Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.N1C=CC=CC=1>CS(C)=O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propan-1-ol, prepared in the previous step, in DMSO (100 mL) at room temperature was added triethylamine (13.1 g, 129 mmol, 18 mL) and SO3.pyridine (4.52 g, 28.4 mmol). The reaction mixture was stirred at room temperature for 30 min, diluted with Et2O, washed with water (1×), saturated NH4Cl (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 5% to 40% EtOAc in hexanes) gave 3,3-bis(4-fluorophenyl)propanal.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][N:9]=1)=[O:6].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:20][CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][N:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)C(=O)Nc1nnc(C(F)(F)F)s1
Solvent: c1ccccc1
Product: CN(CCCl)C(=O)Nc1nnc(C(F)(F)F)s1

Procedure:
The N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 6, thionyl chloride (5 ml) and benzene (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux with stirring, for a period of about one-half hour. After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiaidazol-5-yl)urea as a solid residue.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:15](=[O:17])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:15](=[O:17])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(=O)N(CCNC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CC(=O)N(CCNC(=O)OCc1ccccc1)c1ccc(N)cc1

Procedure:
450 mg (1.26 mmol) of 4-[N-(2-benzyloxycarbonylamino-ethyl)-N-acetyl-amino)-nitrobenzene (prepared analogously to Example I) are dissolved in 20 ml of methanol and after the addition of 100 mg of Lindlar catalyst hydrogenated for 2 hours with hydrogen. The catalyst is filtered off, the solution is evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]=[C:28]=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[NH3:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1ccc(Cn2c(CC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: CO
Product: NC(=S)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 25 parts of 1-[(4-fluorophenyl)methyl]-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1H-benzimidazole and 160 parts of methanol saturated with ammonia was stirred overnight at room temperature. The reaction mixture was evaporated, yielding 25 parts (100%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea (449).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:31])[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br)([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:31])[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:1]=[N+:2]=[N-:3])([CH3:8])([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
Sodium azide (1.5 g, 23 mmol) was added to a solution of compound 3 (1.9 g, 4.1 mmol) in dry DMF (50 mL) and the resulting mixture was stirred at 80° C. overnight. The reaction mixture was concentrated in vacuo and then triturated with CH2Cl2 (20 mL) and filtered to remove sodium azide. The filtrate was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (200 g) and eluted with CH2Cl2:MeOH 100:0 to 20:1 (v/v) to afford compound 4 as a colorless oil (1.0 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[S:14]([CH2:24][N+:25]#[C-:26])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[C-]#N.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[C@H:4]1[O:5][CH:26]=[N:25][C@@H:24]1[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2cc(C(F)(F)F)ccc2F)cc1

Procedure:
In a manner analogous to Preparation 1, 2-fluoro-5-(trifluoromethyl)benzaldehyde (0.26 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) δ2.48 (s, 3H), 5.10-5.14 (dd, 1H), 6.12-6.16 (dd, 1H), 7.16-7.20 d, 2H), 7.40-7.44 (dd, 2H), 7.52-7.56 (d, 1H), 7.66-7.70 (d, 1H), 7.88-7.92 (dd,2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14](Cl)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:37])([F:38])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:39])([CH3:40])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(Cl)c1nccs1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1Cc1nccs1
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
(2R,5R)-5-(Chloro-thiazol-2-yl-methyl)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.03 g, 0.05 mmol), Pd/C (0.01 g, 0 mmol), triethylamine (0.01 g, 0.1 mmol) were dissolved in EtOAc (0.2 mL) and hydrogenated at room temperature and 1 bar for 30 minutes, followed by hydrogenation at 40 psi in a Parr hydrogenator for 1 h. The reaction was filtered and solids washed with EtOAc. The filtrate was concentrated and the crude product was purified by column chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60), to give the title compound (0.011 g). MS: [M+H]+=578.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:11]>>[NH2:11][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: N#Cc1cccnc1Cl
Agent: [OH-]
Product: N#Cc1cccnc1N
Temperature: 120 °C

