Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(C=O)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Yield: 65.5 %

Procedure:
A solution of (E)-3-styryl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (63 mg, 0.166 mmol) in THF (2.0 mL) was treated with TBAF (0.83 mL of a 1M solution in THF) and refluxed overnight. The solvent was removed and the residue re-dissolved into EtOAc. The organics were washed with water (2×), brine (2×) and then dried (MgSO4). The solvent was removed and the residue purified by column chromatography (silica gel, 98:2 CH2Cl2/MeOH) to give the title compound (27 mg, 66%) which was used without further purification. MS ESI 249.0 [M+H]+, calcd for [C16H12N2O+H]+ 249.10.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)OC(C)(C)C)=[C:11]([NH:23][C:24]2[N:29]=[C:28]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:27]([N+:37]([O-])=O)=[CH:26][N:25]=2)[CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[CH:16][N:23]([C:24]3[N:29]=[C:28]4[C:27]([N:37]=[CH:1][N:30]4[CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)[C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Reactant: O=C(O)C(F)(F)F
Product: Fc1ccc2ncn(-c3ncc4ncn(C5CCOCC5)c4n3)c2c1

Procedure:
The title compound as a TFA salt was synthesized from tert-butyl 4-fluoro-2-(5-nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-ylamino)phenylcarbamate via the procedure described in Example 15. 1H NMR (300 MHz, CDCl3): δ 9.73 (s, 1H), 9.29 (s, 1H), 8.5-8.6 (m, 1H), 8.40 (s, 1H), 7.9-8.1 (m, 1H), 7.3-7.4 (m, 1H), 4.8-5.0 (m, 1H), 4.2-4.4 (m, 2H), 3.7-3.8 (m, 2H), 3.05 (d, 1H), 2.2-2.4 (m, 3H). 19F NMR: δ −112.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][C:19]([O:33][CH3:34])=[C:20]([O:31][CH3:32])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>C(O)C.O1CCOCC1>[ClH:35].[ClH:35].[CH3:32][O:31][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:33][CH3:34])[N:16]=[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:24]=[C:23]2[N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCOCC3)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc2nc(NC3CCNCC3)nc(N3CCOCC3)c2cc1OC

Procedure:
A solution of 4-(6,7-dimethoxy-4-morpholin-4-yl-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.45 g, 5.18 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 374.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[C:5]([C:7]2[S:23][C:10]3[C:11]4[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][C:12]=4[O:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[N:6]=1.[Cl-].[NH4+].C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[C:5]([C:7]2[S:23][C:10]3[C:11]4[CH:19]=[CH:18][C:17]([C:20]([NH2:34])=[O:21])=[CH:16][C:12]=4[O:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[N:6]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(-c2ccccc2Cl)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3nc(N)sc3-c3ccccc3Cl)sc1-2

