Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].C[Al](C)C.CO[C:17](=O)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>ClC(Cl)C.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:17]1[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:2]
Reactant: COC(=O)Cn1ccnc1-c1ncccn1
Reactant: CCNc1ccncc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CCn1c(Cn2ccnc2-c2ncccn2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of N4-ethyl-pyridine-3,4-diamine (Justus Liebigs Ann. Chem. (1935) 518, 274, 287) (125 mg, 0.9 mmol) in dichloroethane (10 mL) is added a solution of AlMe3 in toluene (2M, 1.37 mL) dropwise under nitrogen. After addition, the mixture is stirred at room temperature for one hour and (2-pyrimidin-2-yl-imidazol-1-yl)-acetic acid methyl ester (100 mg, 0.45 mmol) is added in one portion. The reaction mixture is heated with stirring at 80° C. for 2 days. After cooled, the mixture is quenched with 5 mL of water, 2 drops of 5 N NaOH and extracted with CH2Cl2 (10 mL×5). The combined organic extracts are dried over Na2SO4, and concentrated. The residue is dissolved in 10 mL of acetic acid and the resulting mixture is heated at 100° C. overnight. After removal of acetic acid under vacuum, the residue is basified with saturated NaHCO3 solution and extracted with CH2Cl2 (10 mL×5). The combined organic extracts are dried over Na2SO4, and concentrated. The residue is purified on a silica gel column with 10:1 CH2Cl2/MeOH as eluent to yield the title compound (40 mg). 1H NMR (CDCl3) δ: 9.09 (s, 1H), 8.85 (d, 2H), 8.46 (d, 1H), 7.26-7.30 (m, 3H), 7.16 (1H), 6.39 (s, 2H), 4.25 (q, 2H), 1.15 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.[ClH:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]2[C@@H:34]3[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]3)[C:28](=[O:35])[N:27]([CH:36]3[CH2:41][CH2:40][N:39](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:38][CH2:37]3)[N:26]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[ClH:14].[ClH:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]2[C@@H:34]3[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]3)[C:28](=[O:35])[N:27]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([C:9]5[N:10]=[N:11][S:12][CH:13]=5)=[CH:5][CH:4]=4)[CH2:38][CH2:37]3)[N:26]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: BrCc1ccc(-c2csnn2)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4ccc(-c5csnn5)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from starting compound A1 and 4-(4-Bromomethyl-phenyl)-[1,2,3]thiadiazole as described for compound 18. M.p. 243-245° C.
Reaction SMILES: [Na].[OH:2][S:3]([C:6]([F:9])([F:8])[F:7])(=O)=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>>[F:7][C:6]([S:3]([C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=1[Cl:17])=[O:2])([F:9])[F:8]
Reactant: Clc1cccc(Cl)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Product: O=S(c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Sodium triflinate (2.37 g, 15 mmol), then 6 equivalents of triflic acid (21.65 g, 144 mmol), after stirring for a few minutes, more than one equivalent of 1,3-dichlorobenzene (3.22 g, 22 mmol) and finally one equivalent of triflic anhydride (4.32 g, 15 mmol) are introduced into a three-necked flask surmounted by a reflux condenser with a silica gel guard under an inert argon atmosphere. The mixture is stirred for 10 h at ambient temperature. It is hydrolyzed with a water-ice mixture (5 g) and then neutralized with a saturated sodium hydrogencarbonate solution to a pH of 6. The mixture is extracted with diethyl ether. The organic phase is dried and evaporated and the residue is recrystallized from pentane (the brown oils are purified by chromatography). White crystals are obtained (m=2.9 g, Yd=70%).
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:29]=[CH:28][C:12]([C:13]([NH:15][C@@H:16]([CH2:24][CH2:25][S:26][CH3:27])[C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:11]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:29]=[CH:28][C:12]([C:13]([NH:15][C@@H:16]([CH2:24][CH2:25][S:26][CH3:27])[C:17]([OH:19])=[O:18])=[O:14])=[C:11]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSCC[C@H](NC(=O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of tert-butyl (2S)-2-{4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate (0.2 g; 0.4 mmol) in dichloromethane (2 ml) was treated at 0° C. with TFA (2 ml). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. After evaporation of the solvent, the residue was taken up with distilled water (5 ml); the pH was adjusted to 6 with NH4OH and the solution was purified on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g/l; pH 7) (40/60) to give the title compound after freeze-drying. Yield: 40%
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([N:7]1[C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH2:3][C@H:2]1[CH3:1])(=[O:20])[CH3:19]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Reactant: CC(=O)Cl
Product: CC(=O)N1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2)C[C@@H]1C

