Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[C:9]=1Br.N#N.C([Sn](CCCC)(CCCC)[C:60]([O:62][CH2:63][CH3:64])=[CH2:61])CCC>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.O1CCOCC1>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[C:9]=1[C:60]([O:62][CH2:63][CH3:64])=[CH2:61]
Reactant: CC(NC(=O)C1(C)COC(C)(C)OC1)c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C(C)NC(=O)C2(C)COC(C)(C)OC2)nc2c(-c3cnc4ccc(F)cc4c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Yield: 83.2 %

Procedure:
N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (63.7 mg, 0.078 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.0 mg, 0.0078 mmol) were combined in a microwave tube, and the cap was crimped on. The headspace was purged with dry N2 (×2), and tributyl[1-(ethyloxy)ethenyl]stannane (53 μL, 0.16 mmol) and 1,4-dioxane (0.69 mL) were added. The suspension was sparged with dry N2 for ca. 3 min. The tube was lowered into a pre-heated 100° C. oil bath and stirred over night. The dark reaction mixture was then cooled, partitioned between aq. KF (2 mL, 0.5 M) and ether (ca. 3 mL). The layers were separated, and the aqueous was extracted with ether (1×3 mL), the organics were combined, washed with brine (2 mL), dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude matrial (105 mg) was adsorbed into silica gel, and purified by flash chromatography (15 g silica, hexanes to 25% EtOAc in hexanes, the 5% MeOH in DCM). Like fractions were combined, and concentrated to give N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-(1-ethoxyvinyl)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (52.5 mg, 83%) as a yellow film. The material contained a small amount of triphenylphosphine oxide, and carried on as is.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C@@H:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:22][C@@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Nitrobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:3])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
1300 ml of a methylene chloride solution titrating 12.5 g/liter of diazomethane was added progressively at 10°-15° C to a solution of 50 g of m-benzoyl-phenyl acetic acid in 500 ml of methylene chloride and after stirring for 15 minutes, excess diazomethane was destroyed by the addition of acetic acid. The organic solution was washed with an aqueous saturated sodium bicarbonate solution and then with water and evaporated to dryness under reduced pressure to obtain 52.5 g of methyl m-benzoyl-phenyl-acetate which was used as is for the α-alkylation step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[CH:11][CH2:10]1.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH:43]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:25][CH2:26]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[CH:11][CH2:10]1
Reactant: CC1CC=C(c2cc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: CC1CC=C(c2cc(C3CCN(Cc4ccccn4)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
This compound was prepared according to the procedure in Example 21 from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide (as prepared in Example 17) and pyridine-2-carbaldehyde. 1H-NMR (400 MHz, DMSO-d6): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.74 (m, 1H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.48-2.22 (m, 3H), 2.18-2.06 (m, 4H), 1.98-1.82 (m, 3H), 1.52 (m, 1H), 1.02 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C28H32N6O, 481.2 (M+H). found 481.2.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[N:20]4[CH:21]=[C:22]([S:25][C:26]5[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=5)[CH:23]=[CH:24][C:19]4=[N:18][N:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:36][C:37]([NH:39][C:40]1[N:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:43]=[C:42]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:41]=1)=O.CCN(C(C)C)C(C)C>CS(C)=O>[C:52]([C:42]1[CH:41]=[C:40]([NH:39][C:37]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([S:25][C:22]3[CH:23]=[CH:24][C:19]4[N:20]([C:16]([C:12]5[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)[CH:11]=5)=[N:17][N:18]=4)[CH:21]=3)=[CH:31][CH:30]=2)=[O:36])[N:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:43]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: Nc1ccc(Sc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Sc3ccc4nnc(-c5cccc(OCCN6CCOCC6)c5)n4c3)cc2)cc1
Yield: 40.9 %

