960, 297) in 20 ml of dimethylformamide, 3.5 g of imidazole and 4.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 2.5 g of crude 3β-(2-tert-butyldimethylsilyloxyethoxy)-androst-5-en-17-one.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.[NH2:44][C:45]1[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:44][C:45]3[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=3)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Reactant: Cc1cc(N)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)nn1C
Reaction time: 24 h

Procedure:
DIPEA (517 mg, 3.00 mmol) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (364 mg, 0.75 mmol), 3-amino-1,5-dimethylpyrazole (109 mg, 0.90 mmol) and HATU (599 mg, 1.58 mmol) in DMF (3.0 mL) and the mixture stirred for 24 hours. Water (25 mL) was added and the mixture extracted with ethyl acetate (2×25 mL) dried (MgSO4) and reduced to a brown oil. The crude product was purified by chromatography on silica, eluting with ethyl acetate, to give the required product as a clear oil. (232 mg).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:29]=[CH:28][C:9]([C:10]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)CCC.Cl[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=1>C1(C)C=CC=CC=1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:26]2[N:25]=[CH:24][N:23]([C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:9]3[CH:28]=[CH:29][CH:6]=[CH:7][CH:8]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:27]=2)=[N:40][CH:41]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)nc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To the solution of 4-Tributylstanny 1-trityl-1H-imidazole (1.00 g, 1.67 mmol) in toluene (1.0 ml) added 2-Chloro-5-fluoropyridine (0.31 g, 2.38 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.19 g, 0.17 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% diethyl ether in hexanes to isolate 4-(5-Fluoro-2-pyridyl)-1-trityl-1H-imidazole (0.23 g) as a clear oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][O:28][CH2:29][C:30]([OH:32])=O)=[C:21]([C:34]([O:36]C)=[O:35])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][O:28][CH2:29][C:30]([N:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][C:9]=2[CH3:10])=[O:32])=[C:21]([CH:20]=1)[C:34]([OH:36])=[O:35]
Reactant: CCNc1cc(-c2ccc(F)cc2)ccc1C
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: CCN(C(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccc(F)cc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-4′-fluoro-4-methylbiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[ethyl(4′-fluoro-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:10]2([N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][C:11]2([F:25])[F:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:10]2([NH:13][CH2:12][C:11]2([F:24])[F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(C1)NCC2(F)F
Reaction time: 14 h
Yield: 81.9 %

Procedure:
To a solution of an optically-active compound of 3,3-difluoro-1,6-diazaspiro[3,4]octane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (397 mg) in methanol/tetrahydrofuran (3.2 ml/3.2 ml) was added 10% palladium carbon (79 mg), and the mixture was hydrogenated at room temperature under ordinary pressure for 14 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=4/1 to 2/1). The fractions which could not be separated and isolated were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=2/1 to 1/1) again. The purified fractions were combined and concentrated under reduced pressure to give the titled compound (211 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=1>CN(C=O)C>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:28][C:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=3)[N:17]=[N:18][C:19]=2[C:11]=1[O:10][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (0.006 g, 0.020 mmol) and cesium carbonate (0.0077 g, 0.024 mmol) suspended in DMF (1 mL) at room temperature was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (=Intermediate 1; 0.0068 g, 0.022 mmol) as a solution in DMF (0.5 mL). After stirring for 1 hour at room temperature, the reaction mixture was quenched with aqueous ammonium chloride (2 mL), and the quenched mixture was extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with water (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to automated silica gel chromatography eluting with a gradient of 25-50% ethyl acetate in hexanes to afford the title product. LRMS (M+1)=435.7
Reaction SMILES: [CH:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:30]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[C:14]([I:30])=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O[C@H]4CC[C@H](C5CCCC5)CC4)ccc3c2)COC(=O)N1

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(trans-4-Cyclopentyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (89 mg, 0.00023 mol), N-iodosuccinimide (110 mg, 0.00050 mol), zirconium chloride (0.007 g, 0.00004 mol), and methylene chloride (3 mL, 0.04 mol). ESI-MS: 519 (M+H). 1H NMR (400 MHz, CDCl3) δ=8.17 (d, J=9.0 Hz, 1 H), 7.72-7.59 (m, 2 H), 7.45 (dd, J=1.9, 8.9 Hz, 1 H), 7.24 (d, J=9.0 Hz, 1 H), 5.90 (s, 1 H), 4.44-4.28 (m, 2 H), 4.20 (t, J=4.1 Hz, 1 H), 2.09 (d, J=10.5 Hz, 2 H), 1.91-1.30 (m, 16 H), 1.15-0.87 (m, 5 H)
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([S:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=1[F:20])=[O:8].[C:24](Cl)([Cl:26])=[S:25]>O.C(Cl)(Cl)Cl>[Cl:26][C:24]([O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([S:9][C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16])=[O:8])=[S:25]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1c(F)c(F)c(F)c(F)c1F)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Sc1c(F)c(F)c(F)c(F)c1F)c1cccc(OC(=S)Cl)c1

