Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:20])([F:19])[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.[CH2:21](O)[CH3:22]>>[F:6][C:7]([F:19])([F:20])[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])=[CH:13][CH:14]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(OC(F)(F)F)cc1
Yield: 91 %

Procedure:
Sulfuric acid (0.484 ml, 9.08 mmol) was added dropwise to a solution of 2-(4-(trifluoromethoxy)phenyl)acetic acid (2.0 g, 9.08 mmol) in ethanol (20 ml), and heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml), washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 0/100 to 20/80) to give ethyl 2-(4-(trifluoromethoxy)phenyl)acetate (2.06 g, yield 91%) as yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Br:26]N1C(=O)CCC1=O>ClCCl>[Br:26][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCn1cc(Br)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Yield: 6.5 %

Procedure:
In a 50 mL pear flask was added (R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (13, 125 mg, 0.368 mmol) in dichloromethane (3.7 ml). At 0° C., 1-bromopyrrolidine-2,5-dione (66 mg, 0.37 mmol) was added to the mixture, and the mixture was kept in the refrigerator over the weekend. After concentration in vacuo, the crude product was purified by preparatory HPLC (TFA mode, 15-65% ACN/water). Combined fractions were neutralized by NaHCO3, concentrated and extracted into EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The residue was then re-suspended in ACN and water, and then freeze dried to give the desired product (R)-N-(3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (20, 10 mg, 7%) as a light orange powder. 1H NMR (DMSO-d6) δ 10.62 (s, 1 H), 8.50 (s, 1 H), 8.36 (s, 1 H), 7.97-8.05 (m, 2 H), 7.70 (s, 1 H), 7.54-7.61 (m, 2 H), 5.00 (s, 1 H), 4.71 (t, J=5.8 Hz, 1 H), 4.21 (d, J=7.1 Hz, 2 H), 3.46 (dd, J=5.8, 2.3 Hz, 2H), 1.42 (s, 4 H), 1.39 (t, J=7.2 Hz, 3 H); ESI-MS: m/z 418 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.I[CH:12]([CH3:14])[CH3:13]>>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CC(C)I
Reactant: Cc1cc(O)ccc1C=O
Product: Cc1cc(OC(C)C)ccc1C=O
Yield: 75.7 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 2-iodopropane (100 μL, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 2-methyl-4-isopropoxybenzaldehyde (54 mg, 76%). Used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:20])[C:17](Cl)=[O:18].[CH3:28][NH2:29].O.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:20])[C:17]([NH:29][CH3:28])=[O:18]
Reactant: CC(C(=O)Cl)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A solution of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetyl chloride (0.007 mol) in CH2Cl2 (20 ml) was added at RT to methanamine 40% in water (0.105 mol). The mixture was stirred at RT for 4 hours, then poured out into water, acidified with HCl (3N) and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 1.25 g (43%) of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,N-dimethylbenzeneacetamide (comp. 1.14).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][NH2:6])[CH2:3][NH2:4].[C:8](#[N:11])[CH:9]=[CH2:10]>C(O)C>[NH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][NH:6][CH2:10][CH2:9][C:8]#[N:11]
Reactant: CC(C)(CN)CN
Reactant: C=CC#N
Solvent: CCO
Product: CC(C)(CN)CNCCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 2,2 dimethyl-1,3-propanediamine (0.22 mol) and 2-propenenitrile (0.22 mol) in ethanol (250 ml) was stirred overnight at room temperature. The solvent was evaporated. A mixture of 2,2-dimethyl-1,3-propanediamine (0.28 mol) and 2-propenenitrile (0.28 mol) in ethanol (250 ml) was stirred for one hour at room temperature. The solvent was evaporated. The residues were combined. This fraction was purified by distillation, yielding 27.2 g of 3-[(3-amino-2,2-dimethylpropyl)amino]-propanenitrile (intermediate 11).
