Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:18](=[O:17])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OC(=O)c4ccccc4)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Reaction time: 23 h
Yield: 163.4 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (200 mg, 0.52 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added benzoyl chloride (0.18 mL, 1.56 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (30 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with NaHCO3 (40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a colourless solid (252 mg, 82%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.21 (d, J=8.0 Hz, 2H), 8.07 (d, J=6.4 Hz, 2H), 8.00 (dm, J=8.4 Hz, 2H), 7.68 (t, J=6.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.49 (t, J=8.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.35 (dm, J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 5.82 (pentet, J=6.3 Hz, 1H), 5.37 (d, J=7.6 Hz, 1H), 5.21 (dd, J=5.9, 7.6 Hz, 1H), 2.34 (s, 3H), 1.51 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH2:33]([SH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(O)C>[CH2:1]([O:17][CH2:18][CH:19]([CH2:25][S:49][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(CSCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 8 h

Procedure:
To a solution of 20 g of 2-[(hexadecyloxy)methyl]-2-propenoic acid, ethyl ester and 10 ml of triethylamine in 60 ml of ethanol is added 53 ml of hexadecyl mercaptan. This mixture is stirred overnight, then the solvents removed and the residue purified by HPLC [hexane:ethyl acetate (9:1)], to give 32.9 g of the desired compound as a white waxy solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
17.1 (19); Leu. 40.6 (39); Phe. 16.6 (16);
Reaction SMILES: [SH2]=N.CNC(C1C=CC=CC=1C(O)=O)=[O:6].C([N:18]([CH2:21]C)[CH2:19]C)C.O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32]>CC(C)=O>[CH3:21][NH:18][C:19](=[O:6])[O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24]
Reactant: CCN(CC)CC
Reactant: COc1ccccc1O
Reactant: CNC(=O)c1ccccc1C(=O)O
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)Oc1ccccc1OC
Temperature: 25 °C

Procedure:
5 g of N-methyl-carbamoyl-benzoic acid sulfimide are suspended in a mixture of 2.6 g of 2-methoxyphenol and 50 ml acetone and while stirring at room temperature, a solution of 2.9 ml triethylamine in 30 ml acetone was added dropwise, in an hour. The mixture is stirred for an additional 2 hours at room temperature, then 240 ml of distilled water are slowly added to the mixture and extracted with 3×30 ml of ether. The ethereal extract is dried with sodium sulfate, the solvent is evaporated in a vacuum at a temperature not above 30° C. 2.43 g of 2-methoxy-phenyl N-methyl-carbamate are obtained, recrystallized from N-pentane, melting at 90°-92° C.
Reaction SMILES: [C:1]1([CH:7]2[O:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[CH:17][C:16](B4[O:23][C:22]([CH3:25])(C)C(C)(C)O4)=[CH:15][CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([C@H:39]2[CH2:44][CH2:43][C@@H:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[N:30]=1.O.C(=O)([O-])[O-:54].[Na+].[Na+]>COCCOC.O>[C:22]([OH:54])(=[O:23])[CH3:25].[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([C@H:39]3[CH2:44][CH2:43][C@@H:42]([N:45]4[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]4)[CH2:41][CH2:40]3)[N:30]=[C:29]([C:16]3[CH:15]=[CH:14][C:13]([N:9]4[CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[O:11][C:10]4=[O:12])=[CH:18][CH:17]=3)[C:37]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(N3CC(c4ccccc4)OC3=O)cc2)OC1(C)C
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N5CC(c6ccccc6)OC5=O)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of 5-phenyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazolan-2-one (0.085 g, 0.000233 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.086 g, 0.000194 mol), tetrakis-(triphenylphosphine)palladium (0.013 g, 0.000012 mol) and sodium carbonate monohydrate (0.060 g, 0.000485 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min) to yield cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-phenyl-1,3-oxazolan-2-one acetate (0.074 g, 0.000121 mol) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][S:29](=[O:32])(=[O:33])[CH2:30][CH2:31]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cn1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
[6-(Dimethylamino)-3-pyridinyl]boronic acid (34 mg, 0.202 mmol), 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (75 mg, 0.202 mmol) and potassium carbonate (84 mg, 0.606 mmol) were suspended in 4 mL of dioxane:water (3:1) and degassed for a few minutes with nitrogen gas. Pd(PPh3)4 (23 mg) was then added and the reaction mixture was heated in a microwave oven at 150° C. for 40 minutes on ‘high’ absorption setting. After heating, LCMS of all crude reaction mixtures showed the desired m/z with few impurities. The crude reaction mixtures were filtered through 500 mg Stratospheres SPE Thiol cartridges eluting with 10 mL methanol/DCM (1:1) and concentrated. The residues were dissolved in DMSO (˜3 mL) and purified via RP-HPLC using an XBridge Prep C18 column with water/acetonitrile (0.1% NH4OH buffer). The desired fractions were concentrated, giving 0.029 g (34.8%) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:32])[N:15]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:7][C:6]=1[Cl:33])=[N+]=[N-].O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C1COCC1.CO>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:32])[N:15]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:7][C:6]=1[Cl:33]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(CN=[N+]=[N-])c(Cl)c4)ccc3=O)ccnc2c1