Procedure:
A solution of 187 mg of sodium hydroxide in 5 ml of water was added to a stirred suspension of S-(pentafluorophenyl) 3-(hydroxy)thiobenzoate (1.0 g) in chloroform (10 ml) at -10° C. Thiophosgene (0.36 ml) was added and the solution stirred whilst being allowed to reach room temperature. The chloroform layer was separated, dried over anhydrous calcium chloride and evaporated to leave a reside which was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluant to give 0.61 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(COC2CCCCO2)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(COC2CCCCO2)ccc1F

Procedure:
A solution of 2.5g (10.49 mmol) 2-fluoro-5-(tetrahydropyrane-2-yloxymethyl)-benzaldehyde in anhydrous methanol is mixed in portions with 0.60 g (15.7 mmol) sodium borohydride while stirring and stirred for another hour at room temperature. After adding water, extraction is performed using diethyl ether, and the organic phase is dried over sodium sulfate. After removing the solvent under vacuum, the benzyl alcohol is obtained in pure form.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:12]>C1COCC1>[CH2:11]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][CH:1]=[O:3])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Oc2ccccc2N)c(OC)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccccc2NC=O)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 126.4 %

Procedure:
To acetic anhydride (0.53 mmol; 51 μL) under argon, at 0° C., was added formic acid (0.66 mmol; 25 μL). The reaction was stirred 2 hours at 60° C. After cooling to 0° C., the mixture was diluted with 1 mL of dry THF, followed by a solution of 2-(4-ethyl-2-methoxyphenoxy)aniline (0.21 mmol; 50 mg) in dry THF (1 mL). The reaction was stirred 2 hours at room temperature. The mixture was concentrated in vacuo to give the title compound (72 mg; quantitative) as a brown oil, used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]O)[N:9]=1)[CH3:3].S(Cl)(Cl)=O.C[N:17]([CH2:19][C:20]1[S:21]C=C(CCl)N=1)C.Cl.NCCS>>[CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:21][CH2:20][CH2:19][NH2:17])[N:9]=1)[CH3:3]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: CN(C)Cc1nc(CCl)cs1
Agent: Cl
Agent: NCCS
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1nc(CSCCN)cs1

Procedure:
When 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Step D]is reacted with thionyl chloride and the resultant 2-dimethylaminomethyl-4-chloromethylthiazole is reacted with an equimolar amount of cysteamine hydrochloride and two equivalents of base according to the general procedure of Example 33, Step D, the title compound is thereby produced.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:34]3C(=O)C4=CC=CC=C4C3=O)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([NH2:34])[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CN
Product: CCCc1nc2c(C)cc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Prepared analogously to Example 1b from tert.butyl 4'-[(2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazol-1-yl)-methyl] -biphenyl-2-carboxylate and methylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
Potassium carbonate (9.12 g, 66.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (5.88 g, 60.0 mmol) and 4-fluoro-3-nitrobenzotrifluoride (12.6 g, 60.0 mmol) in DMF (120 ml), and the mixture was stirred at 50° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (200 ml) and extracted with ethyl acetate (70 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (12.1 g, yield: 69.0%). mp: 89-91° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (s, 3H), 5.77 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.76 (dd, J=2.0 and 8.8 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 10.10-11.05 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:14]=[CH:15][CH:17]=[N:7]2
Reactant: OCC(O)CO
Reactant: Cc1cc([N+](=O)[O-])c(N)cc1Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2ncccc2c1Cl
Yield: 29.7 %

Procedure:
In a similar fashion using route 10 general procedure 20, 5-chloro-4-methyl-2-nitroaniline (1.0 g, 5.3 mmol), glycerol (1.52 g, 16.6 mmol), 3-nitrobenzensulfonic acid sodium salt (1.55 g, 6.8 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (350 mg, 30%) which was used in the next step without purification.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:21]([O:23][CH2:24]Cl)[CH3:22].C(=O)([O-])O.[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:21]([O:23][CH2:24][N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3])[CH3:22]
Reactant: CCOCCl
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOCn1ccc(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.8 %

Procedure:
To 100 ml of methylene chloride, 5.1 g (40 mmol) of 2-thiouracil and 22 ml (88 mmol) of bistrimethylsilylacetamide were added under a nitrogen atmosphere, and stirred for 40 minutes at room temperature. To this mixture, 8.2 ml (88 mmole) of chloromethyl ethyl ether and 0.15 g (0.4 mmol) of tetrabutylammonium iodide were added and heated under reflux for 15 hours. Then, the reaction mixture was poured carefully into 50 ml of saturated aqueous solution of sodium hydrogencarbonate and filtered through Celite. The organic layer was washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1.1 g of 1-ethoxymethyl-2-thiouracil (Yield: 15%).