Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1cc(F)ccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 25 °C
Yield: 63.2 %

Procedure:
The trifluoroacetic acid salt of [4-amino-2-(piperidin-4-ylamino)pyrimidin-5-yl-(4-fluoro-2-methoxy-phenyl)-methanone (72.18 mg, 0.157 mmol, Example 176) in dichloromethane (5 mL) and triethylamine (0.2188 mL, 1.570 mmol) was chilled and methanesulfonyl chloride (0.017 mL, 0.22 mmol, Aldrich) was added and the mixture was stirred at room temperature for several hours. Chromatography provided 42 mg (63%) of the title compound as a white solid. HR-ES(+), observed: 424.1453; Calcd for (M+H)+: 424.1450.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH3:17])=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:26]=2)[C:21]=1OB(O)O>CCOCC>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:26]=2)[C:21]=1[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH3:17])=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2ccc3c(OB(O)O)c(OC)ccc3c2)c1
Reactant: Cc1nnc(NS(=O)(=O)c2cccc(Br)c2)s1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(-c4cccc(S(=O)(=O)Nc5nnc(C)s5)c4)c(OC)ccc3c2)c1

Procedure:
The compound is prepared by the reaction of 3-bromo-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (92.4 mg, 0.28 mmol, 1 eq) with 2-methoxy-6-(3-methoxyphenyl)naphthalene-1-ylboric acid (100 mg, 0.36 mmol, 1.3 eq) according to method C. The raw product was not characterized, but directly subjected to ether cleavage.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>>[O:27]1[CH2:26][CH:25]1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC1CO1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Nc1ccccc1OCC1CO1)c1ccccc1

Procedure:
To a stirred solution of N-(2-Hydroxy-phenyl)-benzamide (0.81 g, 3.80 mmol), and cesium carbonate (1.61 g, 4.94 mmol) in acetontrile was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between dichloromethane and water. After evaporation of the organic solvent the residue was crystallised from petroleum ether and diethyl ether yielding (0.741 g, 73%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[CH3:22][C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([CH3:31])=[C:25]([CH3:32])[C:24]=1[S:33](Cl)(=[O:35])=[O:34].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:33]([C:24]1[C:23]([CH3:22])=[C:28]([CH3:29])[C:27]([CH3:30])=[C:26]([CH3:31])[C:25]=1[CH3:32])(=[O:35])=[O:34])=[N+:2]=[N-:3]
Reactant: Cc1c(C)c(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c(C)c(S(=O)(=O)NCCN=[N+]=[N-])c(C)c1C
Yield: 81 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2,3,4,5,6-pentamethylbenzene-1-sulfonyl chloride (0.304 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.46 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide (0.296 g, 81%). 1H NMR (300 MHz, CDCl3) δ 5.12 (t, 1H) δ 3.35 (t, 2H), δ 3.05 (q, 2H), 2.59 (s, 6H), δ 2.28 (s, 3H), 2.24 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 139.9, 136.1, 135.2, 134.2, 51.1, 42.3, 19.2, 17.9, 17.3 ppm; HRMS (ESI) calcd for C13H20N4O2S (M+) 296.1307. Found 296.1304.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:28][CH:29]2[CH2:33][CH:32]=[CH:31][CH2:30]2)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:29]1([CH2:28][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])[CH2:33][CH:32]=[CH:31][CH2:30]1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2CC=CC2)c(=O)[nH]c1=O
Yield: 49.5 %

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.10 g, 0.40 mmol) and (cyclopent-3-en-1yl)methyl toluenesulfonate (0.12 g, 0.40 mmol) in dimethylformamide (10 ml ) were heated at 90° C. for overnight in the presence of sodium bicarbonate (41 mg, 0.4 mmol). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid (65 mg) by the separation of column chromatography.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1.[ClH:24]>C(O)(C)C>[ClH:24].[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2(O)CN
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Yield: 98 %