Procedure:
Add 100 mL ammonium hydroxide to a sealed tube containing 12.5 gm (90.21 mMol) 2-chloro-3-cyanopyridine. Seal the tube and heat the suspension at 120° C. for 6 hours. Cool the reaction mixture to room temperature and partition between ethyl acetate and saturated aqueous sodium bicarbonate. Extract the aqueous phase with ethyl acetate (3×100 mL) followed by 70:30 ethyl acetate:n-butanol (2×100 mL). Combine organic phases and concentrate under reduced pressure to provide 2-amino-3-cyanopyridine.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1.[C:17](#[N:20])[CH:18]=[CH2:19]>C(O)C>[F:5][C:6]([F:15])([F:16])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:19][CH2:18][C:17]([NH2:20])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Sodium ethoxide (3.9 g, 0.056 mmol) dissolved in ethanol (100 mL) and 3-(trifluoromethyl) phenylhydrazine (5 g, 0.028 mol) added followed by acrylonitrile (2.3 mL, 0.035 mol) and heated to reflux for 24 h. The solution was then evaporated to dryness in vacuo and water added. The solution was then extracted into dichloromethane and the organics combined, dried (Na2SO4), filtered and evaporated to dryness. The residue was then passed through a silica gel column eluting with dichloromethane:methanol. Product fractions collected and evaporated to dryness, dissolved in dichloromethane and 1M hydrogen chloride in diethyl ether added to form a white solid which was collected by filtration and dried (3 g, 40%). 1H NMR (400 MHz, CD3OD) δ ppm 3.23 (2H, br m), 4.04 (2H, br m), 7.32-7.37 (3H, br m), 7.56 (1H, br s). MS (ES) m/z: 230.0 [M+H].
Reaction SMILES: [I:1]I.[C:3]1([CH2:9][CH2:10]O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[C:3]1([CH2:9][CH2:10][I:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
Iodine (12.0 g, 47.4 mmol) was added in one portion to a solution of 2-phenylethanol (5.11 g, 36.5 mmol), triphenylphosphine (11.47 g, 43.8 mmol) and imidazole (3.48 g, 51.04 mmol) in dichloromethane (250 mL) at 0° C. The resulting mixture was allowed to warm slowly to rt and stir overnight, then was transferred to a separatory funnel and washed with water (2×250 mL), saturated aqueous Na2S2O3 (2×100 mL), water (100 mL), and brine (100 mL). The organic phase was dried over MgSO4, filtered and concentrated to a colorless oil that contained a large amount of white solid. The mixture was treated with heptane (2×50 mL) and was filtered. The filtrate was concentrated and the resulting material was again treated with heptane (2×50 mL) and filtered. The filtrate was concentrated to provide 2-phenylethyl iodide as a clear colorless oil (1.74 g, 19%) that contained a trace amount of triphenylphosphine oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:13][C:12]([C:14](=[O:45])[CH:15]([NH:24][C:25]([CH:27]2[N:32]3[C:33](=[O:44])[CH:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:35][CH2:36][C:37](=[O:38])[N:31]3[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[N:11][CH:10]=1.C(NC1C(=O)N2C(C(NC(C(=O)COC(=O)C3C(Cl)=CC=CC=3Cl)CC(O)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1.[K+].[Br-]>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[O:13][C:12]([C:14](=[O:45])[CH:15]([NH:24][C:25]([CH:27]2[N:32]3[C:33](=[O:44])[CH:34]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH2:35][CH2:36][C:37](=[O:38])[N:31]3[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:16][C:17]([OH:19])=[O:18])=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NS(C)(=O)=O)C(=O)N12)C(=O)c1ncc(-c2c(Cl)cccc2Cl)o1
Agent: O=C(O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)O)C(=O)c3ncc(-c4c(Cl)cccc4Cl)o3)N2C1=O