Reaction SMILES: I[Si](C)(C)C.C[O:7][CH2:8][CH2:9][N:10]1[C:14]([CH2:15][CH2:16][C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[N:13][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:11]1.CO.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([CH2:16][CH2:15][C:14]3[N:10]([CH2:9][CH2:8][OH:7])[N:11]=[C:12]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:13]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: COCCn1nc(-c2ccccc2)nc1CCc1nc2c(C)ncc(C)n2n1
Agent: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3CCO)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodotrimethylsilane (92.0 uL, 0.646 mmol) was added to a stirred solution of 2-{2-[2-(2-Methoxy-ethyl)-5-phenyl-2H-1,2,4-triazol-3-yl]-ethyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (61 mg, 0.16 mmol) in Chloroform (5 mL) under an atmosphere of Argon at rt. The solution was stirred at rt 4 h. More Iodotrimethylsilane (184 uL, 1.29 mmol) was added and the mixture was stirred at rt ON. MeOH (10 ml) and solid sodium sulfite (0.5 g) was added and the mixture was stirred 30 min, filtered and evaporated. The crude product was purified by silica gel chromatography (Eluent: 0-5% MeOH in EtOAc). Yield: 27 mg (46%) of the title compound as a solid. LC-MS: m/z=364.5 (MH+), tR=1.30 min, Method C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[Cl:51][C:52]1([C:67]([O:69][CH3:70])=[O:68])[CH2:57][CH2:56][C:55](B2OC(C)(C)C(C)(C)O2)=[CH:54][CH2:53]1>>[Cl:51][C:52]1([C:67]([O:69][CH3:70])=[O:68])[CH2:57][CH2:56][C:55]([C:7]2[C:8]([CH3:48])([CH3:47])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:46])([C@@:13]4([CH3:45])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:37][CH2:36]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:54][CH2:53]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1(Cl)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(Cl)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in general procedure Step 5, using (1R,3 aS,5aR,5bR,7aR,11aR,11bR,13 aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diastereomers, which was used in next step without purification. MS: m/e 771.5 (M+H)+, 3.06 min (method 4).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[NH2:26].Cl.[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:6]=1[NH:26][N:28]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=N[O-]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(F)cc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-fluoro-6-(naphthalene-1-sulfonyl-methyl)-phenylamine (0.91 g, 2.31 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.16 g, 2.4 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.2 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NC(=O)C(CC)c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of 2-(4-methoxyphenyl)butanoic acid (135 mg, 0.70 mmol) and ethyl 2-aminothiazole-5-carboxylate (100 mg, 0.58 mmol) in DMF were added DIEA (112 mg, 0.87 mmol) and HATU (264 mg, 0.70 mmol). The reaction was stirred at room temperature for 4 hrs and partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The residue was purified by biotage column chromatography to afford ethyl 2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxylate (163 mg).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])[CH:8]=2)[N:3]=1.CCCCCCC>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH2:32])(=[O:31])=[O:30])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(N)(=O)=O)ccc2n1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
1 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-N-tert-butylbenzenesulfonamide is dissolved in 10 ml of trifluoroacetic acid and stirred at 22° C. for 16 h. 10 ml of n-heptane are subsequently added and evaporated to dryness in vacuo. The crude product obtained in this way is purified by column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h
Yield: 89 %

Procedure:
tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (5.0 g, 18.58 mmol, 1 eq) was dissolved in ethanol (20 ml) and degassed for 30 min with nitrogen. Pd—C (500 mg, 10%) was added, and hydrogenation was carried out for 12 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and washed with ethanol (200 ml), and the filtrate was concentrated under reduced pressure. Yield: 89% (4.5 g, 16.6 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C@H:15]1([OH:22])[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.[H-].[Na+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:21][CH:18]2[CH2:19][CH2:20][CH:15]([OH:22])[CH2:16][CH2:17]2)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