Procedure:
The title compound was prepared from (3R,5S)-3,5-dimethyl-1-(4-nitrophenyl)piperazine (Method 27, 16 g, 68.027 mmol) and acetyl chloride (8.22 ml, 115.65 mmol) by the procedure of Method 26. It was obtained as a solid which was dried in vac oven overnight at 50° C. (20.5 g, 109%, contaminated with solvent). NMR (400 MHz) 1.19 (brd, 6H), 2.08 (s, 3H), 3.21 (brd, 2H), 4.00 (d, 2H), 4.34 (v brs, 2H), 7.08 (d, 2H), 8.06 (d, 2H); m/z 278.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([O:25]C)=[O:24])[CH:5]=[C:6]([Br:21])[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)(=[O:10])=[O:9]>[OH-].[Na+]>[Br:21][C:6]1[CH:5]=[C:4]([CH2:22][C:23]([OH:25])=[O:24])[CH:3]=[C:2]([Br:1])[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:19])[CH3:20])[CH:12]=1)(=[O:9])=[O:10]
Reactant: COC(=O)Cc1cc(Br)c(S(=O)(=O)c2ccc(O)c(C(C)C)c2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(S(=O)(=O)c2c(Br)cc(CC(=O)O)cc2Br)ccc1O
Yield: 96.2 %

Procedure:
A suspension of methyl 3,5-dibromo-4-(4-hydroxy-3-isopropylphenylsulfonyl)phenylacetate (2.7 g, 0.0053 mol), from Example 2, in 30 mL sodium hydroxide (5%) was heated at 60° C. for 10 min. The reaction mixture was cooled and extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid (6N) and extracted with ethyl acetate (2X). The combined extract was washed with water and brine and dried (Na2SO4). The residue obtained after removal of the solvent was crystallized from hexane-ethyl acetate to obtain 3,5-dibromo-4-(4-hydroxy-3-isopropylphenylsulfonyl)phenylacetic acid (2.5 g, 0.0051 mol, 96% yield), MP: 171°-172° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:25]=[CH:24][N:23]=2)=[N:27]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 45.6 %

Procedure:
A mixture of methyl thiosalicylate (0.61 g, 3.7 mmol), 4-tert-butoxycarbonylamino-2-cyanopyridine (0.80 g, 3.7 mmol), triethylamine (0.80 ml, 5.7 mmol) and toluene (2.0 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and dried to give the titled compound (0.60 g, 49%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH2:31][CH2:32]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: COCCN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCN1CCN(c2c(C(=O)N(C)OC)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C
Yield: 53.3 %

Procedure:
A stirred mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.120 g, 0.301 mmol), 1-(2-methoxyethyl)piperazine (0.0522 g, 0.362 mmol, from Aldrich), palladium acetate (1 mg, 0.006 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.14 g, 0.42 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane, and filtered. The filtrate was washed with brine, dried over sodium sulfate, and evaporated to dryness. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (63 mg, 53%). LCMS calculated for C19H26ClN4O3(M+H)+: m/z=393.2; found: 393.1.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].CS(O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)(=O)=O>CN(C=O)C>[CH2:1]([S:3][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 0.20 ml (2.6 mmol) of ethanethiol in 7 ml of DMF was added 0.11 g (2.7 mmol) of sodium hydride. The mixture was stirred at 0° C. for 30 min, then 0.50 g, (1.7 mmol) of the title compound from Step A was added. The solution was allowed to stir for 2 h and then quenched with 50 mL of a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a light brown solid that was used without further purification. 1H-NMR (500 MHz, CDCl3) δ 4.00 (s, 2H), 2.90 (m, 2H), 2.82 (m, 1H), 2.58 (q, J=7 Hz, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.45 (s, 9H), 1.29 (t, J=5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]([O:17][CH2:18][N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH:29]C(=O)C)=[N:23][C:24]=2[OH:28])[CH2:8][O:9]CC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].C1CCCCC=1>[Pd].C(O)C>[NH2:29][C:22]1[N:21]=[C:20]2[C:25]([N:26]=[CH:27][N:19]2[CH2:18][O:17][CH:7]([CH2:8][OH:9])[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:24]([OH:28])[N:23]=1
Reactant: CCCCOCC(COCc1ccccc1)OCn1cnc2c(O)nc(NC(C)=O)nc21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCCOCC(CO)OCn1cnc2c(O)nc(N)nc21
Reaction time: 36 h
Yield: 8.7 %

