Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:28]([O:30][CH2:31][C:32]2([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH2:29])[C:5]2[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8](=[O:18])[N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=2[CH:27]=1>ClCCCl.[B-](F)(F)(F)F.CC[C@H]1P(C2C(P3[C@H](CC)CC[C@H]3CC)=CC=CC=2)[C@H](CC)CC1.C1[CH][CH]CC[CH][CH]C1.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]([O:30][CH2:31][C:32]2([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH3:29])[C:5]2[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8](=[O:18])[N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[C:6]=2[CH:27]=1
Reactant: C=C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(COCC[Si](C)(C)C)c(=O)n2COCC[Si](C)(C)C
Agent: [Rh]
Agent: CC[C@@H]1CC[C@@H](CC)P1c1ccccc1P1[C@H](CC)CC[C@H]1CC
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(COCC[Si](C)(C)C)c(=O)n2COCC[Si](C)(C)C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-((1-(6-chloro-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)vinyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (470 mg, 0.616 mmol) in 1,2-dichloroethane (20 mL) was degassed by passing a stream of nitrogen through the solution for 1 h. The reaction was quickly treated with (−)-1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(1)tetrafluoroborate (50 mg, 0.076 mmol) and flushed with nitrogen for 10 minutes longer. The vessel was pressurized to 60 psi of hydrogen and shaken for 24 h. The mixture was concentrated and the crude mixture purified by column chromatography (8%→25% ethyl acetate/n-hexane) to give 420 mg (89%) as a foam semi-solid. 1H-NMR (CDCl3, 500 MHz) δ 7.21 (dd, 8.9, 5.2 Hz, 2H), 7.02 (d, J=1.8 Hz, 1H), 6.98 (dd, J=8.9, 8.6 Hz, 2H), 6.78 (d, J=2.1 Hz, 1H), 5.35 (d, J=11.6 Hz, 1H), 5.23 (m, 2H), 5.03 (d, J=11.6 Hz, 1H), 4.94 (q, J=6.4 Hz, 1H), 3.69 (m, 2H), 3.57 (t, J=8.1 Hz, 2H), 3.51 (m, 2H), 3.18 (m, 2H), 3.01 (m, 2H), 2.07 (m, 2H), 1.84 (m, 2H), 1.42 (s, 9H), 1.34 (d, J=6.7 Hz, 3H), 0.70-0.97 (m, 4H), −0.05 (s, 9H), −0.06 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.4 (d, J=246 Hz), 155.0, 154.8, 138.6, 130.3, 128.7 (d, J=7.7 Hz), 128.5, 128.3, 124.5, 120.0, 115.1 (d, J=21 Hz), 108.3, 79.4, 76.8, 71.5, 71.4, 70.9, 66.5, 66.0, 41.1, 40.2, 40.1, 32.2, 32.0, 28.6, 23.3, 18.0, 17.9, −1.4. Mass spec.: 786.01 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])[CH:7]=1.[C:37]([NH2:41])(=[O:40])[CH2:38][CH3:39].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:41][C:37](=[O:40])[CH2:38][CH3:39])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])[CH:7]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Reactant: CCC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(NC(=O)CC)c2)cc1F
Yield: 16.8 %

