Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:59][N:60]1[CH:64]=[C:63](B2OC(C)(C)C(C)(C)O2)[CH:62]=[N:61]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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]>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH2:11][NH:10][C:8]([C:7]1[CH:6]=[C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[N:4]=[N:3][C:2]=1[C:63]1[CH:62]=[N:61][N:60]([CH3:59])[CH:64]=1)=[O:9]
Reactant: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)nnc2Cl)cc1OC
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)nnc2-c2cnn(C)c2)cc1OC
Temperature: 175 °C

Procedure:
To a solution of 3-chloro-N-(3,4-dimethoxybenzyl)-6-(3,5-dimethylphenyl)pyridazine-4-carboxamide (1-3, 0.012 g, 0.029 mmol, 1.0 equiv) in DMF (0.20 mL) was added Pd2(dba)3 (0.0027 g, 0.003 mmol, 0.1 equiv), S-Phos (0.0024 g, 0.006 mmol, 0.2 equiv), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.036 g, 0.18 mmol, 6.0 equiv) and K3PO4 (0.025 g, 0.12 mmol, 4.0 equiv) and the reaction was heated to 175° C. for 30 minutes in the microwave. The reaction mixture was cooled and partitioned between EtOAc and water. The organic phase was washed three times with water and dried over MgSO4 and concentrated. The residue was purified by normal phase column chromatography (5 to 100% EtOAc in hexanes) and then purified by reverse phase column chromatography (5 to 85% ACN in water, 0.1% TFA buffer) to afford the product as a solid after freebasing the purified fractions. HRMS [M+H] C26H27N5O3 calc'd 458.2227. found 458.2210.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([F:20])([F:19])[CH2:7][CH2:8]/[C:9]/2=[N:12]\[S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[C:22]([F:29])([F:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[C:22]([C@:9]1([NH:12][S@@:13]([C:15]([CH3:17])([CH3:16])[CH3:18])=[O:14])[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[C:6]([F:20])([F:19])[CH2:7][CH2:8]1)([F:29])[F:28])[CH3:27]
Reactant: CC(C)(C)[S@@](=O)/N=C1\CCC(F)(F)c2ccc(Br)cc21
Reactant: CCOC(=O)C(F)(F)Br
Product: CCOC(=O)C(F)(F)[C@@]1(N[S@](=O)C(C)(C)C)CCC(F)(F)c2ccc(Br)cc21
Yield: 58 %

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [7-bromo-4,4-difluoro-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-amide (intermediate A2.4) and ethyl 2-bromo-2,2-difluoroacetate, the product [(R)-7-bromo-4,4-difluoro-1-((R)-2-methyl-propane-2-sulfinylamino)-1,2,3,4-tetrahydro-naphthalen-1-yl]-difluoro-acetic acid ethyl ester (58% yield) was obtained as a brown solid. MS (ISP): m/z=488.1 [M+H]+ and 490.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH: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][C:11](Br)=[CH:10][C:9]=2[CH3:22])=[O:4].[CH2:24](B(CC)CC)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH: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][C:11]([CH2:24][CH3:25])=[CH:10][C:9]=2[CH3:22])=[O:4]
Reactant: CCB(CC)CC
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)cc(C)c2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C)c2[nH]c(=O)c(C(=O)OC)c(-c3ccccc3)c2c1
Temperature: 65 °C
Yield: 69.5 %

Procedure:
A mixture of 6-bromo-8-methyl-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (25 mg, 67.2 μmol, Eq: 1.00), triethylborane (134 μl, 134 μmol, Eq: 2), potassium carbonate (18.6 mg, 134 μmol, Eq: 2) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5.49 mg, 6.72 μmol, Eq: 0.1) in DMF was heated to 65° C. for 16 h in a sealed tube. Then water was added and the reaction mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 4:1) to afford the title compound as light brown solid (15 mg). MS (ESI): 322.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]4[N:27]=[N:28][N:29]([CH3:30])[C:25]=4[CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]4[N:27]=[N:28][N:29]([CH3:30])[C:25]=4[CH:24]=3)[CH2:17]2)[CH:15]=1)[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4nnn(C)c4c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4nnn(C)c4c3)C2)c1
Temperature: 78 °C

