Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:31])[CH2:5][N:6]1[CH2:11][CH2:10][C@H:9]2[CH2:12][C@@H:13]([C:26]([O:28]CC)=[O:27])[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C@H:8]2[CH2:7]1)[CH3:2].C1COCC1.O.[OH-].[Li+]>O>[CH2:1]([NH:3][C:4](=[O:31])[CH2:5][N:6]1[CH2:11][CH2:10][C@H:9]2[CH2:12][C@@H:13]([C:26]([OH:28])=[O:27])[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C@H:8]2[CH2:7]1)[CH3:2]
Reactant: CCNC(=O)CN1CC[C@H]2C[C@@H](C(=O)OCC)N(S(=O)(=O)c3ccc(OC)cc3)[C@H]2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)CN1CC[C@H]2C[C@@H](C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl rel-(2S,3aS,7aR)-6-[2-(ethylamino)-2-oxoethyl]-1-[(4-methoxyphenyl)sulfonyl]octahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate under step a) (62 mg, 0.13 mmol) was made in 1:1 THF:H2O (20 vols). Lithium hydroxide monohydrate (65.5 mg, 1.56 mmol) was added and the reaction stirred at room temperature for 18 hours. The THF was removed in vacuo, and the aqueous layer extracted with EtOAc (3×10 mL). The organic extracts were collected, dried over magnesium sulfate and filtered. The solvent was then removed in vacuo, before being placed on a high vacuum line for 2 hours. The product was used in the next step with no further purification.
Reaction SMILES: [NH:1]1[CH:9]2[CH:4]([N:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[NH:34][CH:35]=[CH:36][C:29]=12>CN1C(=O)CCC1>[NH:34]1[C:30]2=[N:31][CH:32]=[CH:33][C:28]([N:1]3[CH:9]4[CH:4]([N:5]([C:10]([O:12][CH2:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[O:11])[CH2:6][CH2:7][CH2:8]4)[CH2:3][CH2:2]3)=[C:29]2[CH:36]=[CH:35]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C(OCc1ccccc1)N1CCCC2NCCC21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(OCc1ccccc1)N1CCCC2C1CCN2c1ccnc2[nH]ccc12
Temperature: 160 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product of Example 1, Step 1 (136 mg, 0.524 mmol) in NMP (0.262 mL), in a microwave vial, was added Et3N (0.073 mL, 0.52 mmol) and 4-chloro-1H-pyrrolo[2,3-b]pyridine (16 mg, 0.11 mmol). The resulting solution was heated at 160° C. for 2 hours in a Biotage Initiator microwave. An additional 4 equivalents of 4-chloro-1H-pyrrolo[2,3-b]pyridine (64 mg, 0.42 mmol) was added to the reaction mixture and the resulting solution was stirred at 160° C. for another 2 hours in a Biotage Initiator microwave. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc (50 mL) and saturated sodium bicarbonate (50 mL). The layers were separated, and the organic layer was collected, dried over sodium sulfate and concentrated in vacuo to afford a crude oil that was purified by reverse phase HPLC. Lyophilization of the product fractions afforded the title compound (TFA salt) as a white solid. LRMS calc'd for C22H25N4O2 [M+H]+, 377; found 377. Jak1 activity: +.