Procedure:
A mixture of Example 10 step c (315 mg, 0.703 mmol), 5-(2,2,2-trichloroethoxycarbonyl)amino-3-tert-butyl-1-p-tolyl-1H-pyrazole (299 mg, 0.703 mmol) and DIPEA (116 μL, 0.675 mmol) in DMSO (3 mL) was heated at 55° C. for 24 h. The reaction was concentrated in vacuo and the residue purified by reverse phase preparative HPLC (Method 3) to afford the title compound (202 mg, 41%) as an off-white solid. LCMS (Method 4): Rt 8.46 min, m/z 703 [MH+]. 1H NMR (400 MHz, CDCl3): δ 9.30 (1 H, br s), 8.34 (1 H, br s), 8.16 (1 H, s), 7.49-7.41 (3 H, m), 7.37 (1 H, d, J 9.6), 7.29 (2 H, d, J 8.4), 7.25-7.20 (2 H, m), 7.18 (2 H, d, J 8), 7.09-7.04 (2 H, m), 6.90 (2 H, d, J 8), 6.44 (1 H, s), 4.15 (2 H, t, J 5.4), 3.72 (4 H, t, J 4.5), 2.88 (2 H, t, J 5.4), 2.64 (4 H, t, J 4.4), 2.11 (3 H, s), 1.30 (9 H, s).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[C:17]([NH:24][C@@H:25]([C:27](O)=[O:28])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:20]([O:19][C:17]([NH:24][C@H:25]([CH3:26])[C:27]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])=[O:28])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of L-Serine methyl ester hydrochloride (5.0 g, 32.0 mmol), in CH2Cl2 (150 mL) at 0° C., were added Et3N (4.88 mL, 35.2 mmol), Boc-D-Alanine (6.06 g, 32 mmol), and DCC (7.26 g, 35.2 mmol) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (70% ethyl acetate/30% chloroform) to yield 86% of methyl 2-((R)-2-(tert-butoxycarbonylamino)propanamido)-3-hydroxypropanoate.
Reaction SMILES: [CH2:1](O)C.[NH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([F:16])[CH:12]=2)[N:7]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:6]=1.N1(CO)C2C=CC=CC=2N=N1.[BH4-].[Na+]>O>[CH:18]1([NH:17][C:10]2[CH:9]=[C:8]3[C:13]([C:14](=[O:15])[C:5]([NH:4][CH3:1])=[CH:6][N:7]3[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:12][C:11]=2[F:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCO
Reactant: CCC(CC)n1cc(N)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCC(CC)n1cc(NC)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 4 ml ethanol solution of 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one was added 105 mg of 1H-1,2,3-benzotriazol-1-ylmethanol, followed by overnight stirring at room temperature. Next, 48 mg of sodium borohydride was added to the reaction mixture, followed by stirring for 3 hours. By adding water to the resulting reaction mixture and collecting the insoluble materials by filtration, 100 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-3-(methylamino)quinolin-4(1H)-one was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:20](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](/[CH3:32])=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:19][C:9]2[C:10]3([CH3:18])[CH:15]([OH:16])[C:14]([CH3:17])([C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:5][C:6]1[C:20](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](/[CH3:32])=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:19][C:9]2[C:10]3([CH3:18])[CH:15]([OH:16])[C:14]([CH3:17])([C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)OCC)C1(C)CCCC2(C)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)O)C1(C)CCCC2(C)C1O

Procedure:
This ester was dissolved in 7 ml of ethanol/THF=1/1 and treated under argon with 2.1 ml of 2N NaOH. The mixture was left to react at room temperature for 64 h. and then poured into ice/HCl/ethyl acetate. The organic phase was washed twice with water, dried and evaporated. Recrystallization from hexane/ethyl acetate=7/3 yielded 153 mg of (2E,4E,6E)-(5RS,9SR,10RS)-7-(3-butoxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl)-3-methyl-hepta-2,4,6-trienoic acid as yellow crystals of m.p. 176-178°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].[Se](=O)=[O:23]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Yield: 58 %

Procedure:
6-Hydroxy-3-phenyl-1H-indene-2-carboxylate ethyl ester (1 g, 3.57 mmol) was dissolved in 1,4-dioxane (50 ml), and then selenium dioxide (5.49 g, 53.55 mmol) was added thereto. The mixture was refluxed for 12 hour with vigorous stirring. The resulting mixture was filtered and concentrated, and the concentrate was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (58%) as a rich red solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:24])[C:11]=2[C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:15]([O:17][CH3:18])=[O:16])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39]>CN1C(=O)CCC1>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:39][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:24])[C:11]=2[C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:15]([O:17][CH3:18])=[O:16])[N:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Cl)ccc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Oc4ccc(F)cc4F)ccc23)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 3-(2-chloro-6-oxo-6H-pyrido[1,2-b]pyridazin-5-yl)-4-methoxybenzoate (1.05 g, 3.05 mmol) and Cs2CO3 (2.97 g, 9.15 mmol) dissolved in NMP (20 mL) was added 2,4 difluoro phenol (475 mg, 3.66 mmol). The mixture was heated to 80° C. for 1 hr until the reaction was complete via LCMS analysis. The reaction was poured into 500 mL of ice/H2O and the solid precipitate was collected. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Fc1ccc2sc(Cl)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Temperature: 90 °C

Procedure:
2-Chloro-5-fluoro-1,3-benzothiazole (29 mg, 0.16 mmol) and methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate (50 mg, 0.16 mmol) were combined in 1-butanol. The solution was treated with 4 M HCl in dioxane (4 μL, 0.016 mmol) and heated at 90° C. for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in methanol, and the resulting solid was collected by filtration and dried in vacuo. The title compound was obtained as a pale yellow solid (55 mg, 77%); LC-MS m/z 475.3 (MH+), retention time 3.97 minutes.
Reaction SMILES: [Li].[CH3:2][CH2:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8].CN(C)C(=O)N(C)C.[CH2:19]([C:21](=[CH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[CH2:22][CH2:23]I)[CH3:20]>>[CH2:19]([C:21](=[CH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[CH2:22][CH2:23][CH:5]([C:4](=[O:10])[CH2:3][CH3:2])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:20]
Reactant: CCC(=O)CC(=O)CC
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCI
Agent: [Li]
Solvent: CN(C)C(=O)N(C)C
Product: CCC(=O)C(CCC(=CCCc1ccc2c(c1)OCO2)CC)C(=O)CC