Procedure:
1 Aminomethyl-5,6-dimethoxy-1-hydroxy-3-phenyl-1,2,3,4-tetrahydro-naphthalene (11.5 g, 37 mmol), from Step 1, was heated at reflux temperature in 300 mL of isopropyl alcohol saturated with hydrochloric acid for 2 h. The resultant solution was concentrated and the solid residue was triturated with hot toluene to give 10.6 g (98% yield) of 1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3-phenyl-naphthalene hydrochloride, m.p. 189.5°-190° C. 1H NMR (d6 -DMSO) delta 2.78 (dd, 1H), 3.11 (dd, 1H), 3.2-3.4 (m, 2H +H2O), 3.6 (s, 3H), 3.81 (s, 3H), 3.93 (d, 1H), 6.1 (d, 1H), 6.93 (d, 1H), 7.12 (d, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:27]([CH3:28])[CH3:29])[CH:24]([CH3:26])[CH3:25])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[O:9][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCc1ccc(C(O)c2cc(Br)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCc1ccc(C(O[Si](C(C)C)(C(C)C)C(C)C)c2cc(Br)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
Step 4) To a solution of (5-bromo-2-((triisopropylsilyloxy)methyl)phenyl)(4-ethylphenyl)methanol (4.76 mmol) and 2,6-lutidine (1.6 mL, 13.51 mmol) in dichloromethane (30.0 mL) was slowly added TIPSOTf (1.8 mL, 6.75 mmol) at 0° C., and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was quenched with CH3OH, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide the title compound (2.94 g, 97% 2-step) as yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[K+].[CH2:22]([SH:24])[CH3:23]>CN(C)C=O.C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([S:24][CH2:22][CH3:23])[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCS
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCSc1nc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A solution of 3.40 g (12 mmol) 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 60 ml N,N-dimethylformamide heated to 60° C. was treated with a solution of 3.36 g (60 mmol) potassium hydroxide and 6 ml (81 mmol) ethanethiol in 30 ml absolute ethanol. After stirring 15 minutes at 60° C. the mixture was poured into 240 ml ice cold 0.5 N hydrochloric acid, and the precipitate was filtered, washed with water and crystallized from acetic acid--water to give 3.10 g, mp 242°-244° C. of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[CH3:39][NH:40][CH2:41][CH:42]([OH:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:40]([CH2:41][CH:42]([OH:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH3:39])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2s1)CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.300 g) from Example No. 35 in DMF (17 mL) are added DMAP (16 mg), 2,4,6-collidine (0.27 mL), and methanesulfonyl chloride (0.16 mL). The reaction mixture is stirred at room temperature for 1 h and then α-(methylaminomethyl)benzyl alcohol (1.26 g) is added. The mixture is stirred at room temperature for 18 h and is then poured into water (50 mL). The resulting off-white solid is filtered off and purified by column chromatography (CH2Cl2/methanol, 99/1; 97/3) to yield 0.261 g (63%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13].C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:20]1[CH2:21][CH2:22][N:17]([S:14]([C@@H:12]([C@:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])([OH:29])[CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(S(=O)(=O)[C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Reaction time: 0.5 h

Procedure:
In dichloromethane (10 ml) was dispersed 1[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H ,1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine.dihydrochloride (Compound 20, 0.40 g) obtained in Working Example 14. To the dispersion were added, under ice-cooling, triethylamine (0.40 ml) and acetic anhydride (0.13 g). The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was then washed with water, dried and concentrated. The concentrated was subjected to a silica gel chromatography (eluent: dichloromethane/methanol=20/1) for purification. The object fraction was concentrated and processed with hydrogen chloride, followed by addition of isopropyl ether to give 1-acetyl-4-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine (Compound 25).hydrochloride (336 mg) as colorless powder.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]([OH:29])([CH3:28])[CH2:26][CH3:27])=[CH:19][C:18]=2[F:30])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:29])([CH3:28])[CH2:26][CH3:27])=[CH:19][C:18]=2[F:30])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CCC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(O)CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 98 %

