Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](O)[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:10][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: CC(O)c1ccc(Br)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cccnc1)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(5-bromopyridin-2-yl)ethanol (600 mg, 3.00 mmol), pyridin-3-ol (283 mg, 2.98 mmol) and triphenyl phosphine (1.54 g, 5.88 mmol) was stirred in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere. After stirring for 1 hour, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (658 mg, 3.26 mmol) was added dropwise and the reaction was stirred at room temperature for 18 hours. Then the solvent was evaporated and the residue was purified by column chromatography (silica gel, pure ether) to 5-bromo-2-(1-(pyridin-3-yloxy)ethyl)pyridine (744 mg, 89%). 1H NMR (300 MHz, CD3OD): δ 8.63-8.62 (m, 1H), 8.21-8.19 (m, 1H), 8.08-8.06 (m, 1H), 7.98-7.94 (m, 1H), 7.45 (d, J=5.1 Hz, 1H), 7.33-7.28 (m, 2H), 5.51 (q, J=6.3 Hz, 1H), 1.68 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[CH2:21]([Sn](CCCC)(CCCC)C(C)=C)[CH2:22][CH2:23]C>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>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:22]([CH3:23])=[CH2:21])=[CH:9][CH:10]=1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)c1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)s1
Yield: 63.4 %

Procedure:
15.0 g (41.17 mmol) of 3-(5-bromo-thiophen-2-yl)-2(R)-tert-butoxycarbonylamino-propionic acid methyl ester was treated with tributyl-isopropenyl-stannane (17.88 g, 54.07 mmol) and Pd(PPh3)4 (4.8 g, 4.15 mmol) as described in the general procedure M to afford 8.50 g of 2(R)-tert-butoxycarbonylamino-3-(5-isopropenyl-thiophen-2-yl)-propionic acid methyl ester.
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>C(O)C>[CH2:19]([O:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1)[CH:18]=[CH2:17]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
In a 1 L, three-necked, round bottom flask 4,4'-biphenol (40 g, 215 mmol) and potassium hydroxide (24 g, 430 mmol) were dissolved in 600 mL of absolute ethanol. The solution was warmed and allyl bromide (26 g, 215 mmol) was added. The reaction mixture was heated to reflux overnight, after which additional allyl bromide (13 g, 157 mmol) was added. The reaction mixture was refluxed for an additional 24 hours. The reaction mixture was cooled to room temperature and the solids were filtered. The filtrate was poured into distilled water (4 L) and then acidified with concentrated aqueous HCl. The solid product was filtered off and washed with a large amount of water and then dried. The product was purified by repeated recrystallization from ethanol. Product characterization included: m.p. 168°-170° C., 1H (200 MHz, CDCl3): 7.05 (m, 4H), 6.8 (m, 4H), 6.1 (m, 1H), 4.4 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[C:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Temperature: 77.5 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (0.2 g, 1 mmol) in toluene (10 mL) and ethanol (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.46 g, 2 mmol) and Pd(PPh3)4 (0.057 g, 0.05 mmol). The reaction mixture was purged with argon for 5 min, 2M Na2CO3 solution (3.5 mL, 0.74 g, 7 mmol) was added, and the reaction mixture was stirred at 75-80° C. for 6 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted into ethyl acetate (2×100 mL). The organic layer was washed with brine and ice-cold water (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel, using 15-16% ethyl acetate in hexane) to obtain 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile as white solid (0.18 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (dd, 1H), 9.20 (dd, 1H), 8.54 (dd, 1H), 8.46 (dd, 1H), 8.23 (dd, 1H), 8.09 (dd, 1H), 2.68 (s, 3H); LC-MS m/z calculated for [M+H]+ 224.07. found 224.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].O[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2)cc1C
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with crude 7.3 (prepared from 7.2 (30.0 g, 90.2 mmol)) and DMF (200 mL) and cooled to 0° C. Next, 4-hydroxybenzotrifluoride (17.5 g, 108 mmol) and K2CO3 (24.9 g, 180 mmol) were added at 0° C., and the reaction heated to 70-80° C. and stirred for 2 h. The reaction mixture was poured into ice-water (400 mL), and the product was extracted with toluene (400 mL). The organic layer was successively washed with water (2×300 mL) and brine (400 mL), dried over MgSO4, and concentrated to give a slightly yellow oil which was purified by flash chromatography (SiO2 gel 60 N, eluted with AcOEt/hexane=⅙). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (40.9 g). 1H NMR (400 MHz) (CDCl3) δ 7.53 (2H, d, J=8.6 Hz); 7.30-7.20 (4H, m); 7.17 (2H, d, J=8.4 Hz); 7.00 (2H, d, J=8.7 Hz); 6.68 (1H, d, J=8.4 Hz); 5.04 (2H, s); 4.66 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.27 (3H, s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Li+].[Cl-]>C1COCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:22]=[CH2:23])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2c(C(=O)OCC)sc(SC)c2C#N)cc1
Yield: 38 %

