Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:22][C@H:21]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][C@H:15](C(OC(C)(C)C)=O)[C:14](=[O:30])[N:13]1[C@@:9](N)([CH2:10][C@@H:11]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=4)[N:35]=[C:34]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:33]=3)[CH2:12]1)[C:8](=[O:51])[NH:7]2)=[O:5])C.[Li+].[OH-:53]>C1COCC1.O.CO>[C:6]([O:53][C:14]([NH:13][C@@H:15]1[C:14](=[O:30])[N:13]2[C@@H:9]([CH2:10][C@@H:11]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=4)[N:35]=[C:34]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:33]=3)[CH2:12]2)[C:8](=[O:51])[NH:7][C@@:6]2([C:4]([OH:3])=[O:5])[C@@H:21]([CH2:22]2)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1)=[O:30])([CH3:22])([CH3:21])[CH3:4]
Reactant: [OH-]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCC[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@@]1(N)C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C/CCC[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@@]1(N)C(=O)N2
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C/CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1

Procedure:
Following the experimental and purification procedure of Step 1i, (1S,4R,6S,12S,16R)-7-trans-12-tert-butoxycarbonyl-amino-16-(7-methoxy-2-phenylquinolin-4-yloxy)-2,13-dioxo-3,14-diazatricyclo-[12.3.0.04,6]heptadec-7-ene-4-carboxylic acid ethyl ester (185 mg, 0.265 mmol) was reacted with 64 mg (1.6 mmol) of LiOH in 15.5 mL of 9:5:1.5 of THF/H2O/MeOH to afford (1S,4R,6S,12S,16R)-7-trans-12-tert-butoxycar-bonyiamino-16-(7-methoxy-2-phenylquinolin-4-yloxy)-2,13-dioxo-3,14-diazatricyclo[12.3.0.04,6]heptadec-7-ene-4-carboxylic acid (180 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 1.24 (s, 9H), 1.33-1.43 (m, 1H), 1.61-1.97 (m, 6H), 2.10 (brs, 1H), 2.28-2.36 (m, 1H), 2.70 (m, 2H), 3.94 (s, 3H), 4.17 (d, J=10.6 Hz, 1H), 4.28 (d, J=4.8 Hz, 1H), 4.65-4.70 (m, 1H), 5.34 (dd, J=15.7, 5.9 Hz, 2H), 5.53-5.62 (m, 2H), 7.14 (d, J=9 Hz, 1H), 7.32 (s, 1H), 7.39 (s, 1H), 7.56 (m, 3H), 8.01-8.02 (m, 2H), 8.22 (d, J=9.2 Hz, 1H). LC-MS (Method E-retention time: 1.49), MS m/z 671 (M++1). HRMS m/z (M+H)+ calcd for C37H43N4O8: 671.3081, found 671.3080. Step 3j: Preparation of Compound 3, Example 3 (1S,4R,6S,12S,16R)-7-trans-[4-Cyclopropanesulfonyl-aminocarbonyl-16-(7-methoxy-2-phenylquinolin-4-yloxy)-2,13-dioxo-3,14-diazatricyclo[12.3.0.04,6]heptadec-7-en-12-yl]carbamic acid tert-butyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[N:8]([CH3:20])[C:9]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:11]=3[CH2:12][S:13][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[N:8]([CH3:20])[C:9]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:11]=3[CH2:12][S:13][C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cc1cc2c(n1C)C(=O)c1ccc(Cl)cc1SC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CC(=O)O)cc2c1C(=O)c1ccc(Cl)cc1SC2

Procedure:
Ethyl 7-chloro-4,10 dihydro-1-methyl-10-oxo-1H-[1]benzothiepino[4,3-b]pyrrole-2-acetate (73 mg, 0.21 mmol) is dissolved in hot ethanol (2 ml) and 2.5 N aqueous sodium hydroxide (1 ml, 2.5 mmol) is added. The mixture is heated to 70° and stirred until it becomes homogeneous. Stirring is continued an additional fifteen minutes, then the mixture is cooled and treated with 2.5 N aqueous HCl (1.5 ml) to precipitate 58 mg (86%) of 7-chloro-4,10 dihydro-1-methyl-10-oxo-1H-[1]benzothiepino [4,3-b]pyrrole-2-acetic acid, m.p. 202° (dec).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15](C3C=CN=C(N4CC5C=CN=CC=5C4=O)C=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1SC2C(C3C=CC(Cl)=CC=3)=C([C@H](OC(C)(C)C)C(OCC)=O)C(C)=CC=2N=1.[CH3:72][C:73]1[CH:74]=[C:75]2[C:79](=[CH:80][CH:81]=1)[NH:78][CH2:77][CH2:76]2.C1C2C=CN=CC=2C(=O)N1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([N:78]3[C:79]4[C:75](=[CH:74][C:73]([CH3:72])=[CH:81][CH:80]=4)[CH2:76][CH2:77]3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1ccc2c(c1)CCN2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: O=C1NCc2ccncc21
Product: Cc1ccc2c(c1)CCN2c1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2s1