Procedure:
The product of Example 13, 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-pentynyl)anilino]-N-(2-hydroxyethoxy)benzamide was hydrogenated in absolute ethanol in the presence of 5% Pd/C by the general procedure of Example 1, Step D. The resulting crude solid was purified by filtration through a plug of silica (MeOH as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methylpentyl)anilino]-N-(2-hydroxyethoxy)benzamide (98%) as a light yellow foam (hygroscopic). 1H NMR [400 MHz, (CD3)2SO] δ 9.62 (br s, 1 H), 7.54–7.48 (m, 1 H), 7.04–6.96 (m, 2 H), 6.86 (dd, J=8.2, 1.6 Hz, 1 H), 6.75 (ddd, J=8.6, 5.2 Hz, 1 H), 4.08 (br s, 1 H), 3.80 (t, J=4.9 Hz, 2 H), 3.53 (t, J=4.9 Hz, 2 H), 2.55–2.50 (m, 2 H), 1.60–1.54 (m, 2 H), 1.41 (q, I=7.6 Hz, 2 H), 1.06 (s, 3 H), 0.84 (t, J=7.6 Hz, 3 H). HRMS (EI+) calcd for C21H25F3N2O4 426.1766 (M+), found 426.1770.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C(=O)N([Br:39])C(=O)C1>C(O)(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([Br:39])=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2cc(Oc3ccc(S(C)(=O)=O)cc3F)ncn2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2Br)CC1
Yield: 57.2 %

Procedure:
4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (1.02 g, 2.25 mmol) and NBS (601 mg, 3.38 mmol) in acetic acid (10 mL) was stirred at 40° C. for three days. The mixture was purified through HPLC to provide compound C155 as a solid (685 mg, 50%). 1H NMR (CDCl3, 400 MHz) δ 1.24 (d, 6H), 1.82-1.86 (m, 2H), 1.94-1.98 (m, 2H), 3.08 (s, 3H), 3.46-3.52 (m, 2H), 3.68-3.74 (m, 2H), 4.92 (hept, 1H), 5.38-5.42 (m, 1H), 7.42-7.46 (m, 1H), 7.77-7.81 (m, 2H), 8.18 (s, 1H). Exact mass calculated for C20H23FBrN3O6S 531.1, found 532.4/534.4 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:14]=2[CH:13]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([CH:21]=[O:22])[CH:19]=[CH:20][C:14]=2[CH:13]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CO)cc2s1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (600 mg, 1.86 mmol) in DCM (3 mL) was added MnO2 (2.1 g, 24.1 mmol). The mixture was stirred at ambient temperature for 30 min and then filtered through celite. The filtrate was concentrated to afford the title compound (435 mg, 82%). LCMS m/z 320 [M+−H]+, 1H NMR (300 MHz, MeOD), δ: 0.94 (6H, d J=6.7 Hz, 2×CH3), 1.45 (3H, d J=5.3 Hz, CH3), 1.87 (1H, m, CH), 3.40 (2H, m, CH2), 5.08 (1H, dd J=5.2, 10.6 Hz, CH), 7.89-8.09 (3H, m, ArH), 8.55 (1H, s, ArH), 10.11 (1H, s, CHO).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=3)[C:19]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:37][CH:38]=3)[C:19]([C:21]3[CH:25]=[N:24][NH:23][CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3cn[nH]c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)c3cn[nH]c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(1H-pyrazol-4-ylcarbonyl)amino]methyl}phenoxy)acetate and NaOH 1N in the presence of MeOH/THF as a white powder (30%). 1H NMR (MeOD, 300 MHz) δ 7.76 (m, 2H), 7.45 (m, 4H), 7.17 (m, 6H), 6.88 (m, 2H), 4.64 (s, 2H), 3.94 (s, 4H), 2.59 (t J=7.7 Hz, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.90 (t, J=7.3 Hz, 3H). HPLC, Rt: 4.62 min (Purity: 88%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9](O)[C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc2c(c1)C(O)Cc1c(Cl)cccc1S2
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOc1ccc2c(c1)CCc1c(Cl)cccc1S2
Temperature: 25 °C
Yield: 49.9 %