Procedure:
To compound 50a, 4-Methyl-2-{5-[1-(3-methyl-3H-benzotriazol-5-ylmethyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester (59.0 mg, 0.10 mmol) in EtOH (5.0 ml) was added 2M KOH (0.50 ml, 1.0 mmol). The reaction was heated to 78° C. for 2 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (32 mg, 53%). 1H NMR (400 MHz, MeOD) δ ppm 0.89-0.97 (m, 6 H) 1.49 (dt, J=13.39, 6.63 Hz, 1 H) 1.62-1.70 (m, J=13.72, 7.09, 6.94, 2.32 Hz, 1 H) 1.90-2.02 (m, 3 H) 2.11 (s, 2 H) 3.11-3.20 (m, 2 H) 3.30-3.50 (m, 1H) 3.57 (s, 2 H) 4.75 (t, J=7.70 Hz, 1 H) 4.33-4.37 (m, 3 H) 4.53-4.62 (m, 2 H) 7.32 (s, 1 H) 7.50 (s, 1 H) 7.56 (s, 1 H) 7.72-7.81 (m, 5 H) 7.90 (d, J=8.56 Hz, 1 H) 8.23 (s, 1 H) Calcd for C32H35F3NO4 (M+H) 564.64, Found 565.3.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:18](OC)=O)=[C:16]([CH2:22][CH3:23])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(C1N=CN=C(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)C=1CO)C.C(N(S(F)(F)[F:51])CC)C>>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][F:51])=[C:16]([CH2:22][CH3:23])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C(=O)OC
Reactant: CCN(CC)S(F)(F)F
Agent: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1CO
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CF

Procedure:
This compound can be prepared starting from 5-carbomethoxy-4-(cis-4-tert-butylcyclohexylamino)-6-ethylpyrimidine (Example 5) by reduction to the 5-hydroxymethyl compound (in analogy to Example 37) and fluorination with diethylaminosulfur trifluoride (DAST).
Reaction SMILES: C(C1SC2C(=O)N(C3C=CC=C([B:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]4)C=3C)CC=2C=1)(C)(C)C.[C:30]([O:33][CH2:34][C:35]1[C:40]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([N:50]([CH3:52])[CH3:51])[CH:47]=3)[C:42]2=[O:53])=[CH:39][CH:38]=[CH:37][C:36]=1Br)(=[O:32])[CH3:31].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1>>[C:30]([O:33][CH2:34][C:35]1[C:36]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[CH:37][CH:38]=[CH:39][C:40]=1[N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([N:50]([CH3:52])[CH3:51])[CH:47]=2)[C:42]1=[O:53])(=[O:32])[CH3:31]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Reactant: CC(=O)OCc1c(Br)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Yield: 100 %

Procedure:
Using the same general procedure as described for the preparation of 102g reaction of 123d (2.65 g, 6.59 mmol) with bis(pinacolato)diboron (5.02 g, 19.8 mmol) gave a 100% yield (3.00 g) of 123e as a brown solid: mp 75-76° C.; 1H NMR (300 MHz, CDCl3) δ 7.85 (dd, 1H, J=4.2, 1.8 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.45 (m, 2H), 6.80 (dd, 1H, J=8.7, 2.1 Hz), 6.69 (s, 1H), 5.13 (s, 2H), 4.69 (s, 2H), 3.08 (s, 6H), 1.93 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[OH-].[Na+].[CH3:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>CC(C)=O.O>[CH3:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)=[O:15]
Reactant: Cc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 20 °C
Yield: 96.6 %