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-methylindolin-1-yl)benzo[d]thiazol-6-yl)acetic acid was prepared in similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid except (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate was used instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate, 5-Methylindoline was used instead 1H-pyrrolo[3,4-c]pyridin-3(2H)-one and Pd(P-tBu3)2 was used instead of Pd2(dba)3. LCMS-ESI+: C29H30ClN2O3S: 521.2 (M+H+); Found: 521.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ: 7.75 (s, 1H), 7.67-7.64 (m, 1H), 7.57-7.50 (m, 3H), 7.44 (s, 1H), 7.12 (d, 1H), 6.84 (d, 1H), 5.17 (s, 1H), 4.07 (dd, 2H), 3.19 (dd, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41].N1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:40](=[O:42])[CH3:41])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic anhydride, pyridine and dimethylaminopydriine in methylene chloride to give the title compound.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([NH:16][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: O[C@@H](CNC1CC1)c1ccc2nnnn2c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 652 mg (11.4 mmol) of cyclopropyl amine in 0.9 ml of absolute ethanol in a sealed reaction tube was heated at 100° C. for 3 hours. The reaction mixture was concentrated to dryness to yield 452 mg of crude product. Chromatography on silica gel (90:10:1 methylene chloride:methanol:conc. ammonium hydroxide) afforded 356 mg of product, m.p. 137°-39°.
Reaction SMILES: [N:1]([C:4]([F:8])([F:7])[CH2:5][OH:6])=[N+:2]=[N-:3].Br[C:10](F)(F)[C:11](OCC)=[O:12].[N-]=[N+]=[N-].[Na+]>CS(C)=O>[N:1]([C:4]([C:5]([O:12][CH2:11][CH3:10])=[O:6])([F:8])[F:7])=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: [N-]=[N+]=NC(F)(F)CO
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)N=[N+]=[N-]

Procedure:
The preparation of 2-azido-2,2-difluorethanol can be summarized as follow: ##STR1## The ethyl 2-bromo-2,2-difluoroacetate, CBrF2COOCH2CH3, starting material is available from chemical laboratory supply houses. The ethyl 2-bromo-2,2-difluoroacetate used in example 1 was obtained from PCR, Inc., P.0. Box 1466, Gainesville, Fla. 32602. The ethyl 2-bromo-2,2-difluoroacetate reacts with sodium azide, NaN3, in dry dimethyl sulfoxide at room temperature (20° C.) to produce ethyl 2-azido-2,2-difluoroacetate, N3CF2COOCH2CH3. The reaction conditions are illustrated in example 1. Next, the ethyl 2-azido-2,2-difluoroacetate reacted with sodium borohydride, NaBH4, in water to produce the desired 2-azido-2,2-difluoroethanol, N3CF2CH2OH. The reaction conditions are illustrated in example 2. The reactivity of 2-azido-2,2-difluoroethanol is demonstrated by example 3 in which the alcohol reacts with phenylisocyanate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:14]=[C:13]([C:15](F)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1[NH2:10].[OH-].[Na+]>O1CCCC1>[CH3:7][C:8]1[CH:14]=[C:13]([CH:15]([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])[CH:12]=[CH:11][C:9]=1[NH2:10]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(C(F)(F)F)C(F)(F)F)ccc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 221.6 %

Procedure:
To 30 ml of tetrahydrofuran (THF) was added 0.5 g (13.2 mmol) of lithium aluminum hydride. While keeping the resulting suspension at a temperature of 0° C., a solution of 13.8 g (20 mmol) of 2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline in 20 ml of THF was dropped into the suspension with stirring over a period of 15 minutes. After completion of the dropping, the resulting mixture was stirred at room temperature for 30 minutes, and then heated under reflux for one hour to make progress a reaction. The reaction mixture was poured into ice water, 20 ml of 1N-aqueous solution of sodium hydroxide was added, and the resulting mixture was stirred. The mixture was extracted with 50 ml of methyl tert-butyl ether, the organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by distillation under reduced pressure. Thus, 11.4 g (yield: 89%) of 2-methyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (Compound No. 1-3) was obtained as a fraction having a boiling point of 103° C. (6 mmHg). (1-2) In 10 ml of acetonitrile was dissolved 750 mg (2.0 mmol) of N-(1,1-dimethyl-2-methylthioethyl)-6-iodophthalic acid isoimide, to which were added 515 mg (2.0 mmol) of 2-methyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline and 10 mg of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours. The deposited crystal was collected by filtration and washed with a small quantity of ether. Thus, 1.0 g of the objective compound was obtained (yield: 79%).
Reaction SMILES: [CH2:1]([C:3]1([C:9]([CH2:11]C#N)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]>Cl>[C:9]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:10])[CH3:11]
Reactant: CCC1(C(=O)CC#N)CCCCC1
Agent: Cl
Product: CCC1(C(C)=O)CCCCC1