Procedure:
Combine 4-cyano-3-(4-iodo-phenyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (0.1 g, 1.0 eq) in THF (5.0 mL) and stir. Add Pd(PPh3)4 (1%), tributyl-vinyl-stannane (0.9 eq) and LiCl. Reflux the mixture overnight. Concentrate to dryness. Wash with hexane to remove excess of stannane. Add water and filter the precipitate to provide the title compound (0.04 g, Yield 38%). MS (ES+, m/e): 330 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[S:19][CH2:18]1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[N:22]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:52][CH:51]=2)[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[S:19][CH2:18]1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1

Procedure:
This intermediate is prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[3,4-dihydro-4-oxo-1,5-benzothiazepin-3 (S )yl]butanamide (Example 10, Step C) and 2'-[(t-butoxycarbonylamino)methyl]-1,1 '-biphenyl-4-methanol, methanesulfonate ester (Example 8, Step F) by the procedure described in Example 1, Step D.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11](S(C)=O)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(S(C)=O)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 85 °C
Yield: 78.5 %

Procedure:
Prepared from 400 mg (1.57 mmol) of 1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 600 mg (3.14 mmol) of 1-(4-aminophenyl)-4-methylpiperazine and 605 μL (7.85 mmol) of trifluoroacetic acid in 6.4 mL of acetonitrile. The reaction mixture is heated at 85° C. for 48 hours. After the workup, the crude residue is triturated in ethyl acetate/dichloromethane and filtered. The solids are redissolved in dichloromethane, and the solvent is evaporated under a flow of nitrogen while ethyl acetate is added to maintain a volume of 5 mL. The suspension is filtered, and the solids are washed with ethyl acetate/dichloromethane, and dried to give 470 mg (78%) of the title compound:
Reaction SMILES: [CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)(=[O:39])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)C2CCCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)(=O)C2CCCC2)cc1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of methyl 4-(2-cyclopentylsulfinylamino-5-trifluoromethylphenoxymethyl)benzoate (305 mg; prepared in Reference Example 33.) in methylene chloride (4.0 ml), meta-chloroperbenzoic acid (456 mg) was added at 0° C. The mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure to give the title compound (317 mg) having the following physical data.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][C@@H:24]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.OC1C2N=NNC=2C=CC=1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([NH:23][C@@H:24]([CH2:42][C:43]3[CH:44]=[C:45]([F:50])[CH:46]=[C:47]([F:49])[CH:48]=3)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]3([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)[CH2:30][CH2:29]3)=[O:20])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cccc2c1CCN(Cc1ccccc1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1)c1cccc2c1CCN(Cc1ccccc1)C2=O
Yield: 169.5 %

Procedure:
A solution of 100 mg of 2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 168 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 7.2 mg of hydroxybenzotriazole, 85 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.243 cm3 of N,N-diisopropylethylamine in 10 cm3 of dichloromethane is stirred at a temperature close to 20° C. for 20 h. Dichloromethane is added to the reaction medium. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 400 mg of product obtained are purified by flash chromatography over silica (column: 50 g; particle size: 15-40 μm; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 103 mg of 2-benzyl-N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:15]([Mg]Br)=[CH2:16]>C1COCC1>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:5]([OH:6])[CH:15]=[CH2:16])[C:7]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1c(C(F)(F)F)ccc(Cl)c1F
Solvent: C1CCOC1
Product: C=CC(O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution of 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde (2.052 g, 9.06 mmol) in THF (30 mL) under nitrogen at −78° C. was added dropwise vinyl magnesium bromide (1 M in THF) (11.77 mL, 11.77 mmol). The mixture was stirred for 15 minutes at this temperature then the cooling bath was removed allowing the solution to warm to ambient temperature where it was stirred for 1 h. The reaction was cooled to 0° C. and quenched with 20 mL of aqueous NH4Cl (saturated) and the solvent was removed under a stream of nitrogen. The solid residue was taken up in water/ethyl acetate and phases were separated. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give an oil. The oil was then purified using silica gel chromatography. The desired fractions were combined together to give 1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-ol (1.322 g, 57%) as a faint yellow colored oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6](Cl)=[O:7])[CH3:4].Cl.Cl.[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:32]4[CH2:37][CH2:36][N:35]([C:6](=[O:7])[CH2:5][N:3]([CH3:4])[CH3:2])[CH2:34][CH2:33]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)CN(C)C)CC1
Yield: 44.9 %