Agent: [Na+]
Agent: [S-2]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(4-(azidomethyl)-3-chlorophenyl)-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (400 mg, 864 μmol) in THF (8 mL), MeOH (1 mL), and water (1 mL) was added sodium sulfide, nonahydrate (540 mg, 6913 μmol) and stirred overnight at 40° C. The reaction was then partitioned between DCM and 5% NaHCO3. The organic layer was dried over MgSO4, concentrated, then purified on silica (40 g) eluting with 0>6% of NH3 in MeOH (2 M)/DCM. The product was further purified on RP-HPLC eluting with ACN/water (0.1% TFA). Desired fractions concentrated under reduced pressure then residue partitioned between DCM and NaOH (1 M). The organic was then dried over MgSO4 and concentrated under reduced pressure to provide a white solid. MS (ESI pos. ion) m/z: 437 (MH+); calc'd for C23H21ClN4O3: 436. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 3.99 (s, 2 H) 4.65 (t, J=5.38 Hz, 2 H) 4.80 (t, J=5.28 Hz, 2 H) 6.67 (d, J=5.48 Hz, 1 H) 6.98-7.09 (m, 2 H) 7.32 (d, J=2.35 Hz, 1 H) 7.48 (d, J=8.02 Hz, 1 H) 7.58 (dd, J=8.02, 1.76 Hz, 1 H) 7.64 (d, J=9.78 Hz, 1 H) 7.79 (d, J=1.76 Hz, 1 H) 8.02 (d, J=9.19 Hz, 1 H) 8.64 (d, J=5.28 Hz, 1 H)
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1
Reactant: [N-]=[N+]=NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The compound of example 3, described above (254 mg, 0.79 mmol), was dissolved in THF (2 mL) an added dropwise to a 0° solution of 1N LiAlH4 in THF (1.2 mL, 1.2 mmol), stirred at 0° for 15 min, EtOAc (4 mL) was carefully added and the mixture was added to ice cold 10% NaOH (15 mL) and the product was extracted with EtOAc (4×25 mL), dried (K2CO3) and concentrated to a waxy solid, (175 mg, 5%). mp=81°-82°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:27]1COCC1.BrC[C:34]#[N:35]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([CH3:27])([CH2:16][C:34]#[N:35])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(Cl)nc1OC
Reactant: N#CCBr
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)C(C)(CC#N)c1ccc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 126.3 %

Procedure:
The following reaction was repeated twice and combined to provide the yield below. To a −78° C. solution of crude ethyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (69 g, 0.28 mol) in dry THF (1.0 L) was added lithium bis(trimethylsilyl)amide/THF (1.0 M, 400 mL, 0.40 mol) dropwise and stirred for 40 min. A solution of 2-bromoacetonitrile (54.5 g, 0.45 mol) in THF (70 mL) was then added dropwise over 1 h at −70° C. The reaction was then warmed to r.t. and stirred overnight. The reaction was quenched with saturated aqueous NH4CI and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (2-8% EtOAc/PE) provided ethyl 2-(6-chloro-2-methoxypyridin-3-yl)-3-cyano-2-methylpropanoate (100 g, 62%) as an oil which solidified over several days. 1H NMR (600 MHz, CDCl3) δ 1.19 (t, 3H), 1.76 (s, 3H), 3.13 (q, 2H), 3.96 (s, 3H), 4.14-4.24 (m, 2H), 7.02 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH2:12][CH2:13][Cl:14]>C(O)C.O.C(OCC)(=O)C>[Cl:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccccc1S
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccccc1SCCCl
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a stirred solution of 2-aminobenzenethiol (0.513 mL, 4.79 mmol) in ethanol (5 mL) was added sodium hydroxide (192 mg, 4.79 mmol) as a solution in water (5.00 mL). To the resulting mixture was added 1-bromo-2-chloroethane (1.197 mL, 14.38 mmol), and the resulting mixture was stirred vigorously for 20 minutes The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated, giving a yellow liquid, 2-(2-chloroethylthio)aniline (875 mg, 97%). 1H NMR (DMSO-d6) δ 7.27 (d, J=7.5 Hz, 1H), 7.10-7.04 (m, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.56-6.49 (m, 1H), 5.41 (brs, 2H), 3.62 (t, J=7.4 Hz, 2H), 3.02 (t, J=7.4 Hz, 2H). ESI-MS (m/z, %): 188 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([Cl:16])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1ccc(F)cc1F
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1ccc(F)cc1F

Procedure:
To a solution of (E)-2,4-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,4-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,4-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 369.80; mp: 194.8-196.8° C.; 1H-NMR (DMSO) δ: 8.84-8.79 (1H, m), 8.30-8.08 (2H, m), 7.96-7.82 (3H, m), 7.78-7.69 (1H, m), 7.61-7.13 (6H, m).