Procedure:
To 180 g. of (1-ethylcyclohexylcarbonyl)-acetonitrile was added 1 liter of 12 N hydrochloric acid, and the mixture was stirred under reflux for 2.5 hours and was cooled. The mixture was then extracted with one 1000 ml. and one 500 ml. portion of pentane, and the organic layers were combined, dried over magnesium sulfate and concentrated under vacuum at a temperature near 30°. The desired product was found to co-distill, in part, with the solvent, and so the vacuum and temperature were carefully watched to avoid excessive loss of the product, which was identified by its molecular ion in mass spectroscopic analysis, 154. Its boiling point was 44°-45° at 0.4 torr.
Reaction SMILES: C(N1C2C([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=5)[NH:24][CH:23]=4)[CH2:17][CH2:16]3)=CC=CC=2NC1=O)(C)=C.[C:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38](CCCl)[C:37]1=[O:48])([CH3:35])=[CH2:34].FC1C=C2C(=CC=1)NC=C2CC1CCNCC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[C:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][CH:23]=3)[CH2:19][CH2:20]2)[C:37]1=[O:48])([CH3:35])=[CH2:34]
Reactant: C=C(C)n1c(=O)[nH]c2cccc(CCN3CCC(Cc4c[nH]c5ccc(F)cc45)CC3)c21
Reactant: C=C(C)n1c(=O)n(CCCl)c2ccccc21
Agent: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 10 h

Procedure:
3-Isopropenyl-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one may be prepared in the following manner: the procedure is as in Example 25, starting with 3-isopropenyl-1-(2-chloroethyl)-2H-benzimidazolin-2-one (2.4 g), 4-[(5-fluoro-3-indolyl)methyl]piperidine (2.3 g) and sodium bicarbonate (0.8 g) in a mixture of dimethylformamide (40 cc) and tetrahydrofuran (20 cc). The mixture is heated to boiling for 10 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen and moderate pressure (0.5-1.5 bar) with dichloromethane and ethyl acetate as eluents, 3-isopropenyl-1-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one (3 g), m.p. 132° C., is obtained.
Reaction SMILES: I[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:4][C:3]=1[F:20].[O:21]1[CH2:26][CH2:25][O:24][CH2:23]C1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]1[C:26](=[O:21])[CH:4]=[CH:3][C:2]([C:2]2[C:7]([F:8])=[CH:6][C:5]([N:9]3[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]3=[O:19])=[CH:4][C:3]=2[F:20])=[CH:7][CH:6]=1
Reactant: C1COCCO1
Reactant: CC(=O)NCC1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2c(F)cc(N3CC(CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Yield: 28 %

Procedure:
The (±)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl]methyl ]acetamide (250 mg, 0.631 mmol) was dissolved in 1,4-dioxane (15 mL) and then treated with the stannyltropone (226 mg, 0.757 mmol). After degassing the solution 3 times with N2, the bis(triphenylphosphine)palladium(II) chloride (70 mg, 0.10 mmol) was added. The solution was degassed again (3×) and then it was heated to reflux (110° C.) for 7 h. At this point, the reaction was incomplete; fresh catalyst (70 mg, 0.10 mmol) was added, and after degassing again (3×), the solution was again heated to reflux for 7 h. At this time, the solvent was removed in vacuo and the residual oil was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with aqueous KF (40 mL) and brine (40 mL). After drying over anhydrous Na2SO4, the organic layer was filtered and concentrated under reduced pressure to yield a foamy, brown solid. This solid was chromatographed on silica gel (100 g), eluting with a gradient of 0-10% MeOH in 10% CH3CN/CHCl3 to give impure product. This product was repurified by preparative TLC (5% MeOH/CHCl3) to yield 72 mg (28%) of the title compound as an off-white solid with mp 218° C. (dec) and identical in all respects to material prepared as described above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(Nc1ccccc1)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 73.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxy-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.96 mmol) and aniline (97 μL, 1.061 mmol) to give 274 mg of the title compound (74%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (s, 1H), 10.45 (s, 1H), 7.59 (d, 2H, J=7.5 Hz), 7.34 (t, 2H, J=7.5 Hz), 7.23 (d, 1H, J=1 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.07 (d, 1H, J=1 Hz), 5.31 (dd, 1H, J=10, 5 Hz), 4.32 (d, 2H, J=5.6 Hz), 3.78 (dd, 1H, J=17, 10 Hz), 3.35 (dd, 1H, J=17, 5 Hz),
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[C:26]([NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:39][CH:38]=3)[CH2:33][CH2:32]2)=[O:27])[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CO>[C:18]([C:9]1[CH:8]=[C:7](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[C:26]([NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:39][CH:38]=3)[CH2:33][CH2:32]2)=[O:27])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:19])([CH3:20])[CH3:21]
Reactant: COCCOCOc1c(C(C)(C)C)cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1C(C)(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(C(C)(C)C)c1O
Yield: 65.3 %