Procedure:
m-Toluidine (1772 g) is dissolved in acetone (3.5 L), and thereto is added a solution of sodium hydroxide (648 g) in water (6.25 L), and the mixture is cooled to around 20° C. To the mixture is added o-methylbenzoyl chloride (2507 g) over a period of about 20 minutes with stirring, by which the temperature of the reaction mixture raises to around 60° C. After stirring for about one hour, the reaction mixture is cooled around 10° C. and the resulting crystals are taken by filtration. The crystalline product is washed 2 times with methanol/water (4:1, 3.75 L), and dried at about 60° C. to give the desired product (3530 g, yield 96.62%).
Reaction SMILES: C(OCC[O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH2:16][CH2:17]OCC)[CH:11]=[CH:10][C:9]=1Br)C.C(OCCOCC1C=CC=C(COCCOCC)C=1Br)C.C([Li])CCC.[F:48][C:49]1[CH:56]=[CH:55]C(C=O)=[CH:51][CH:50]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:48][C:49]1[CH:56]=[CH:55][C:17]([CH:16]2[C:11]3[C:12](=[CH:13][C:8]([CH2:7][OH:6])=[CH:9][CH:10]=3)[CH2:14][O:15]2)=[CH:51][CH:50]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOCCOCc1ccc(Br)c(COCCOCC)c1
Agent: CCOCCOCc1cccc(COCCOCC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: -40 °C
Yield: 88.7 %

Procedure:
An about 93:7 mixture (34.7 g) of 2,4-bis(1′-ethoxyethoxymethyl)bromobenzene and 2,6-bis(1′-ethoxyethoxymethyl)bromobenzene was dissolved in dehydrated tetrahydrofuran (250 ml) under a nitrogen atmosphere and cooled to −40° C. Thereto was added dropwise a hexane solution (1.57 mol/L, 64.3 ml) of n-butyllithium at a temperature of from −40° C. to −30° C. The mixture was heated to −20° C. and thereto was added dropwise p-fluorobenzaldehyde (12.5 g). The mixture was allowed to warm to 15° C. over 1 hr. The reaction mixture was poured into 20% aqueous ammonium chloride solution (200 ml) and the organic layer was separated. The aqueous layer was extracted with toluene (200 ml). The combined organic layer was washed twice with 20% brine (250 ml) and the solvent was evaporated. To the residue (38.5 g) was added 60% phosphoric acid (300 g) and the resulting solution was stirred at 80-85° C., 9.31-13.3 kPa (70-100 Torr) for 2 hr with heating and cooled to 10° C. The resulting crystals were collected by filtration, washed thoroughly with ethanol and dried to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (20.8 g, 88.7%) as fine yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]([CH2:17][NH:18][CH:19]([CH3:21])[CH3:20])[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10].C[Si](N[Si](C)(C)C)(C)C>CC#N.O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]2[CH2:13][C:14](=[O:15])[N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17]2)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CC(C)NC[C@H](CC(=O)O)Nc1ccc(C#N)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(C)N1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 60 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
The crude (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-[(1-methylethyl)amino]butanoic acid hydrochloride was dissolved in MeCN (20 mL) and treated with HMDS (4 mL) and the reaction was stirred at 60° C. for 15 h. After cooled down, the reaction was diluted with H2O and extracted with Et2O (2×). The combined organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography with 25% EtOAC in hexane grading to 100% EtOAc in hexane to yield the titled product (0.13 g, 49%). LC-MS (ES) m/e 277.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([C:12]1[C:13]([S:23](Cl)(=[O:25])=[O:24])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]>N1C=CC=CC=1.CC(O)C>[C:10]([C:12]1[C:13]([S:23]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:24])=[O:25])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)c(C#N)c2n1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)c(C#N)c2n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A solution of 0.67 g (4.1 mmole) of 2,6-dichloroaniline was stirred at room temperature as a solution of 1.1 g (4.1 mmole) of 3-cyano-5,7-dimethylpyrazolo-[1,5-a]pyrimidine-2-sulfonyl chloride in 3 ml pyridine was added. The mixture was heated at 70° C. for 15 hours, then at 130° C. for 24 hours, and cooled to room temperature. The mixture was diluted with 2-propanol and stirred at room temperature for 1 hour. The tan solid was collected by filtration, washed well with 2-propanol and dried to give 0.9 g tan powder. This was completely dissolved in 2N NaOH and extracted with CH2Cl2. The aqueous layer was separated and acidified with glacial HOAc, which gave a precipitate. This was collected by filtration, washed well with water and dried to give 0.2 g (12.3-percent) of the product as an off-white solid, m.p. 280°-285° C. (decomposition and degassing). 1H NMR (DMSO-d-6): 11.1 (br., 1H, NH), 7.5-7.4 (m, 3H, benzene), 7.5 (s, 1H, pyrazolopyrimidinyl H-6), 2.67 (s, 3H, CH3), 2.63 (s, 3H, CH3). 13C NMR (DMSO-d-6): 165, 156, 150, 148, 136, 130, 129, 114, 111, 80, 24, 16. IR (KBr): 3220, 2240, 1620, 1540, 1440, 1355, 1170 cm-1.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N+]=[N-])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1>C1(C)C=CC=CC=1>[CH:8]1[CH:3]=[CH:4][C:5]2[C:6](=[N:9][O:13][N+:12]=2[O-:14])[CH:7]=1
Reactant: COc1ccc(N=[N+]=[N-])c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: [O-][n+]1onc2ccccc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of the 4-methoxy-2-nitrophenylazide (5.06 g, 26.1 mmol) and 7.8 mL of fleshly distilled toluene was heated to 110° C. for three hours and then cooled to 95° C. and stirred for an additional two hours. The toluene was removed in vacuo to give a brown solid. The crude product was recrystallized from methanol to yield 3.35 g (77% yield) of benzofuroxan as orange-brown crystals (m.p. 114°-115° C.). Rf 0.30 in 20% ethyl acetate/hexane. 1HNMR (CDCl3) δ 6.19 7.45 (m, 3H), 3.89 (s, 3H).
Reaction SMILES: FC1C=C(C=CC=1)CO[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:21][C:19]([F:22])([F:20])[CH:16]1[CH2:15][CH2:14][C:13]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)([C:10]2[CH:9]=[CH:8][C:7]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(C2(c3ccc(OCc4cccc(F)c4)cc3)CCC(C(F)(F)F)CC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(c3ccc(C#C[Si](C)(C)C)cc3)CCC(C(F)(F)F)CC2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 2, step A (200 mg, 0.39 mmol) in 1.2 mL of DMF was added trimethylsilylacetylene (0.085 mL, 0.59 mmol), bis(triphenylphosphine)palladium (II) chloride (83 mg, 0.12 mmol) and triethylamine (0.27 mL, 2.0 mmol). The mixture was stirred at 70° C. under N2 for 1 hour and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% to 20% EtAOc/hexanes to provide the title compound. LC-MS (ESI): m/z=459.4 [M+1]+.
Reaction SMILES: BrC1C=CC2CCC3C=CC=CC=3SC=2C=1.[CH:17]1[C:27]2[CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[S:22][C:21]=2[CH:20]=[C:19]([C:32]([NH2:34])=O)[CH:18]=1>CN(C)C=O>[C:32]([C:19]1[CH:18]=[CH:17][C:27]2[CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[S:22][C:21]=2[CH:20]=1)#[N:34]
Reactant: NC(=O)c1ccc2c(c1)Sc1ccccc1CC2
Agent: Brc1ccc2c(c1)Sc1ccccc1CC2
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)Sc1ccccc1CC2