Procedure:
Following Example 47, 2-(2-amino-5-(2-chlorophenyl)thiazol-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid and ammonium chloride were coupled with HATU and DIPEA in DMF to give 268.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:22])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.O.[F-].[K+].[Br-].[Na+]>FC(F)(F)C1C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:22])[C:14]([C:26]3[CH:27]=[CH:28][O:24][CH:25]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Agent: [Pd]
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Solvent: FC(F)(F)c1ccccc1
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Temperature: 175 °C
Yield: 66.2 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 52, 0.39 g), furan-3-yl boronic acid (0.16 g), potassium fluoride monohydrate (0.45 g), tetrakis-(triphenylphosphine) palladium (0.11 g), and sodium bromide (0.15 g) in α,α,α-trifluorotoluene (10 ml) and dioxane (2 ml) was degassed and heated in the microwave at 175° C. for 30 minutes. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 15-30% to give ethyl 6-benzenesulphonylmethyl-3-(furan-3-yl)-2-hydroxybenzoate (0.25 g) as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]1[CH2:19][C@H:18]([O:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
4-Dimethylaminopyridine (2.28 g) and p-toluenesulfonyl chloride (2.66 g) were added to a cold (0° C.) stirred solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline methyl ester (J, 2.76 g) in dichloromethane (50 mL). After stirring at room temperature for 16 hr, the solvent was removed in vacuo. The residue was diluted with ethyl acetate, and washed with 0.5 M saturated citric acid, water, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (3.10 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.35-1.52 (m, 9H), 2.30-2.53 (m, 2H), 2.46 (s, 3H), 3.51-3.78 (m, 2H), 3.68-3.69 (s, 3H), 4.30-4.56 (m, 1H), 5.00-5.09 (m, 1H), 7.32-7.38 (m, 1H), and 7.74-7.79 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[S:5]1(=[O:22])=[O:21].[CH3:23][C@H:24]1[CH2:29][NH:28][CH2:27][C@@H:26]([CH3:30])[NH:25]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:3][CH2:2][N:28]3[CH2:27][C@H:26]([CH3:30])[NH:25][C@H:24]([CH3:23])[CH2:29]3)[S:5]2(=[O:22])=[O:21])=[C:14]([CH3:20])[CH:15]=1
Reactant: Cc1cc(Cl)ccc1N1c2ccccc2N(CCBr)S1(=O)=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1cc(Cl)ccc1N1c2ccccc2N(CCN2C[C@@H](C)N[C@@H](C)C2)S1(=O)=O