Procedure:
The mixture of 1.1 g of 9-chloro-10,11-dihydro-2-ethoxy-11-hydroxydibenzo[b,f]thiepin and 35 ml of thionyl chloride was refluxed for 3 hrs. and evaporated to obtain the residue, to which was added 50 g of ice-water. The resulting mixture was extracted with chloroform and the extract was washed with water and dried over calcium chloride. The solvent was evaporated to obtain the concentrated which was added with stirring at room temperature to a mixture of 70 ml of anhydrous tetrahydrofuran and 400 mg of lithium aluminum hydride. The thus obtained mixture was refluxed with stirring for 4 hrs., to which was added 30% sodium hydroxide solution with stirring under cooling with a mixture of ice and sodium chloride. The mixture was filtered and the filtrate was evaporated to obtain the residue, to which was added 100 ml of chloroform and 100 ml of water, and the chloroform layer was collected. This was washed with water, dried and the solvent was evaporated to obtain 520 mg of 9-chloro-10,11-dihydro-2-ethoxydibenzo[b,f]thiepin as oily substance.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[CH3:24])#[N:2].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[CH3:24])#[N:2]
Reactant: COc1ccc(CN)cc1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (1.0 g, 3-09 mmol) was dissolved in dimethyl sulfoxide (60 ml), then at room temperature, triethylamine (560 μl, 4.02 mmol) was added, followed by heating at 150° C. 4-Methoxybenzylamine (525 μl, 4.02 mmol) was added to the solution all at a time, followed by stirring for 1.5 hours. The reaction liquid was cooled to room temperature, and the solvent was evaporated away under reduced pressure. The residue was fractionated with chloroform and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:acetone=98:2, v/v) to obtain the entitled compound (665 mg, 49%) as a yellow solid.
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:13][C:14]1[NH:15][C:16]([NH2:23])=[C:17]2[C:21]([N:22]=1)=[N:20][CH:19]=[N:18]2.C(O[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[F:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[C:16]([NH2:23])[N:15]=1
Reactant: Nc1[nH]c(F)nc2ncnc1-2
Reactant: CC(=O)OC1CCCCO1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2C1CCCCO1
Temperature: 0 °C

Procedure:
N,O-bis(trimethylsilyl)acetamide (975 ml, 3.988 mol) was added to a stirred suspension of 2-fluoro-1H-purin-6-amine (200 g, 1.306 mmol) (available from, for example, AlliedSignal, US) in anhydrous acetonitrile (4 L) in a 10 L controlled lab reactor and the resulting mixture heated to reflux and maintained at that temperature for 2 hours. The circulator was then re-programmed and the reaction mixture cooled to 0° C. A solution of tetrahydropyranyl acetate (preparation described in Tetrahedron Letters 2006, 47(27), 4741) (282 g, 1.959 mol) in anhydrous acetonitrile (500 ml) was then added slowly via a dropping funnel followed by trimethylsilyl trifluoromethanesulfonate (283 ml, 1.567 mol) dropwise via a dropping funnel. No significant exotherm was observed. The circulator temperature was re-adjusted to 10° C. and stirring maintained for a further 1 hour. The mixture was then quenched by addition of 1M sodium carbonate (4 L). A solid precipitate was observed and the pH checked to be basic. Additional water was added to the suspension (1 L) and on standing the layers separated with the aqueous layer containing significant solid inorganics. The majority of the aqueous and inorganic solid was separated. The organic layer still contained significant solid and was cooled to 0° C. with stirring to encourage further precipitation. The solid was the collected by filtration and the pad was washed very well with water then dried in vacuo at 40° C. overnight to give the title compound as a cream coloured solid (152.8 g).