Procedure:
A mixture of N-[9-[[1-(butoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-6-hydroxy-9H-purin-2-yl]acetamide (1.15 g, 25.9 mmol), 20% palladium on carbon (0.2 g), cyclohexene (20 ml), and ethanol (10 ml) is heated at reflux under N2. After 8 and 2O hours, additional amounts of catalyst (0.1 g) are added. After 36 hours, the solution is cooled, filtered through celite, and the filter cake is washed with DMF/ethanol. The filtrates are combined, refiltered and concentrated. The residue is mixed with aq. methyl amine (20 ml) and the mixture is heated at reflux for two hours, filtered and concentrated. The residue is recrystallized from water to give the desired product (0.7 g), mp 208°-211° C.
Reaction SMILES: [O:1]([C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[NH:10][C:11](OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]>O1CCCC1>[CH3:11][NH:10][C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Oc1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Product: CNc1ccccc1Oc1ccccc1
Temperature: 65 °C
Yield: 94.4 %

Procedure:
To a solution of 2-phenoxy-N-(t-butoxycarbonyl)aniline (1.43 g, 5.0 mmol) in anhydrous tetrahydrofuran (50 ml) was added lithium aluminumhydride (10 ml, 10.0 mmol, 1.0 M solution in tetrahydrofuran) at −10° C. The mixture was then refluxed at 65° C. overnight. The reaction mixture was quenched with slow addition of MeOH (10 ml) and concentrated under reduced pressure. The reaction mixture was then poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). Organic extracts were combined and washed with brine (2×100 ml) and dried over (Na2SO4), concentrated under reduced pressure to give N-methyl-2-phenoxyaniline (0.94 g, 94.0%) as a pale yellow oil. The product was confirmed by LC-MS and subjected to next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:14])([SH:13])[CH3:12]>>[CH3:10][C:11]([CH3:14])([S:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:12]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)(C)S
Product: CC(C)(C)Sc1ccccc1C=O

Procedure:
reacting 2-chlorobenzaldehyde with 1,1-dimethylethanethiol in the presence of a base to form 2-(1,1-dimethylethylthio)benzaldehyde;
Reaction SMILES: Cl.[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23]([O:11][C:10](=[O:12])[CH:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:20][CH:19]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:22]2
Reactant: O=C(O)C(NCc1ccc(F)cc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
A mixture of (4-fluoro-benzylamino)-phenyl-acetic acid hydrochloride (233 mg, 0.79 mmol), (R)-quinuclidin-3-ol (200 mg, 1.57 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (596 mg, 1.57 mmol), TEA (0.22 mL, 1.57 mmol) and HOBT (241 mg, 1.57 mmol) in acetonitrile (10 mL) is stirred at RT for 48 hours. THF is removed under vacuum and the crude is partitioned between EtOAc and water. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The crude is purified by preparative HPLC. The combined fractions are dried and partitioned between EtOAc and 2M K2CO3. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness to achieve the title compound as colorless oil (61 mg, 21% yield, mixture of diastereoisomers).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](I)[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)(C)(C)C>>[Cl:1][C:2]1[CH:11]=[C:10]([Si:18]([CH3:21])([CH3:20])[CH3:14])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(I)cc(Cl)c2cccnc12
Product: C[Si](C)(C)c1cc(Cl)c2cccnc2c1O

