Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([C:8]1C=C(NC(=O)NCC)N=C[C:9]=1[C:20](O)=[O:21])C1C=CC=CC=1.[NH:23]([C:30]1[CH:35]=[C:34]([NH:36][C:37](=[O:41])[NH:38][CH2:39][CH3:40])[N:33]=[CH:32][C:31]=1[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([I:51])=[CH:47][CH:46]=1)=[O:43])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C(O)C#C>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.[Cu]I.CN(C=O)C>[NH:23]([C:30]1[CH:35]=[C:34]([NH:36][C:37](=[O:41])[NH:38][CH2:39][CH3:40])[N:33]=[CH:32][C:31]=1[C:42]([NH:44][C:45]1[CH:46]=[CH:47][C:48]([I:51])=[CH:49][CH:50]=1)=[O:43])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:39]([NH:38][C:37]([NH:36][C:34]1[N:33]=[CH:32][C:31]([C:42]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:8]#[C:9][CH2:20][OH:21])=[CH:49][CH:50]=2)=[O:43])=[C:30]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:35]=1)=[O:41])[CH3:40]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(C#CCO)cc2)cn1
Temperature: 100 °C

Procedure:
4-anilino-6-(ethylcarbamoylamino)-N-(4-iodophenyl)pyridine-3-carboxamide (i) was prepared by coupling 4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid and 4-iodoaniline Compound (i) (50 mg, 0.10 mmol) and PdCl2(PPh3)2 (2.8 mg, 4.0 μmol) were placed in a 0.5-1.5 mL microwave vial and anhydrous DMF (1 mL) added, quickly followed by triethylamine (83 wok 0.60 mmol) and propargyl alcohol (17 μmol, 0.30 mmol). The solution was bubbled with argon for ˜3 minutes then CuI (0.38 mg, 2.0 μmol) was added. The vial was capped and mixture degassed then heated in the microwave at 100° C. for 30 minutes. The mixture was filtered on celite and then the filtrate concentrated in vacuo to give a residue that was purified by flash chromatography, eluting with methanol and DCM. The resulting product mixture was further purified by chromatography (reverse phase; ACN gradient in water), to afford Compound 135. 1H NMR (400 MHz, DMSO) δ 10.40 (br s, 1H), 9.84 (br s, 1H), 9.11 (br s, 1H), 8.57 (s, 1H), 7.94 (br s, 1H), 7.73 (br d, J=8.4 Hz, 2H), 7.45-7.36 (m, 4H), 7.27 (br d, J=7.8 Hz, 3H), 7.15 (m, 1H), 5.33-5.25 (m, 1H), 4.29 (d, J=5.0 Hz, 2H), 3.24-3.04 (m, 2H), 1.06 (t, J=7.2 Hz, 3H), [M+H]+ m/z=430.12.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH:19]1[CH2:21][CH2:20]1)[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:23][C@@H:24]1[CH2:28][C@@H:27]([C:29]([NH:31][C@:32]2([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C@H:33]2[CH:35]=[CH2:36])=[O:30])[NH:26][CH2:25]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH:19]1[CH2:21][CH2:20]1)[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]([N:26]1[C@H:27]([C:29]([NH:31][C@:32]2([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C@H:33]2[CH:35]=[CH2:36])=[O:30])[CH2:28][C@@H:24]([OH:23])[CH2:25]1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Reactant: C=CCCCN(C[C@@H](C(=O)O)C(=O)OC(C)(C)C)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CCCCN(C[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A solution of crude (S)-2-(tert-butoxycarbonyl)-3-(cyclopropyl(pent-4-enyl)amino)propanoic acid 1b (1.47 g, 4.71 mmoL) in 20 mL of DCM was treated sequentially with (1R,2 S)-ethyl 1-((3R,5S)-3-hydroxypyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride (1.44 g, 4.71 mmoL), N-methyl morpholine (1.80 mL, 16.3 mmoL), and HATU (2.14 g, 5.53 mmoL). The reaction mixture was stirred at rt under N2 for 3 h, and then concentrated in vacuo. The residue was dissolved in water, and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The combined organic phases were washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 1.55 g (58%) of (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(cyclopropyl(pent-4-enyl)amino)propanoyl)-3-hydroxypyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate 1c as a white foam: LC-MS (Phenomenex-Luna S10 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 1.38 min), MS m/z 564 (M++1).
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.ClCCl.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[CH2:2]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:6][N:5]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 20 L temperature controlled reactor charge tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (2.06 moles; 600.00 g) followed by dichloromethane (6.00 L), then triethylamine (4.33 moles; 604 mL) is added. Set the jacket of the reactor to 0° C. When the temperature of the reaction mixture reaches 5° C., add benzyl chloroformate (2.10 moles; 311 mL) over about 20 minutes keeping the internal temperature below 20° C. When the addition is complete, warm the jacket to room temperature and stir the mixture overnight. Pour the reaction mixture into water (4 L) and separate the mixture. Concentrate the organics under reduced pressure to give the title compound (838 g; assumed 95.65% purity and 100% yield for the purposes of calculation in the next reaction) mass spectrum (m/z): 411.2 (M+23).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:28]([Li])([CH3:31])([CH3:30])[CH3:29]>CCCCC>[C:28]([C:12]1([OH:15])[CH2:13][CH2:14][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: CCCCC