Procedure:
4.61 G. 3-bromo-10,11-dihydrodibenzo[b,f]thiepin and 4.3 g. cuprous cyanide are refluxed in 50 cc. dimethylformamide for 51/2 hours. The mixture is poured onto ice and the solid filtered. The solid is triturated with chloroform and filtered. The chloroform is evaporated to yield 4.5 g. residue which is chromatographed on silica gel. Elution with benzene affords 2.83 g. (75.4%) of the desired pure oily compound which crystallizes on standing. Elution with ethyl acetate gives 440 mg. 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid amide as a white solid, m.p. 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([Mg]Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+].ClC1C=CC2C(C(C)(C)C)(O)C3=NC=CC=C3CCC=2C=1>C1COCC1>[CH3:19][C:18]([C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:15](=[O:16])[C:10]2=[N:11][CH:12]=1)([CH3:21])[CH3:20]
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Reactant: CC(C)(C)[Mg]Cl
Agent: CC(C)(C)C1(O)c2ccc(Cl)cc2CCc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 20.05 grams (82.28 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 400 ml of dry THF at -72° C. and under an atmosphere of nitrogen was added dropwise over 40 minutes 66.0 ml of 2.7M t-butyl magnesium chloride in THF. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was then poured into 10% aqueous ammonium chloride and extracted four times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to give the title tom pound, along with 8-chloro-11-(1,1-dimethyl-1-ethyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol. These compounds were separated via flash chromatography to give the title compound, which was recrystallized from isopropyl ether to give 4.37 grams (18%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:22])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(Cl)ccc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(N)=S
Yield: 129.9 %