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=4)[N:13]=3)=[CH:8][CH:7]=2)=[N:4]N=N1.[OH-:25].[Na+].OO>CS(C)=O>[CH3:24][O:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:4])=[O:25])=[CH:7][CH:8]=1)[CH:21]=[CH:20]2
Reactant: [OH-]
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(C(N)=O)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(6-methoxyquinolin-2-yl)benzonitrile (5.00 g, 15.4 mmol, prepared following Scheme 2, Step 1 starting from Intermediate 1 and 4-cyanophenylboronic acid) in DMSO (40 mL) was added aqueous NaOH (1M, 10 mL). The mixture was cooled to 0° C. The aqueous H2O2 (30%, 30 mL) was added dropwise. After addition, the mixture was stirred at 0° C. for 30 minutes. The mixture was quenched with saturated Na2SO3 (100 mL) and filtered. The precipitate was washed with H2O (50 mL) and MeOH (50 mL). The filter cake was dried via high vacuum to give the desired product (5.50 g, yield: 99+%) as a solid.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([O:18][CH3:19])=[O:17])=[N+]=[N-].CO>C(O)(C(F)(F)F)=O.[Pd].O1CCOCC1>[NH2:1][C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:10])[CH3:11])[C@@H:5]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@@H]1[C@@H](N=[N+]=[N-])C(=O)N1[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1[C@@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 132 (5.85 mmol) in 3:1 methanol:dioxane (25 mL) was added a few drops of TFA and 10% Pd/C (10 wt %). The reaction was stirred under atmospheric hydrogen for one hour and then filtered through Celite. The solvent was removed and the residue triturated with diethyl ether to afford 133, which was used in the next step without further purification.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1.CCOCC>CC#N>[Cl:3][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:17]([Cl:20])(=[O:19])=[O:18])[CH:12]=2)[C:7]([Cl:6])=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Cl)c2ccc(S(=O)(=O)Cl)cc12
Solvent: CC#N
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Yield: 84.2 %

Procedure:
Anal. Found: C, 39.37; H, 2.09; N, 4.94. Calc for C9H5Cl2NO3S: C, 38.87; H, 1.81; N, 5.04. ##STR109## POCl3 (9.65 mL, 103.5 mmol) was added to a stirred suspension of 4-chloro-1-oxo-1,2-dihydro-7-isoquinolinesulphonyl chloride (22.1 g, 79.6 mmol) in MeCN (500 mL) at room temperature and the mixture was then heated at reflux for 15 h. On cooling, the MeCN solution was decanted from the insoluble sludge and evaporated in vacuo. The residue was extracted with hot EtOAc and evaporated to leave a solid which was stirred with Et2O (1.2 L) at room temperature overnight. The ethereal solution was decanted from the insoluble material and evaporated in vacuo to give 1,4-dichloro-7-isoquinolinesulphonyl chloride (20 g, 67 mmol) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31]([OH:33])=[O:32]>>[CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([C:35]5[C:36]([O:37][CH3:38])=[CH:28][CH:29]=[C:30]([C:31]([OH:33])=[O:32])[CH:34]=5)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)O)cc1I
Reactant: O=c1c2ccc(OCc3cccc(B(O)O)c3)cc2sn1C1CCCC1
Product: COc1ccc(C(=O)O)cc1-c1cccc(COc2ccc3c(=O)n(C4CCCC4)sc3c2)c1

Procedure:
A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), 3-iodo-4-methoxybenzoic acid (0.053 g, 0.20 mmol) were coupled according to the general procedure to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as pale yellow solid (0.013 g, over two steps 10%). 1H NMR (400 MHz, CDCl3): δ 7.80-7.66 (m, 2H), 7.60-7.34 (m, 5H), 7.23-7.21 (m, 2H), 6.79 (d, 1H, J=8.5 Hz), 5.02 (s, 2H), 4.44-4.30 (m, 1H), 3.61 (s, 3H), 1.93-1.91 (m, 2H), 1.78-1.45 (m, 6H), LC-MS (ESI) Calcd for C27H25NO5S [M+H]+: 475.14. Found: 475.80.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[C:12]([CH3:17])[C:13]([OH:16])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:18]=[O:19]>CC1C=CC(O)=CC=1.CC1C=CC(O)=CC=1.CC1C=CC(O)=CC=1.CC1C=CC(O)=CC=1.[Ti].C1(C)C=CC=CC=1>[CH3:17][C:12]1[CH:11]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[C:14]([CH:18]=[O:19])[C:13]=1[OH:16]