4-Fluoro-1-nitro-2-trifluoromethyl-benz ene (11.5 mmol), trans-cyclohexane-1,4-diol (17.2 mmol), and sodium hydride (60% in oil, 11.5 mmol) are suspended in dry dimethylsulfoxide (20 mL) and the resulting mixture is reacted under stirring for 3 hours at 50° C. The reaction is allowed to reach room temperature and is then further reacted at this temperature overnight. The reaction is treated with water (20 mL), the precipitate formed is removed by filtration and the filtrate is extracted with dichloromethane (50 mL). The organic phase is washed with aqueous saturated ammonium chloride (10 mL), dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The precipitate is triturated with diethylether (20 mL), filtered and the filtrate concentrated under reduced pressure. Both fractions of crude product are combined, dissolved in dichloromethane and filtered trough a short pad of silica gel to afford the desired product (36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:36].[H][H]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:36]
Reactant: [H][H]
Reactant: O=C(NCC/C=C\c1ccccc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Agent: O=[Pt]=O
Agent: [Na+]
Solvent: CO
Product: O=C(NCCCCc1ccccc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of sodium (Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate (0.16 g, 0.31 mmol) in methanol (2 mL) was added platinum(IV) oxide (0.018 g, 0.079 mmol), and to the resulting stirred mixture at ambient temperature was fitted a balloon of hydrogen. The flask was purged and refilled five times with hydrogen, and the resulting mixture was stirred at ambient temperature under a balloon of hydrogen for 30 minutes, by which time the catalyst had clumped up. The methanol supernatant was decanted away from the catalyst with a pipet and concentrated, and the residue concentrated from diethyl ether to afford sodium 6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate as a white glass (142 mg, 87% yield). MS (apci) m/z=514.1 (M+2H-Na).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:35])[N:20]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:21]3=[O:26])=[O:15])=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:35])[N:20]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:6]([NH2:5])=[O:7])[CH2:31][CH2:30]2)[C:21]3=[O:26])=[O:15])=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: ClCCl
Product: NC(=O)N1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At room temperature, 0.18 ml of trimethylsilyl isocyanate are added dropwise to a suspension of 50 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide in 2.5 ml of absolute dichloromethane. The mixture is stirred at room temperature for 48 h and then, after concentration, chromatographed on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[C:24]([CH:25]([F:27])[F:26])=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[C:24]([CH:25]([F:26])[F:27])=[CH:23][N:22]=[C:21]([C:45]4[CH:44]=[C:43]5[C:48](=[CH:47][CH:46]=4)[N:40]([CH3:39])[N:41]=[CH:42]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3C(F)F)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)ncc3C(F)F)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A microwave vial containing (S)-ethyl 2-(tert-butoxy)-2-(2-(2-chloro-5-(difluoromethyl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate (44 mg, 0.076 mmol) was charged with (1-methyl-1H-indazol-5-yl)boronic acid (26 mg, 0.15 mmol), then Pd(PPh3)4 (18 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (1.0 mL) and to this was added 2M aqueous K2CO3 (0.15 mL, 0.30 mmol). The vial was sealed, heated to 120° C. for 3 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10-40% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C36H34ClF2N4O3S: 675.2 (M+H+); Found: 675.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:31]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 113, 48.0 mg, 0.10 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 42.0 mg (93%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 3-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].O1CCCC1.C[O-].[Na+].[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:20][CH2:19][Cl:18]
Reactant: COc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1OCCCl
Yield: 67.2 %

Procedure:
24.83 g (0.2 mole) of o-methoxyphenol and 100 ml of tetrahydrofuran were placed in a 500 ml-flask equipped with a stirring device and a cooling pipe. A solution in which sodium methoxide (0.2 mole) was dissolved in methanol was added to the flask while stirring the contents. Then tetrahydrofuran and methanol were eliminated at reduced pressure. 300 ml of tetrahydrofuran was added to the flask and then 46.94 g (0.2 mole) of 2-chloroethyl-p-toluene sulfonate was added thereto. The mixture was then stirred under heating reflux for 20 hours to promote reaction. After reaction, insoluble matters were eliminated by filtration, and the product was condensed at reduced pressure. The reaction mixture was then refined by column chromatography using silica gel, and 25.1 g of 2-(o-methoxyphenoxy)ethyl chloride was produced.