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:7][CH2:6][CH:2]1[CH2:1][O:5][CH2:4][O:3]1)(=[O:18])=[O:17]
Reactant: OCC1COCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1COCO1

Procedure:
The glycerol formal (Aldrich, 0.26 g, 2.5 mmol), triethylamine (1.1 mL, 8.3 mmol), and methanesulfonyl chloride (0.30 mL, 3.7 mmol) in 20 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH2:16]([O:19][N:20]=[C:21]([C:45]1[N:46]=[C:47]([NH:50]C(OC(CC)(C)C)=O)[S:48][CH:49]=1)[C:22]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:23])[CH:17]=[CH2:18]>>[CH2:16]([O:19][N:20]=[C:21]([C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1)[C:22]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:23])[CH:17]=[CH2:18]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)OC(C)(C)CC)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were added under ice-cooling to 7-[2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g.) and the mixture was stirred for 40 minutes at ambient temperature. The reaction mixture was post-treated according to a similar manner to that of Example 17 to give 7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.425 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[C:16](=[N:18]O)[CH3:17].N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[CH:16]([NH2:18])[CH3:17]
Reactant: CC(=NO)c1ccc(Oc2ccccc2Cl)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)c1ccc(Oc2ccccc2Cl)cc1Cl
Temperature: 25 °C

Procedure:
1.8 g (6.08 mmol) of 1-[2-chloro-4-(2-chloro-phenoxy)-phenyl]-ethanone-oxime was dissolved in 50 mL methanol and 50 mL 7M methanolic ammonia were added, followed by 400 mg Raney nickel. The mixture was shaken at RT and 50 psi hydrogen pressure. The catalyst was suction filtered and the filtrate was evaporated down. The residue was purified by chromatography (silica gel column, dichloromethane:methanol=50:1 to 9:1)
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:1]1([C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[CH2:9][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(F)(F)F)cc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A 100 mL round-bottom flask was charged with 2-(morpholin-4-yl)-4-(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.650 g, 3.51 mmol, 0.91 equiv), dichloromethane (15 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (2.23 g, 10.5 mmol, 2.73 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with dichloromethane (15 mL). The organic layers were washed with H2O (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to yield 1.30 g (78% yield) of tert-butyl 4-[[2-(morpholin-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 430 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.COC(=O)C1C=CN=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccncn2)noc1C
Agent: COC(=O)c1ccnc(OCc2c(-c3ccccc3)noc2C)c1
Product: Cc1onc(-c2ccncn2)c1C(=O)O
Yield: 74.5 %

Procedure:
As described for example 58b, 5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid ethyl ester (500 mg, 2.1 mmol) was converted, instead of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid methyl ester, to the title compound (321 mg, 73%) which was obtained as an off white solid. MS: m/e=204.1 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:32]([O-:46])([O:34][CH2:35][C@@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40]O)=[O:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([O:13][CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:35][O:34][N+:32]([O-:46])=[O:33])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=[N+]([O-])OC[C@H](CCCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)OCCCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 12 h

Procedure:
To a dichloromethane (20 mL) solution of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (1.76 g, 3.72 mmol), (2S)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 3, 0.83 g, 3.72 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.85 g, 4.46 mmol), and 1-hydroxybenzotriazole (0.68 g, 4.46 mmol) was added N-methylmorpholine (1.84 mL, 16.7 mmol), followed by N,N-dimethylaminopyridine (4.5 mg, 0.04 mmol). After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Purification of the reaction mixture by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound. 1H NMR (500 MHz, CD3CN) δ 7.69 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 5.63 (s, 2H), 5.34-5.41 (m, 1H), 4.83 (dd, J=2.5, 12.8 Hz, 1H), 4.58 (dd, J=6.2, 13.0 Hz, 1H), 4.25 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 1.79 (q, J=7.5 Hz, 2H), 1.71 (quintet, J=6.8 Hz, 2H), 1.48-1.60 (m, 4H), 1.28 (sextet, J=7.4 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); LC-MS: m/z 643 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([OH:16])=[C:6]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+](C1C=C(S(O[CH2:47][C@@H:48]2[CH2:50][O:49]2)(=O)=O)C=CC=1)([O-])=O>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])=[CH:4][C:5]([O:16][CH2:47][CH:48]2[CH2:50][O:49]2)=[C:6]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(C)[Si](Oc1cc(O)c(NC(=O)C2CCCC2)cc1Cl)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1cc(OCC2CO2)c(NC(=O)C2CCCC2)cc1Cl)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 17.8 %