Product: CC(C)(C)C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 50 parts by volume of benzene under nitrogen atmosphere is added 30 parts of 1.6 M solution of tertiary-butyllithium in pentane. The resultant solution is stirred for about 24 hours and then quenched with the careful addition of 60 parts by volume of 10% ammonium chloride solution. After 1 hour, the organic layer is separated, washed with water and brine, dried with magnesium sulfate, and concentrated to give clear red oil. This oil is chromatographed on silica gel using successively methylene chloride and 10% ethanol-methylene chloride solution as eluents to give pale yellow solid which upon sublimation affords 4-tert-butyl-1-(2,2-diphenylethyl)-4-piperidinol. This compound melts at about 105°-110° C. and is represented by the following structural formula ##STR36##
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[C:31]([O:35][C:36]([NH:38][C@@H:39]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:16][CH3:17])[CH2:11][N:10]([C:40](=[O:41])[C@@H:39]([NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an iced slurry of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-2-carboxylate, TFA (174 mg, 0.394 mmol), (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (100 mg, 0.434 mmol), and HATU (225 mg, 0.591 mmol) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.207 mL, 1.182 mmol). The formed colorless slurry was stirred at room temperature overnight. Diluted with DCM, quenched with 5% citric acid. The organic layer was washed with 0.1 M NaOH and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with 5˜35% etOAc-hexane to yield the desired product (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylate (178 mg, 0.296 mmol, 75% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.12 (s, 9H), 1.46 (s, 9H), 1.86 (s, 3H), 2.60 (dd, J=12.97, 6.87 Hz, 1H), 2.90 (dd, J=12.82, 7.93 Hz, 1H), 3.74 (s, 3H), 4.11 (d, J=11.29 Hz, 1H), 4.35-4.48 (m, 2H), 4.73 (d, J=10.99 Hz, 1H), 7.36 (t, J=7.02 Hz, 1H), 7.42-7.51 (m, 3H), 7.54-7.71 (m, 5H). LC-MS (retention time: 3.34 min, method B), MS m/z 541 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:47]([O:49][C:50](=[O:55])[CH2:51][CH2:52][CH2:53][NH2:54])[CH3:48].CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.C1COCC1.CO>[CH2:47]([O:49][C:50](=[O:55])[CH2:51][CH2:52][CH2:53][NH:54][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4])[CH3:48]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.15 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (33 mg, 0.24 mmol), CH2Cl2 (3 mL), and EDC (53 mg, 0.28 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (41 mg, 0.24 mmol) and Hunig's base (0.1 mL, 0.56 mmol) were added, and the mixture was stirred for 48 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 39 mg of the title compound. MS: (+) m/z 492.44 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([CH3:67])=[C:61]([S:63](Cl)(=[O:65])=[O:64])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:61]1[N:62]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[S:59][C:60]=1[CH3:67])(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)c(C)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1nc(NC(C)=O)sc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (130 mg) was reacted with 2-acetylamino-5-methyl-thiazole-4-sulfonyl chloride (54 mg) to furnish (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z:. 965) according to General Procedure E. The title compound (16 mg) was prepared by the hydrolysis of (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (20 mg) using General Procedure B. LCMS (m/z): 952.
Reaction SMILES: [PH3:1]=[O:2].[C:3]1([Li])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C.CC(O)C.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[PH3:1]=[O:2].[C:3]1([PH:1](=[O:2])[C:22]2[CH:21]=[CH:20][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: [Li]c1ccccc1
Agent: O=[PH3]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=[PH](c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirred solution of phosphine oxide 10 (45 mg, 77 μmol) in anhydrous THF (600 μl) a 1.5 M solution of phenyl lithium in THF (75 μl, 105 μmol) was added at −20° C. under argon. The mixture was stirred for 20 min. and then cooled to −78° C. A precooled solution of 9 (6 mg, 33 μmol) in anhydrous THF (200 μl) was added via cannula and the reaction mixture was stirred for 3 h at −78° C. After that the reaction mixture was stirred at 4° C. overnight. Then ethyl acetate was added and organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on Waters silica gel Sep-Pack cartridge (hexane to 3% ethyl acetate/hexane) and then on HPLC (0.03% 2-propanol/hexane, 4 mL/min., Zorbax-silica 10×250 mm) to give 11.4 mg (21 mmol, 64% yield) of 11 at Rt=7.08 min. UV (hexane) λmax=242, 250, 261 nm; 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, s), 0.04 (3H, s), 0.07 (3H, s), 0.08 (3H, s), 0.80 (3H, d, J=6.8 Hz), 0.86 (9H, s), 0.89 (9H, s), 2.18 (1H, dd, J=12.4 Hz, J=7.7 Hz), 2.86 (1H, br d, J=13.8 Hz), 4.42 (1H, m), 4.93 (1H, s), 4.96 (1H, s), 5.93 (1H, d, J=11.2 Hz), 6.20 (1H, d, J=11.2 Hz); 13C NMR (100 MHz, CDCl3) δ −5.1, −4.9, −4.8, 18.2, 18,2, 18.3, 21.6, 24.6, 25.8, 25.8, 27.8, 28.9, 29.8, 31.9, 38.7, 47.5, 50.7, 50.8, 52.7, 71:9, 72.3, 106.3, 113.7, 122.4, 132.9, 143.7, 153.0; MS (EI) m/z 544 (3, M+), 448 (9), 412 (36), 366 (14), 313 (11), 290 (100); exact mass calculated for C33H60O2Si2 544.4132, found 544.4131.
Reaction SMILES: [CH3:1][C:2]12[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH:11]([NH:12]1)[C:4]1[CH:5]=[C:6]([O:9]C)[CH:7]=[CH:8][C:3]2=1.Cl.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][C:2]12[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH:11]([NH:12]1)[C:4]1[CH:5]=[C:6]([OH:9])[CH:7]=[CH:8][C:3]2=1
Reactant: COc1ccc2c(c1)C1Cc3ccccc3C2(C)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC12NC(Cc3ccccc31)c1cc(O)ccc12
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 98.1 %