Procedure:
The title compound is prepared in two steps from 5-chloro-8-hydroxy-7-iodo-quinoline, which is commercially available, according to the procedures described in Preparation 11 and Example 41, substituting trimethylchlorosilane for t-butyldimethylchlorosilane in the former procedure. Column chromatography (elution with 0-1% EtOAc/hexane) gives 0.147 g of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=3[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:31])[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]1
Reactant: O=C=NC1CC=CCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2
Product: O=C(NC1CC=CCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepin-7-sulfonamide and 3-cyclohexen-1-ylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-(3-cyclohexen-1-yl)-3-{[2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepin-7-yl]sulfonyl}urea, m.p. 211°-212° C.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25]C)=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:22][O:21][C:20]1[C:3](=[O:2])[C:4]([CH3:27])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:18](=[O:25])[C:19]=1[O:23][CH3:24]
Reactant: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Yield: 99.9 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-methoxybenzoic acid (0.257 g, 0.684 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.937 g, 1.71 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.237 g, 0.683 mmol, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:16]=[N:15][C:9]2[O:10][CH2:11][C:12](=[O:14])[NH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:17]C([O-])(C)C.[K+].CI.O>CN(C)C(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:16]=[N:15][C:9]2[O:10][CH2:11][C:12](=[O:14])[N:13]([CH3:17])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1cnc2c(c1)NC(=O)CO2
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cnc2c(c1)N(C)C(=O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid ethyl ester (1.518 g) in N,N-dimethylacetamide (15 ml) were added KOtBu (0.843 g) and methyl iodide (1.067 g). The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (0.936 g) as a brown solid.
Reaction SMILES: BrC1C(F)=CC2OCC(F)C3SC(C(OCC)=O)=[N:11]C=3C=2C=1.C([C@]1(O)CCN(C)C1=O)#C.[F:33][CH:34]1[C:43]2[S:42][C:41]([C:44]([O:46]CC)=O)=[N:40][C:39]=2[C:38]2[CH:49]=[C:50]([C:54]#[C:55][C@:56]3([OH:63])[CH2:60][CH2:59][N:58]([CH3:61])[C:57]3=[O:62])[C:51]([F:53])=[CH:52][C:37]=2[O:36][CH2:35]1>>[F:33][CH:34]1[C:43]2[S:42][C:41]([C:44]([NH2:11])=[O:46])=[N:40][C:39]=2[C:38]2[CH:49]=[C:50]([C:54]#[C:55][C@:56]3([OH:63])[CH2:60][CH2:59][N:58]([CH3:61])[C:57]3=[O:62])[C:51]([F:53])=[CH:52][C:37]=2[O:36][CH2:35]1
Reactant: CCOC(=O)c1nc2c(s1)C(F)COc1cc(F)c(Br)cc1-2
Reactant: CCOC(=O)c1nc2c(s1)C(F)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCC(F)c2sc(C(N)=O)nc2-3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic ethyl 9-bromo-4,8-difluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of ethyl 4,8-difluoro-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) a diasteromeric mixture of the titled compounds was obtained after purification by prep HPLC.
Reaction SMILES: C(OC([N:8]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](Br)[CH:31]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]([CH3:26])=[CH2:25])[C:9]1=[O:34])=O)(C)(C)C.N1C2C(=CC=CC=2)[CH2:37][C:36]1=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH:11]([C:24]([CH3:26])=[CH2:25])[C:10]32[C:27]2[C:32](=[CH:31][C:30]([C:36]#[CH:37])=[CH:29][CH:28]=2)[NH:8][C:9]3=[O:34])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c(c1)NC(=O)C21C(C(=C)C)NC(=O)CC1c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
A mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester-1,3-dihydro-indole-2-one (54 mg, 0.1 mmol) prepared in example 173a, Pd(PPh3)4 (20 mg, 0.02 mmol), K3PO4 (110 mg, 0.5 mmol), dimethyl trimethylsilylethynylborate (1 mL, 0.5 M, 0.5 mmol) in toluene (3 mL) was heated under microwave irradiation at 130° C. for 1 hour. The solvent was removed in vacuo. To the residue was added methanol (3 mL) and aqueous NaOH (2 N, 3 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, the residue was diluted with ethyl acetate (20 mL), washed with brine, saturated NH4Cl, brine, then organic layer was separated, and concentrated. The residue was purified by preparative HPLC to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-ethynyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (2 mg).