Procedure:
N-{5-chloro-2-hydroxy-4-[(triisopropylsilyl)oxy]phenyl}cyclopentanecarboxamide (140 mg, 0.3 mmol) was dissolved in 1,4-dioxane (20 mL). Caesium carbonate (170 mg, 0.5 mmol) was added, followed by (2S)-oxiran-2-y-methyl 3-nitrobenzenesulfonate (90 mg, 0.3 mmol). After stirring over night at room temperature the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and concentrated. Purification by HPLC on C18 (Xterra, 5 um, 19×50 mm; acetonitrile/water 60/40 to 100/0 over 15 min) yielded 25 mg (17%) of the titled intermediate compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.N1(O)C2C=CC=CC=2N=N1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:12])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(SCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(SCc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
A solution of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid (500 mg, 1.47 mmol, 1.00 equiv), EDCI (340 mg, 1.78 mmol, 1.21 equiv), 1H-1,2,3-benzotriazol-1-ol (240 mg, 1.78 mmol, 1.21 equiv), pyridin-3-ylmethanamine (190 mg, 1.76 mmol, 1.19 equiv) and triethylamine (450 mg, 4.46 mmol, 3.02 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of an ice/water mixture. The precipitate was collected by filtration, washed with 3×10 mL of hexane and 4×10 mL of 66% aqueous methanol to give 0.33 g (52%) of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 471 [M+CH3CN+H]+, 430 [M+H]+, 347, 306. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.22-9.20 (s, 1H), 8.57 (s, 1H), 8.46 (d, 1H), 8.02-7.97 (t, 4H), 7.75-7.73 (d, 1H), 7.38-7.35 (t, 1H), 7.30-7.28 (d, 2H), 7.14-7.13 (d, 2H), 4.52-4.51 (d, 2H), 4.07 (s, 2H), 2.27 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]12[CH2:17][CH2:16][C@@H:15]([C:18]3([CH3:21])[O:20][CH2:19]3)[CH2:14][C:13]1=[C:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][CH2:9]2>CCOCC>[CH3:7][C:8]12[CH2:17][CH2:16][C@@H:15]([C:18]([OH:20])([CH3:19])[CH3:21])[CH2:14][C:13]1=[C:12]([CH2:22][CH2:23][CH3:24])[CH:11]([OH:25])[CH2:10][CH2:9]2
Reactant: CCCC1=C2C[C@H](C3(C)CO3)CCC2(C)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCC1=C2C[C@H](C(C)(C)O)CCC2(C)CCC1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.69 g (18.3 mmol) of LiAlH4 in 150 mL of anhydrous ether cooled with ice bath was added a solution of the compound obtained from step B in anhydrous ether. The reaction mixture was stirred for 30 min. with cooling, 3 hours at room temperature, then quenched with water saturated ether and 2 mL of 10% NaOH solution. After filtration, the solvent was removed by evaporation to give title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:26]=[C:25]([CH2:27][CH3:28])[NH:24][N:23]=1>>[CH2:27]([C:25]1[NH:24][N:23]=[C:22]([NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH:26]=1)[CH3:28]
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: CCc1cc(N)n[nH]1
Product: CCc1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2OC)n[nH]1

Procedure:
Using an analogous procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted at 75° C. for 3 hours with 3-amino-5-ethylpyrazole to give N-(5-ethylpyrazol-3-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.15 (t, 3H), 2.55 (q, 2H), 3.48 (s, 2H), 3.73 (s, 3H), 5.09 (s, 2H), 6.24 (s, 1H), 6.54 (m, 1H), 6.62 (d, 1H), 7.06 (d, 1H), 7.33 (t, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 10.15 (br s, 1H); Mass Spectrum: M+H+ 366; which material was hydrogenated to give N-(5-ethylpyrazol-3-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.15 (t, 3H), 2.53 (q, 2H), 3.43 (s, 2H), 3.68 (s, 3H), 6.24 (br s, 1H), 6.28 (m, 1H), 6.37 (d, 1H), 6.93 (d, 1H), 9.29 (br s, 1H), 10.09 (br s, 1H); Mass Spectrum: M+H+ 276.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O=[C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]([C:36]([O-:38])=[O:37])[O:28]1.[Li+]>C(COC)OC>[O:10]=[C:2]1[C:3](=[C:27]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]([C:36]([OH:38])=[O:37])[O:28]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C1OC(C(=O)[O-])c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OC(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