Procedure:
N,N-Dimethylaminoacetyl chloride hydrochloride (100 mg) was added portionwise to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg, 0.57 mmol) and diisopropylethylamine (300 μl) in methylene chloride (25 ml) at 0° C. The reaction mixture was allowed to stir for 2 hours to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4), filtered and evaporated. The residues were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10), followed by methylene chloride/methanol (saturated with ammonia) (90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a white foam (0.125 g, 45%); 1H NMR Spectrum: (DMSO d6) 1.50-1.65 (m, 1H); 1.65-1.80 (m, 1H); 1.95-2.15 (m, 2H); 2.25 (s, 6H); 3.10-3.50 (m, 4H); 3.75-4.05 (m, 2H); 3.95 (s, 3H); 4.90 (m, 1H); 7.30 (m, 1H); 7.35 (s, 1H); 7.40-7.60 (m, 2H); 7.85 (s, 1H); 8.40 (s, 1H); 9.65 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:12])/[C:8](=[CH:10]/[CH3:11])/[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])/[C:8](=[CH:10]/[CH3:11])/[CH3:9]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C(\C)C(=O)c1ccccc1

Procedure:
Benzene (1 mL), tigloyl chloride (236 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (126 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:16]2[CH2:17][O:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5 g of 6-phenyl-1-hexanol, 4.6 ml of epibromohydrin, 1.23 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:7 by volume mixture of ethyl acetate and hexane as the eluent, to give 4.35 g of the title compound as a colorless oil having an Rf value of 0.60 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C[Si]([N:13]=[N+:14]=[N-:15])(C)C.CCOCC>O>[N:13]1[NH:14][N:15]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccccn1
Solvent: O
Solvent: CCOCC
Product: c1ccc(-c2cn[nH]n2)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
2-Ethynylpyridine (3.1 g, 30 mmol) and trimethylsilylazide (7.9 mL, 60 mmol) were combined under Ar (g) and heated at 95° C. for 18 h. After cooling to ambient temperature, Et2O (50 mL) and H2O (2 mL) were added and the resulting reaction mixture was stirred for 2 h. The reaction mixture was then extracted with H2O (3×50 mL) and the organic layer extracted with 1M KOH (3×30 mL). The two aqueous layers were combined and the pH adjusted to 7 with HCl (2M), extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated in vacuo to afford 2-(2H-1,2,3-triazol-4-yl)pyridine as a brown solid that was used without further purification.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1.[H-].[Na+].I[CH2:14][CH2:15][CH3:16]>CN(C)C=O.O>[CH2:14]([C:3]1([C:8]([OH:10])=[O:9])[C:4](=[O:7])[CH2:5][CH2:6][S:1][CH2:2]1)[CH2:15][CH3:16]
Reactant: CCCI
Reactant: O=C(O)C1CSCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC1(C(=O)O)CSCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (1.0 g, 5 mmol) in 1 mL of dimethylformamide was added to a stirred mixture of sodium hydride (60% in oil, 0.2.2 g, 5.5 mmol) and 1-iodopropane (0.934 g, 5.5 mmol) in 2.5 mL of dimethylformarnmide at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ether. The etheral layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluted with hexane:ether (19:1) to give 0.277 g of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:8][CH2:7]1)C.CO.[OH-].[Na+].Cl>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:7][CH2:8]1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ccccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCN(c2ccccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
To a suspension of 0.34 g (0.85 mmol) of {1-[2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester in a 1:1 mixture of water:methanol (10 mL) is added 0.64 mL (1.6 mmol) of sodium hydroxide as a 10% aqueous solution. The mixture is heated to 60° C. for 3 hours then cooled to room temperature, diluted with water, and the pH of the mixture is adjusted to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.29 g (92%) of {1-[2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid as a yellow oil.