Procedure:
Using the procedure of Example 12, N-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.05 g, 0.094 mmol), propionamide (10 mg, 0.14 mmol), Cs2CO3 (0.05 g, 0.14 mmol), Xantphos (6 mg, 0.010 mmol), Pd2(dba)3 (5 mg, 0.005 mmol) and dioxane (2 mL) were combined to obtain N-(5-chloro-2-fluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (9 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1 H), 10.46 (s, 1 H), 8.46 (d, J=7.8 Hz, 1 H), 8.13 (d, J=5.7 Hz, 1 H), 7.87 (d, J=7.8 Hz, 1 H), 7.57 (d, J=2.4 Hz, 1 H), 7.45 (m, 3 H), 7.31 (t, J=8.7 Hz, 2 H), 6.62 (dd, J=5.7, 2.4 Hz, 1 H), 6.50 (d, J=7.9 Hz, 1 H), 4.23 (q, J=7.0 Hz, 2 H), 2.28 (q, J=7.5 Hz, 2 H), 1.29 (t, J=7.0 Hz, 3 H), 0.95 (t, J=7.5 Hz, 3 H); MS (ESI) m/z: 569.1 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3]1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(C(C)C)CC)(C)C>CC#N>[CH3:1][C@@H:2]1[CH2:3][N:4]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:6][N:7]1[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CBr
Reactant: C[C@@H]1CN(C2CCCCc3ccccc32)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN1CCN(C2CCCCc3ccccc32)C[C@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of (3R)-3-methyl-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazine (620 mg, 2.537 mmol) in MeCN was added methyl 2-bromoacetate (466 mg, 3.044 mmol) followed by diisopropylethylamine (0.884 ml, 5.074 mmol). The reaction mixture was stirred at rt for 5 h. The solvent was evaporated under high vacuum and the residue was loaded on column (SiO2, hexane to hexane/EtOAc=100:10 to 100:20 to 100:30 to 100:40) to give methyl 2-((R)-2-methyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazin-1-yl)acetate (800 mg, 99.6% yield) as a gum.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][F:42].C(OCC)(=O)C>CS(C)=O>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:32]/[O:33][CH2:41][F:42])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FCBr
Reactant: CCOC(=O)/C(=N\O)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
Ethyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-hydroxyiminoacetate (60.4 g) was dissolved in dimethyl sulfoxide (210 ml). Potassium carbonate (96.48 g) was added under ice cooling, followed by stirring for 10 minutes. Bromofluoromethane (19 g) was added further, followed by stirring at room temperature for 3 hours. The reaction mixture was added with ethyl acetate (1 l) and washed with water and then with saturated saline. Anhydrous magnesium sulfate was added to the thus-washed reaction mixture to dry the same. The solvent was distilled off, and ethanol (120 ml) was added to the residue. Deposited crystals were collected by filtration and then washed with ethanol to obtain the target product (58.2 g). Infrared spectrum (cm- 1, Nujol) 1735, 1530.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][F:18])[CH:10]=2)[N:3]=1.BrC1C=C(C(=O)C(C2C=CC(OC(F)F)=CC=2)=O)C=CC=1[F:36].C(O)C#C>>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:24]=2)([C:9]2[CH:14]=[CH:13][C:12]([F:36])=[C:11]([C:15]#[C:16][CH2:17][F:18])[CH:10]=2)[N:3]=1
Reactant: O=C(C(=O)c1ccc(F)c(Br)c1)c1ccc(OC(F)F)cc1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCF)c2)N=C1N
Agent: C#CCO
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2ccc(F)c(C#CCF)c2)N=C1N

Procedure:
This material was synthesized in a fashion similar to 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one by coupling 1-(3-bromo-4-fluorophenyl)-2-(4-(difluoromethoxy)phenyl)ethane-1,2-dione with prop-2-yn-1-ol in step 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:30]([CH:27]3[CH2:29][CH2:28]3)(=[O:32])=[O:31])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CC1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and cyclopropanesulfonyl chloride (0.039 mL, 0.383 mmol) the title compound of Step A was obtained as a yellow solid (125 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 8.27-8.39 (m, 1H), 7.54 (td, J=7.6, 1.7 Hz, 1H), 7.22-7.42 (m, 2H), 6.62-6.72 (m, 1H), 5.30 (s, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.6 Hz, 4H), 2.59-2.70 (m, 1H), 0.75-0.93 (m, 3H).
Reaction SMILES: NC1[S:3][C:4]2[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([F:12])=[C:10]([Cl:11])[C:4]=1[SH:3]
Reactant: Nc1nc2ccc(F)c(Cl)c2s1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(F)c(Cl)c1S