Procedure:
A mixture of 8-methoxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1.75 g, 0.00696 mol) and pyridinium hydrochloride (10.5 g) is stirred at 190° for 2.5 hr. The melt is cooled to 50° C. and slurried with water (50 ml). The slurry is made basic with aqueous saturated NaHCO3 and extracted with ethyl acetate (3×50 ml). The combined extracts are dried over MgSO4 and filtered and the filtrate evaporated to dryness under reduced pressure to give 1.62 g (98%) of crude title compound. A sample recrystallized from ethyl acetate has m.p. 245°-247° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CC1
Yield: 55.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-methoxyphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.153 g, 0.317 mmol) obtained in step 5 and methanesulfonamide (0.175 g, 1.85 mmol), the title compound (0.099 g, 56%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:17]2[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=2)[CH:7]=[CH:8]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cccc2cc[nH]c12
Product: CC(=O)c1ccc(-c2cccc3cc[nH]c23)cc1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 4-acetylphenylboronic acid: ESMS m/e: 235.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:17]1[C:21](=[O:22])[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=[O:23])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (2 mmol, Example 1, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 70% yield.
Reaction SMILES: CC([N:5]([C@H:9]([CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]Br)=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.[NH2:33][C:34]1[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:33]=[C:34]3[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]3[CH:18]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: CC(O)c1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Yield: 174.7 %

Procedure:
A mixture of 1,1-dimethylethyl{(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH:11]=O)[CH2:9][CH2:8][C:7]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][CH3:21]>C1(C)C=CC=CC=1.C(OCC)C.C1COCC1>[CH3:19][N:20](/[CH:11]=[C:10]1\[C:2](=[O:1])[C:3]2[CH:4]=[N:5][N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH2:8][CH2:9]\1)[CH3:21]
Reactant: CNC
Reactant: O=CC1CCc2c(cnn2-c2ccccc2)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN(C)/C=C1/CCc2c(cnn2-c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 62.3 %

Procedure:
To a stirred solution of 4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carbaldehyde (1.1 g, 4.58 mol) in toluene (50 mL) and diethylether (25 mL) was added dimethylamine (3 mL, 6 mmol) as a solution in THF (10 mL). The reaction was stirred for at room temperature for 40 hours. The reaction was then concentrated under reduced pressure to give a brown residue, which was triturated with hexane to give the desired product (1 g, 80%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δδ 7.91 (s, 1H), 7.59-7.53 (m, 4H), 7.45-7.42 (m, 1H), 7.36 (s, 1H), 3.07 (s, 6H), 2.95 (s, 4H); LCMS [M+H]: 267.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:14]=[C:13]([C:24]([O-:26])=[O:25])[C:12]=2[CH3:27])[CH3:10])=[CH:4][CH:3]=1.[Li+].[OH-].C1COCC1.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:14]=[C:13]([C:24]([OH:26])=[O:25])[C:12]=2[CH3:27])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=Cc1ccc(Cl)cc1)c1c(C)c(C(=O)[O-])nn1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=Cc1ccc(Cl)cc1)c1c(C)c(C(=O)O)nn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.3 %

Procedure:
The mixture of 46e (3.34 mmol, 1.5 g), LiOH (13.3 mmol, 319 mg), THF (7 mL), MeOH (7 mL), and H2O (37 mL) was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl to pH=5 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give 46f (202 mg).