Procedure:
In tetrahydrofuran (100 ml), 4-chloro-2-methoxybenzamide (9.40 g, 50.6 mmol) prepared in the Step 7-1-1 and Lawesson's reagent (10.2 g, 25.3 mmol) were suspended, and the suspension was heated under reflux for 2 hours. After the suspension was allowed to cool, a saturated sodium bicarbonate solution was added to the suspension to stop the reaction. Then the reaction mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (6.63 g, 65%) as a yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+]>CCO>[CH:11]([C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1)=[CH2:12]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1c(Br)cncc1C#N
Agent: [K+]
Solvent: CCO
Product: C=Cc1cncc(C#N)c1C

Procedure:
A mixture of 5-bromo-4-methylpyridine-3-carbonitrile (4.40 g, 22.3 mmol), potassium vinyltrifluoroborate (3.70 g, 27.9 mmol) and Pd (dppf)2Cl2 (0.4 g) in 30 mL of EtOH and 30 mL of TEA was refluxed under Ar for 4 hours. Concentrated, the residue was purified by column chromatography (petrol ether: EtOAc=50:1) to afford 5-ethenyl-4-methylpyridine-3-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:10]([C:14]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=3)[OH:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Bi]=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2ccccc2)cc1Cl
Agent: O=[Bi]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2ccccc2)cc1Cl
Yield: 52.4 %

Procedure:
The benzil compound was synthesized according to the procedure of Example 41, Step 3 using the product of Step 1 (3.5 g, 12 mmol) and bismuth oxide (6.6 g, 14 mmol) in acetic acid (35 ml). There was obtained 2.8 g (85%) of the desired benzil as a-crystalline solid: mp 152-154° C. Anal. Calc'd. for C15H10FClO3 (MW .292.70): C, 61.55; H, 3.44. Found: C, 61.40; H, 3.31.
Reaction SMILES: C1COC2(C3C=CC(C(C)CO)=CC=3C=CC3C=CC=CC2=3)O1.[CH:24]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:40](C)[C:41]([OH:43])=[O:42].C1COC2(C3C=CC(CCO)=CC=3C=CC3C=CC=CC2=3)O1>>[CH:24]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH2:40][C:41]([OH:43])=[O:42]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: CC(CO)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: OCCc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
Using the conditions described in Example 1, 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol is converted, in similar yield, to 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid and 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)ethanol is converted in similar yield to 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid.
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].O=[C:11]1[CH:16]([C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12]1>C(O)C>[CH3:7][C:6]1[N:8]=[C:17]([C:18]([F:21])([F:20])[F:19])[C:16]2[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:12][C:11]=2[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(c(C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 15.4 %

Procedure:
1.3 mL of sodiumethoxide (21% wt. ethanol solution) was added at room temperature to a solution in which 283 mg (3.0 mmol) of acetamidine hydrochloric acid salt was dissolved in 5 mL of absolute ethanol. After stirring of 15 minutes, to the resulting solution, was added a solution in which 590 mg (2.0 mmol) of t-butyl 3-oxo-4-(trifluoroacetyl)-piperidin-1-carboxylate obtained in PREPARATION 47 was diluted with 5 mL of absolute ethanol. The resulting mixture was heated to 80° C. and stirred for 18 hours. After cooling to room temperature, ethanol was distilled off under reduced pressure, followed by washing with saline which was diluted with ethylacetate. An organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and then the residue was purified by column chromatography (10:1 hexane:ethyl acetate) to give 98 mg of the title compound in a yield of 16%.