Procedure:
reacting 2-amino-6-fluoro-7-chlorobenzothiazole with sodium hydroxide to produce the disulfide of 2-amino-5-fluoro 6-chlorothiophenol,
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[N:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C=O)C>[Si:28]([O:14][CH:11]1[CH2:10][CH2:9][CH:8]([C:7]2[N:6]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[CH:3][C:2]=2[F:1])[CH2:13][CH2:12]1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(F)c(C2CCC(O)CC2)n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of methyl 5-fluoro-6-(4-hydroxycyclohexyl)picolinate (1.0 equiv.) in DMF (0.15 M) was added imidazole (4.0 equiv.) and TBDMSCl (2.5 equiv.). The reaction mixture was stirred at room temperature for 2 days, then added to ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinate in 97% yield as a mixture of isomers (3:1). LC/MS=368.3 (M+H), Rt=1.4 and 1.42 min.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[S:13]([CH2:23][N+:24]#[C-:25])([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[C-]#N.[Na+]>>[C:19]1([CH3:20])[CH:18]=[CH:17][C:16]([S:13]([C@@H:23]2[C@@H:6]([C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)[O:7][CH:25]=[N:24]2)(=[O:14])=[O:15])=[CH:22][CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2cccc(C(F)(F)F)c2)cc1

Procedure:
In a manner analogous to Preparation 1, 3-(trifluoromethyl)benzaldehyde (0.16 g, 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 4.98-5.04 (dd, 1H), 6.08-6.12 (dd, 1H), 7.3-7.42 (d, 2H), 7.50-7.62 (m, 5H), 7.78-7.86 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.N=C=N.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:29]([NH:36][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-phenyl-pyrimidine-5-carboxylic acid, (80 mg), 1-hydroxybenzotriazole (92 mg) and polymer supported-carbodiimide (640 mg, 1.25 mmol/g) in 8 mL of DCM is shaken at room temperature for 30 min and benzylamine (43 mg) is added. After shaking at room temperature for 1.5 days, PS-trisamine (295 mg, 4.08 mmol/g) is added. The mixture is continually shaken at room temperature for 16 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield of 2-phenyl-pyrimidine-5-carboxylic acid benzylamide (98 mg, 85%) as a solid. MS: 290 (M+H); 1H NMR (CDCl3): 9.17 (s, 2H), 8.50 (d, 2H), 7.52-7.55 (m, 3H), 7.36-7.40 (m, 5H), 6.54 (broad, H), 4.69-4.71 (d, 2H); IC50=10 nM.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](F)([F:9])=[O:8]>>[C:2]([CH2:3][O:4][C:7]([F:9])=[O:8])([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: O=C(F)F
Product: O=C(F)OCC(F)(F)F

Procedure:
236faE (CAS Reg. No. 20193-67-3) has been prepared by reaction of 2,2,2-trifluoroethanol with carbonyl fluoride to give the intermediate, CF3CH2OCOF, which was in turn reacted with sulfur tetrafluoride at 150-200° C. to give the product as disclosed by Eisemann in U.S. Pat. No. 3,394,878.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][O:20][P:21]([CH2:25]C(=O)CC(O[Si](C(C)(C)C)(C)C)CCC)(=[O:24])[O:22][CH3:23]>>[CH3:19][O:20][P:21]([CH2:25][C:10](=[O:12])[CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[O:22][CH3:23]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Reactant: CCCC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)CP(=O)(OC)OC
Yield: 61 %