To a solution of oxindole (1.10 g, 8.27 mmol) in dimethoxyethane (30.0 ml) at room temperature was added 1.0M LiHMDS/THF (17.0 ml). The mixture was stirred for 10 minutes at room temperature, and lithium 3-oxo-1,3-dihydro-2-benzofuran-1-carboxylate (1.37 g, 7.44 mmol) was added in one portion. After the reaction was rapidly stirred at room temperature for 18 hours, it was quenched into 4% HCl aqueous solution (200 mL), and the mixture was stirred 5 minutes. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and then extracted with saturated NaHCO3 aqueous solution. The aqueous layer was acidified with 4% HCl aqueous solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to obtain a yellow solid. The yellow solid was triturated at room temperature with CHCl3, and then triturated with hot isopropanol to give 3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-carboxylic acid as a yellow solid (287 mg, 13%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.[CH3:17][C:18](=O)[CH2:19][C:20](=[O:22])[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:17][C:18]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]2=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:19]=1[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
To a stirred solution of 55 mg (0.22 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone in 2 ml acetic acid was added 0.016 ml (0.24 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 80° C. for 15 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 27 mg (39%) 1-(2-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 314 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[C-:37]#[N:38].[K+].CN(C=O)C.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:37]#[N:38])[CH:12]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: [C-]#N
Reactant: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C2C(CC#N)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Combine toluene-4-sulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ylmethyl ester (0.224 g, 0.44 mmol), KCN (0.172 g, 2.65 mmol), and DMF (4 mL), and stir under nitrogen atmosphere at 100° C. After 2 hours, add ethyl acetate and water. Separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (0.139 g, 87%) as a white foam. TLC Rf=0.46 in 4:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.31 (m, 1H), 7.24 (d, 2H, J=8.8 Hz), 6.96 (m, 3H), 6.84 (dd, 1H, J=8.4, 2.6 Hz), 3.86 (m, 6H), 3.59 (m, 1H), 3.34 (s, 1H), 3.18 (dd, 1H, J=12.3, 3.1 Hz), 2.90 (dd, 1H, J=17.2, 4.4 Hz), 2.51 (m, 2H), 1.98 (m, 1H), 1.66 (m, 2H), 1.48 (m, 2H), 1.14 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(N(CCC)C(OC(=O)NC1CC=CC2C=CC=CC=2N=1)=O)CC.C([O-])([O-])=O.[Na+].[Na+].O.[K].[K].C1(P(C2C=CC(S(O)(=O)=O)=CC=2)C2C=CC(S(O)(=O)=O)=CC=2)C=CC=CC=1.N#N.CN(C)C(C1C=CC(B(O)O)=CC=1)=O>CCO.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH2:14]([N:13]([CH2:17][CH2:18][CH3:19])[C:12]([C:10]1=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)=[CH:29][C:6]=2[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9]1)=[O:20])[CH2:15][CH3:16]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCN(CCC)C(=O)OC(=O)NC1=Nc2ccccc2C=CC1
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by these procedures using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and 4-hydroxyphenylboronic acid. Preparation of tert-butyl (1E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-((dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate: To Na2CO3 (129 mg, 1.214 mmol) in a 50 mL round-bottom flask was added water (3.7 mL) was bubbled with N2 for 10 min. To this mixture was added tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate (200 mg, 0.40 mmol) in EtOH (4.9 mL) at room temperature. The resulting mixture was bubbled with N2 for 10 min. Pd(OAc)2 (9.3 mg, 0.040 mmol) and 4,4′-(phenylphosphinidene)bisbenzenesulfonic acid dipotassium hydrate (45 mg, 0.081 mmol) were added. The resulting mixture was warmed to 65° C. with N2 bubbling. To this mixture was added a solution of 4-(dimethylcarbamoyl)phenylboronic acid (97 mg, 0.49 mmol) in EtOH (0.6 mL). The resulting mixture was stirred at 65° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was diluted with water (5 mL) and EtOAc (10 mL) The mixture was filtered through GF/F filter. The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was purified by silica gel flash column chromatography (CH2Cl2 to 2% MeOH in CH2Cl2). MS APCI (+) m/z 478 (M+1) detected.