Procedure:
A solution of 15 g. of the lithium salt of 3,5-heptanedione (prepared as described in Example 3 below) in 100 ml. of tetramethylurea was stirred under nitrogen at room temperature, and 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) was added. The reaction mixture was stirred for forty-eight hours, then concentrated to remove the solvent, and the residue slurried in ether and treated with excess glacial acetic acid. Water was added, the ether layer separated, washed with water and concentrated. The residue was distilled in a molecular still to remove volatile material at 110° C. (0.001 mm.), and the non-volatile residue was chromatographed on 10 g. of activated magnesium silicate in benzene solution and eluted with ethyl acetate to give 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][OH:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[CH3:27]I.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][O:26][CH3:27])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CI
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 25 mg (0.07 mmol) of 1-9 in 1 mL of DMF was added a small amount of MeI and NaH (60% suspension in oil) and the mixture was left to stir for 15 h at room temperature. The reaction was quenched with 1 drop of water and loaded directly onto a RP HPLC and eluted with CH3CN/H2O with 0.1% TFA to provide 2-1 as a white solid. Data for 2-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.4 (s, 1H), 4.8 (d, 1H), 4.7 (d, 1H), 4.45 (d, 1H), 4.35 (d, 1H), 3.4 (s, 3H), 2.8 (s, 6H) ppm. HRMS (MS) calc'd M+H for C21H22F2N2O2: 373.1722. Found: 373.1722.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH2:6]1)=[O:4].[CH3:20][C:21]([O-])(C)[CH3:22].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][C:3]([C:5]1([CH2:22][CH:21]=[CH2:20])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2Cl)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)(C)O
Product: C=CCC1(C(=O)OC)CN(Cc2ccccc2Cl)CCC1=O
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
14.60 g (51.8 mmol) of methyl-1-[(2-chlorophenyl)methyl]-4-oxo-3-piperidine carboxylate was dissolved in 40 ml of tertbutanol and warmed to 30° C. Within 2 minutes 6.57 g (58.4 mmol) of potassium tert-butylate in 45 ml of tert-butanol was added. After 15 minutes of stirring, 25 ml of tert-butanol was added once more. Then 6.34 g (51.4 mmol) of allylbromide was added within 10 minutes and stirred for 2 more hours at 30° to 35° C. The reaction mixture was concentrated by evaporation and 70 ml of water and 70 ml of ether were added to the residue. The organic phase was washed with 50 ml of sodium sulfate solution, dried on magnesium sulfate and concentrated by evaporation. The yield was 40.68 g of methyl1-[(2-chlorophenyl)methyl]-4-oxo-3-(2-propenyl)-3-piperidine carboxylate, which equals 88.1 percent. Data concerning the compound was:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[SH:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:21][CH:22]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(O)CCc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11](O)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11]([O:4][CH:1]2[CH2:3][CH2:2]2)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: OC1CC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
0.9 ml of cyclopropanol were added to a mixture of 5.5 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 26 ml of methylene chloride and 1 g of 4-dimethylamino-pyridine and 3 g of dicyclohexylcarbodiimide were added thereto at 0° C. The mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 85-15 cyclohexane-ethyl acetate mixture yielded 3.6 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-(cyclopropyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate melting at 62° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1OB(O)O>>[C:12]1([CH3:22])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1OB(O)O
Reactant: O=C1Cc2ccc(Br)cc2N1
Product: Cc1ccccc1-c1ccc2c(c1)NC(=O)C2

Procedure:
Prepared from 6-bromo-2-indolinone and 2-tolylboric acid
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=2)=[C:15]([CH3:27])[S:14][C:13]=1[NH2:28])=[O:11])[CH3:8].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=2)=[C:15]([CH3:27])[S:14][C:13]=1[NH:28][C:4](=[O:5])[CH2:3][C:1]#[N:2])=[O:11])[CH3:8]
Reactant: N#CCC(=O)O
Reactant: C=CCOc1ccc(-c2c(C)sc(N)c2C(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(-c2c(C)sc(NC(=O)CC#N)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To PCl15 (854 g, 4.1 mol) in 10 mL anhydrous CH2Cl2 was added cyanoacetic acid (348 g, 4.1 mmol). The reaction mixture was refluxed for 0.5 h, and then 4-(4-Allyloxyphenyl)-2-amino-5-methyl-thiophene-3-carboxylic acid ethyl ester from Example 29B (1.0 g, 3.1 mmol) in 5 ml anhydrous CH2Cl2 was added dropwise at room temperature. The reaction mixture was refluxed for 1 h and cooled to room temperature, and then saturated aq. Na2CO3 was added until pH=7. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo to give the titled compound (1.2 g, 100% yield) as a pale yellow oil which was pure enough to used in next step. 1H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.07 (d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=9.0 Hz), 6.05 (m, 1H), 5.44, 5.38, 5.28, 5.25 (4d, 2H, J=3.0 Hz), 4.60 (d, 2H, J=6.0 Hz), 4.25 (s, 2H), 3.97 (q, 2H, J=6.0 Hz), 2.12 (s, 3H), 0.84 (t, 3H, J=6.0 Hz). MS (ESI) m/e 385 (M+H)+, 383 (M−H)−.