Procedure:
To a solution of 1-[2-[5-[3,5-di-tert-butyl-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoylamino]ethyl]-4-(3-indolyl)piperidine (0.5 g) in methanol (5 ml) was added dropwise methanesulfonic acid (0.26 ml) at 18°-25° C. After 2 hours the reaction mixture was adjusted to pH 7.5 with 2N-sodium hydroxide and then poured into saturated sodium bicarbonate solution (50 ml). The resulting precipitate was collected and washed with water. The precipitate was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (20:1, V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from 1,4-dioxane, to give white crystals of 1-[2-{5-(3,5-di-tert-butyl-4-hydroxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (0.28 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH:7]=[CH:8][CH2:9]Br.[CH3:16][NH2:17]>O1CCCC1>[CH3:16][NH:17][CH2:9]/[CH:8]=[CH:7]\[CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1]
Reactant: Fc1ccc(Br)cc1COCC=CCBr
Reactant: CN
Solvent: C1CCOC1
Product: CNC/C=C\COCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 250 ml flask 4-(2-fluoro-5-bromobenzyloxy)but-2-enyl bromide (1.968 g, 5.89 mmol) was dissolved in dry tetrahydrofuran (40 5 ml). To this solution methylamine (29.5 ml, 58.9 mmol) was added in one portion and the resulting mixture was stirred at ambient temperature for five hours. The progress of the reaciton was monitored by thin layer chromatography. The solvents were removed in vacuo and the residue was taken up in 1 M potassium carbonate and extracted thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:12][S:11][N:10]=2)[CH2:3]1.ClCCl.C(N(CC)CC)C.[N:32]([C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)=[C:33]=[O:34]>CCOC(C)=O>[F:42][C:41]([F:43])([F:44])[C:39]1[CH:40]=[C:35]([NH:32][C:33]([N:7]2[CH:6]([CH3:8])[CH2:5][N:4]([C:9]3[C:13]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:12][S:11][N:10]=3)[CH2:3][CH:2]2[CH3:1])=[O:34])[CH:36]=[C:37]([C:45]([F:48])([F:46])[F:47])[CH:38]=1
Reactant: CC1CN(c2nsnc2OCc2ccncc2)CC(C)N1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CN(c2nsnc2OCc2ccncc2)CC(C)N1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
3,5-dimethyl-1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine (104 mg, 0.34 mmol), dichloromethane (1.0 mL), triethylamine (0.10 mL, 0.43 mmol), and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (0.075 ml, 0.43 mmol) are combined and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with H2O (1×), sat'd NaHCO3 (2×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 63 mg (33%) of 2,6-dimethyl-4-[(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CDCl3) 8.67 (d, 2H), 7.91 (s, 2H), 7.53 (s, 1H), 7.36 (d, 2H), 6.74 (s, 1H), 5.51 (s, 2H), 4.31 (m, 2H), 4.10 (d, 2H), 3.11 (dd, 2H), 1.47 (d, 6H) ppm. LC-MS (MH+)=561.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=3)[C:7]=12
Reactant: Cc1ccc(CCl)cc1
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: Cc1ccc(Cn2c(C)c(C)c3ccnc(Cl)c32)cc1
Yield: 75 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 4-methylbenzyl chloride, the titled compound was obtained as a white solid. (Yield: 75%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH:20][S:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]([CH3:30])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:38](I)[CH:39]([CH3:41])[CH3:40].C(OCC)(=O)C.O>CN(C)C(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[S:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]([CH3:30])[CH:5]=1
Reactant: CC(C)CI
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccc(C)o2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)C)S(=O)(=O)c2ccc(C)o2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-[2-[N-(5-methyl-2-furylsulfonyl)amino]4,5-dimethylphenoxymethyl]benzoic acid methyl ester prepared in Reference Example 3 (870 mg) in N,N-dimethylacetamide (2 ml), cesium carbonate (1.37 g) and isobutyl iodide (0.36 ml) were added and the mixture was stirred for 1 hour at 100° C. The reaction mixture was allowed to cool and poured into ethyl acetate-water (40 ml-40 ml). The organic layer was washed, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (toluene-ethyl acetate) to give the title compound (855 mg) having the following physical data.