Procedure:
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared using 1-(2-bromoethyl)-3-(4-chloro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cis-2,6-dimethyl piperazine analogous to the conditions used general procedure V.
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.[Na].[CH:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[CH:21][CH:20]=1)=O>C1COCC1>[CH:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[CH:21][CH:20]=1)=[CH2:1]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To the solution of Ph3PCH3Br (75 mg, 0.21 mmol) in THF (4 mL) was added sodium hexamethyldisilazane (NaHMDS) (1 N, 0.21 mL, 0.21 mmol) at −78° C. After stirring at this temperature for 30 min, Compound 100 (70 mg, 0.21 mmol) was added. The reaction solution was allowed to warm up to room temperature and stirred overnight. The solution was quenched with NH4Cl (20 mL) and extracted with EtOAc (30 mL). The organic portion was collected, dried and concentrated. Column chromatography afforded Compound 101 (42 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.63-7.51 (m, 3H), 7.45-7.38 (m, 1H), 7.26-7.15 (m, 2H), 7.04-6.97 (m, 2H), 6.45 (dd, J=17.4 and 11.1 Hz, 1H), 5.14 (d, J=17.4 Hz, 1H), 4.86 (d, J=11.4 Hz, 1H), 2.37-2.29 (m, 4H), 1.79-1.72 (m, 4H); ESMS cacld (C21H13F2NO): 339.1; found: 340.1 (M+H).
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([S:27]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=3)(=[O:28])=[O:29])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A solution of 4-piperidone ethylene ketal (1.28 ml, 10 mmol) and triethylamine (1.4 ml, 10 mmol) in ethyl acetate (20 ml) was treated with a dropwise addition of 4-nitro-phenylsulphonyl chloride (1.4 ml, 10 mmol) in ethyl acetate (20 ml) and stirred at room temperature for 2 h. The mixture was washed with water, dilute HCl, saturated sodium bicarbonate solution and brine, dried over sodium sulphate and evaporated to leave the title compound as a solid (2.8 g), MS (+EI) 328 (M+), 1H NMR (CDCl3) 8.38 (2H, d, J 8.8 Hz), 7.96 (2H, d, J 8.8 Hz), 3.90 (4H, s), 3.22 (4H, t, J 5.7 Hz), 1.80 (4H, t, J 5.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41](=O)[C:42]([F:45])([F:44])[F:43])[CH:35]=[CH:34]3)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C(Cl)Cl.C([BH3-])#N.[Na+]>CO.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH:9][CH:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([O:30][CH:27]3[CH2:28][CH2:29][CH:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:25][CH2:26]3)[CH:32]=2)[CH:37]=1)[C:42]([F:43])([F:44])[F:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C(=O)C(F)(F)F)ccc3c2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Amino-propionic acid tert-butyl ester (106 mg, 0.727 mmol) was combined with N,N-Diisopropylethylamine (575 uL, 3.30 mmol) and 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethanone (250 mg, 0.66 mmol) in Methylene chloride (4 mL, 60 mmol). 1 M of Titanium(IV) chloride in Methylene chloride (727 uL, 0.727 mmol) was added and the mixture was stirred at RT for 5 hours. TLC (20% EtOAC/Hex) shows only traces of SM with new lower Rf spot. The reaction was cooled to 0° C. and Sodium cyanoborohydride (208 mg, 3.30 mmol) in methanol (5 mL) was added carefully in two portions (lots of bubbling so remove cap.) The reaction was then diluted with 10 mL DCM and the solids were removed via filtration. pH was adjust to 10 with 1 M NaOH and the reaction was extracted three times with methylene chloride. Organics were combined and dried over MgSO4. Solids were removed via filtration and the crude reaction was absorbed onto silica (1 g) and purified via column chromatography on 12 g SiO2 using a gradient of 0-15% Ethylacetate/hexane to give material that was impure by NMR and LCMS (compound eluted around 1% EtOAc.) Material was repurified on 24 g ISCO gold column using a long gradient of 0-10% EtOAc/Hex over 30 minutes (desired compound was 2nd major peak) to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1([C:16](=[O:17])NC(=O)[NH:13]1)[CH2:8][CH2:7][CH2:6]2.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(=O)([O-])[O-:31].[NH4+].[NH4+]>O>[NH2:13][C:9]1([C:16]([OH:17])=[O:31])[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: COc1ccc2c(c1)CCCC21NC(=O)NC1=O
Reactant: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCCC2(N)C(=O)O
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a suspension of 2.95 g (0.012 mol) of the product of Step A in 100 mL of water was added 15.1 g (0.0479 mol) of barium hydroxide octahydrate. The reaction was heated at reflux for 3 days. To the reaction mixture was carefully added 6.4 g (0.067 mol) of ammonium carbonate. Refluxing was continued for another 2 hours. The solid was filtered off while hot and the pH of the filtrate adjusted to 6. The filtrate was then concentrated to give 1.86 g of a tan solid: mp>250° C. 1H NMR (D2O) d 7.20 (d, 1H), 6.85 (d and s, 2H), 3.835 (s, 3H), 2.85 (t, 2H), 1.70-2.40 (m, 4H).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8](=[O:37])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32]C)[C:24]=2[CH2:34][CH2:35][CH3:36])[CH:13]=1)=[O:10])[CH3:6].O>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:37])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=2[CH2:34][CH2:35][CH3:36])[CH:13]=1)=[O:10])[CH3:6]
Reactant: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OCC)c2)ccc(C(C)=O)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OCC)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In the course of 5 minutes 3.0 g of boron tribromide are added dropwise to a solution, cooled to -78° C., of 2.2 g of N-{3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-phenyl}-oxamic acid ethyl ester in 20 ml of methylene chloride. The whole is then stirred for 6 hours at room temperature. While cooling, 5 ml of water are added and the organic phase is separated off and concentrated by evaporation under reduced pressure. After recrystallisation from methylene chloride/ether there is obtained N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-phenyl}-oxamic acid ethyl ester, which can be characterised by hydrolysis to form the free acid having a melting point of 159°-160°.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:39]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:18]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[C:35]([F:38])([F:37])[F:36])=[CH:25][CH:24]=5)[O:20][N:19]=4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:39][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[C:13]([C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]([F:38])([F:37])[F:36])=[CH:25][CH:24]=4)[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3c(-c4noc(-c5ccc(-c6ccccc6C(F)(F)F)cc5)n4)cccc32)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: NC(CO)(CO)CN1CCc2c(-c3noc(-c4ccc(-c5ccccc5C(F)(F)F)cc4)n3)cccc21
Yield: 71 %