Procedure:
Dimethyl (3-((tert-butyldimethylsilyl)oxy)-2-oxoheptyl)phosphonate 6 (1.56 g) was prepared in 61% yield using compound 5 according to the procedures described for compound 3 (see Schemes 1 and 2).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27][Cl:28].Cl.O>CN(C)C=O>[Cl:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CN(CCCl)CCCl
Reactant: O=c1c2ccccc2sc2c(O)ccc(O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCl)CCOc1ccc(O)c2sc3ccccc3c(=O)c12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 0.5 g of 1,4-dihydroxythioxanthone in 20 ml of dimethylformamide is stirred for 0.5 h at room temperature with 6 g of potassium carbonate under anhydrous conditions. Mechlorethamine hydrochloride (0.4 g) is then added and the heterogeneous mixture was stirred for 12 h at 50° C. Water is added and the mixture extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried with sodium sulfate, passed through a plug of alumina and concentrated under vacuum to produce 0.4 g (55%).
Reaction SMILES: [C:1]([N:9]1CCCC(C(OCC)=O)C1)(=O)[C:2]1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](Cl)=[O:35])[CH2:29]1)=[O:27].C(N(C(C)C)CC)(C)C.Cl.C(N)C>>[CH2:1]([NH:9][C:34]([CH:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:26](=[O:27])[CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH2:29]1)=[O:35])[CH3:2]
Reactant: O=C(Cl)C1CCCN(C(=O)Cc2cccs2)C1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C1CCCN(C(=O)Cc2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with 1-(2-thiopheneacetyl)-3-piperidinecarbonyl chloride (609.8 mg; 2.25 mmol), diisopropylethylamine (920 μl; 5.28 mmol) and commercially available ethylamine hydochloride (204.8 mg; 2.51 mmol). The crude product was purified by chromatography on silica, eluting with 100% ethyl acetate, giving N-ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxamide (437.5 mg) as a thick, brown syrup. MS m/z (positive ion) 303 (M+Na+; 25), 281 (MH+; 100), 157 (25).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (1.50 g), tetraethyl methylenediphosphonate (0.84 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.12 g) at room temperature. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate as colorless crystals (1.20 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (4:1 to 9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 114-115° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=O)C.N1CCCCC1.[OH-].[K+].[OH-].[NH4+]>C1(C)C=CC=CC=1.CO>[CH3:24][O:10][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:23])[CH3:1])=[CH:8][CH:7]=2)[C:11]2[C:12](=[CH:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)[C:13](=[O:15])[O:14]1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCNCC1
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21
Temperature: 25 °C

Procedure:
A mixture of 6.3 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid and 150.0 ml of acetic anhydride was stirred for approximately fifteen minutes at ambient temperature. Slowly, 10.0 ml of piperidine and 10.0 ml of methyl alcohol were added to the mixture. Two grams of potassium hydroxide was added to complete the solution. The temperature rose to 55° C. with the addition of the potassium hydroxide. The resulting solution was allowed to stir overnight with gradual return to ambient temperature. Slowly, this solution was poured into a mixture of five percent aqueous ammonium hydroxide and toluene. After separation, the toluene layer was washed first with water and then with saturated aqueous sodium chloride solution. The resulting toluene layer was evaporated to dryness. The residue was slurried in 100.0 ml of isopropyl alcohol and the separated solid was collected by filtration, washed three times, each with 30.0 ml of isopropyl alcohol, and dried to obtain 4.0 g of 3-methoxy-3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green solid which melted at 150° to 153° C. A significant infrared maximum appeared at 1765 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was in accord with the assigned structure. A toluene solution of the product spotted on an acidic clay-coated paper developed a green-colored image.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32].[OH-].[Na+]>CS(C)=O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][NH:32][CH3:31])[CH:22]=[CH:21]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC[C@H]1C=Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 60 °C
Yield: 70 %

Procedure:
To a solution of [(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate, prepared in Example 35, step 7 (0.33 g, 0.715 mmol) in anhydrous dimethyl sulfoxide (1.2 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 3.58 mL, 7.15 mmol) and the mixture heated at 60° C. in a sealed vial for 26 hours. The cooled reaction mixture was then poured into 1:1 v/v 2.0 M aqueous sodium hydroxide solution:saturated brine (50 mL) and the product extracted with ethyl acetate (50 mL). The separated organic extract was washed with 1:1 v/v 2.0 M aqueous sodium hydroxide solution:saturated brine (50 mL), and half saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 160 mg (70%) of {[(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl}methylamine as a yellow syrup. The product was dissolved 2-propanol (1.5 mL) and diethyl ether (3 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.36 mL, 0.36 mmol) was added followed by hexane (4 mL). The resulting white precipitate was filtered to afford 121 mg (47%) of {[(2R)-8-(2.6-dichlorophenyl)-2H-chromen-2-yl]methyl}methylamine hydrochloride as a tan solid. HRMS: calcd for C17H15Cl2NO+H+, 320.06034. found (ESI, [M+H]+), 320.0619.