Reactant: C=O
Reactant: CCCCCCCCCc1ccc(O)c(C)c1
Agent: [Ti]
Agent: Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1cc(C)c(O)c(C=O)c1
Temperature: 215 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
To toluene (500 mL) in a 2-I Parr pressure reactor at 220° C. was added a slurry of 4-nonyl-2-cresol (1a) (234 g, 1 mol), titanium(IV) cresylate (2 mL) and powder paraformaldehyde (83 g, 2.8 mol) for 10 mins. maintaining the temperature at 210-220° C. The reaction was kept for additional 20 mins. Crude product was collected in an expansion tank and the residue in the pressure reactor washed with toluene (200-mL×2). Combined toluene phases were concentrated in vacuo. The resulting viscous dark amber liquid was distilled in vacuo to obtain 3-methyl-5-nonylsalicylaldehyde (183 g) in 70% yield.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1([CH2:21][NH2:22])[C:13]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH2:11][CH2:10][O:9]1>C(O)=O>[CH:1]([NH:22][CH2:21][CH:8]1[C:13]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH2:11][CH2:10][O:9]1)=[O:3]
Reactant: NCC1OCCc2c1sc1ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCC1OCCc2c1sc1ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of formic acid (4.7 ml) and acetic anhydride (11.3 ml) is heated at 60° C. for 2 hr. 3,4-Dihydro-1H-[1]benzothieno[2,3-c]pyran-1-methylamine (1.0 g), described in Example 34, is added at room temperature and the mixture is allowed to stand overnight. The mixture is poured on ice and extracted with chloroform. The extract is washed (brine), dried (MgSO4) and evaporated to give 3,4-dihydro-N-formyl-1H-[1]benzothieno[2,3-c]pyran-1-methylamine, nmr (CDCl3) δ 3.16 and 4.95.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:23]([Si:27]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[O:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][CH:47]=1)[CH2:32][C@:33]1([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=O)([CH3:26])([CH3:25])[CH3:24].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:34]3[C@:33]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])([CH2:32][C:31]4[CH:45]=[CH:46][CH:47]=[C:29]([O:28][Si:27]([C:23]([CH3:26])([CH3:24])[CH3:25])([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:30]=4)[CH2:38][CH2:37][CH2:36][CH:35]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCCC2=O)c1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [Li]CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of (4,5-diphenyl)oxazole (17 g) in THF (100 ml) was added n-BuLi (57 ml, 1.6N-solution in hexane) at −78° C. After stirring for 30 minutes, a solution of (R)-1-[3-(tertbutyldiphenyl-silyloxy)benzyl]-1-trimethylsilyoxy-2-cyclohexanone (27 g) in THF (50 ml) was added to the above mixture at the same temperature. After stirring for 1 hour, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with 1N-HCl solution and brine. The organic solvent was evaporated in vacuo to give a residue. The residue was dissolved in toluene (100 ml) and then added with (methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide, inner salt(20.4 g) at room temperature. After refluxing under stirring for 5 hours, the reaction mixture was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (36 g).