Procedure:
When the product of Step E was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 71% yield, as a creamy solid. 1H-NMR (CD3OD+CDCl3) 3.1 (s, 2H); 3.35-3.6 (m, 8H); 4.1 (HDO); 6.76 (d, 1H, J=7.8 Hz); 7.17 (tr, 1H, J=7.8 Hz); 7.33 (tr, 1H, J=7.5 Hz); 7.41-7.51 (m, 4H); 7.57 (tr, 1H, J=7.3 Hz); 8.19 (d, 2H, J=8.3 Hz).
Reaction SMILES: [S].[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1>C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:19]
Reactant: CCOC(=O)CC1CCCc2ccc(OC)cc21
Agent: [S]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc2ccc(OC)cc12
Temperature: 215 °C
Reaction time: 10 h
Yield: 103.9 %

Procedure:
17.6 g sulfur and 90 g ethyl (7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-acetate were added into the reaction flask and heated to 215° C. with stirring. The reaction was carried out for 10 hours. After completion of the reaction, the reaction system was cooled to 60° C. 500 ml ethyl acetate was added and the mixture was stirred for 30 minutes. The mixture was filtered and the filter cake was washed with 100 ml ethyl acetate. Then, the filtrate was combined and vacuum evaporated to obtain 92 g brown oil with 82.4% content (HPLC). The yield is 85%.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: Nc1ccccc1I
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccccc2I)cc1

Procedure:
The subject compound was prepared utilizing the procedure described above from 4-isothiocyanatobenzenesulfonamide and 2-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.60 (s, 1H), 7.90-7.81 (m, 8H), 7.76 (bs, 2H); (M+H)+ (434).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21]C)=O)[C:13](OC)=[O:14].FC(F)(F)C([NH2:27])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.O>[S:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:17][CH2:18][C:19](=[O:21])[NH:27][C:13]1=[O:14]
Reactant: NC(=O)C(F)(F)F
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3ccccc3C2=S)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.4 %

Procedure:
A mixture of compound 208 (81 mg, 0.276 mmol), trifluoroacetamide (57 mg, 0.50 mmol), 1-hydroxybenzotriazole (145 mg, 1.07 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (200 mg, 1.04 mmol) and triethylamine (0.21 mL, 1.51 mmol) in CH2Cl2 (1.5 mL) was stirred at ambient temperature for 3 days. Water (10 mL) and CH2Cl2 (10 mL) were added. The dichloromethane layer was separated, washed with water, dried over Na2SO4 and evaporated under reduced pressure. Purification by chromatography, with EtOAc:CH2Cl2 (1:10) as the eluent, gave compound 212 (48 mg, 63%) as a red solid: mp 255° C.; 1H NMR (CDCl3) δ 8.00-7.98 (m, 1H), 7.80-7.71 (m, 3H), 5.63 (br, 1H), 2.98-2.70 (m, 3H), 2.18-2.15 (m, 1H); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([C:16](O)=[O:17])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>O1CCCC1>[CH:19]1([C:11]2([CH2:16][OH:17])[CH2:10][CH:9]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(CO)(C1CCCCC1)C2
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 8-(tert-butoxycarbonyl)-3-cyclohexyl-8-azabicyclo[3.2.1]octane-3-carboxylic acid (3-2) (1.47 g, 4.35 mmol) in 50 mL of anhydrous tetrahydrofuran was added borane-methyl sulfide complex (8.70 mL, 17.4 mmol, 2.0 M in tetrahydrofuran) dropwise at room temperature. The mixture was stirred at 50° C. for 48 hours and the volatiles were removed under vacuum Purification of the crude residue by flash chromatography over silica gel (50% ethyl acetate/hexanes as eluent) afforded (3-3) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:50]1[CH2:51][CH2:52][N:47]([C:46](=[O:53])[CH2:45][O:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:48][CH2:49]1)(=[O:18])[CH3:16]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 88 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 88% yield. LCMS for C25H27ClN7O3 (M+H)+: m/z=508.0.