Procedure:
was prepared from 219b in an analogus way to compound 217e as a pale cream powder (396 mg, 87%): mp 100-200° C.; [α]D27 −129 (c 0.12, MeOH); IR (KBr) 3310, 3153, 1713, 1667, 1557, 1510, 1432, 1421, 1329, 1273, 1258, 1221, 1193, 1153, 1134, 992, 789; 1H NMR (d6 DMSO) δ7.88 (1H, s), 7.81-7.60 (4H, m), 5.49-5.28 (1H, m), 5.24-5.14 (1H, m), 4.46-4.22 (2H, m), 3.30-3.03 (2H, m), 2.97-2.76 (3H, m), 2.96 (3H, s), 2.46-2.24 (1H, m), 2.16-2.05 (1H, m), 2.03-1.78 (3H, m), 1.68-1.46 (2H, m); MS (ES−) 632/30/28 (M−1, 68%), 149/7/5 (100). Accurate mass calculated for C24H26N5Cl2O9S (MH+): 630.0828. Found: 630.0852.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH:5]=2)[CH2:27][CH2:26]1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC1CC1
Product: COc1ccc(C(=O)NC2CC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned-compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and cyclopropylamine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.CCN(CC)CC.C[CH2:18][O:19][C:20](C)=[O:21]>CO.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:18][O:19][C:20]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)=[O:21]
Reactant: Cc1cc(F)cnc1Br
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ncc(F)cc1C
Reaction time: 20 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-methyl-pyridine (4.90 g) in AcOEt (100 ml) and MeOH (10 ml) was subsequently added NEt3 (5.4 ml) and 1,1′-bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane adduct (490 mg) and the mixture was carbonylated at 100 bar CO and 110° C. for 20 h. The mixture was evaporated and the residue purified by chromatography on silica gel using n-heptane/AcOEt (7:1) to give the title compound (3.44 g) as a pale red solid. MS: m/z=170.1 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[CH:16][C:15]=2[CH:30]=1)(C)(C)C.[C:32]1(OB(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F-].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:26]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:5])=[O:31])=[CH:30][C:15]=3[CH:16]=2)[CH:24]=[CH:23][C:22]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2oc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2c1
Reactant: OB(O)Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)CCNCc1ccc2oc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1

Procedure:
To a solution of 3-{[2-(4-chloro-3-trifluoromethyl-phenyl)-benzofuran-5-ylmethyl]-amino}-propionic acid tert-butyl ester (1 eq) and phenyl boric acid (1.5 eq) in THF (0.5 M) is added palladium(II) acetate (0.1 eq), 2-(dicyclohexylphosphino)biphenyl (0.2 eq) and potassium fluoride (4.0 eq). The mixture is irradiated with microwave at 120° C. for 45 minutes. The product, 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzofuran-5-ylmethyl]-amino}-propionic acid tert-butyl ester, is purified with column chromatography. The ester is hydrolyzed with TFA in CH2Cl2 (1:2, v/v) at room temperature. It is purified with preparative LCMS to afford 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzofuran-5-ylmethyl]-amino}-propionic acid, which is converted to HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.29 (d, 1H), 8.18 (dd, 1H), 7.82 (d, 1H), 7.71 (d, 1H), 7.55-7.30 (m, 8H), 4.36 (s, 2H), 3.32 (t, 2H), 2.77 (t, 2H); MS (ES) 440.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH:19]=[CH:20][CH:21]=[O:22]
Reactant: CN(CCOc1ccc(/C=C/CO)cc1F)c1ccccn1
Agent: [Mn+4]
Agent: [O-2]
Product: CN(CCOc1ccc(C=CC=O)cc1F)c1ccccn1

Procedure:
In substantially the same manner as in Reference Example 35, (E)-3-[3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]-2-propen-1-ol was subjected to oxidation reaction with activated manganese dioxide to yield 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamaldehyde, which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.93-94° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][C:28]([OH:35])=[CH:29][CH:30]=2)[N:25]=1>>[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][C:28]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:29][CH:30]=2)[N:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1cc(C)c2ccc(O)cc2n1
Product: COc1cc2c(Oc3ccc4c(C)cc(C)nc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 26.6 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 10), was reacted with 2,4-dimethyl-7-hydroxyquinoline (87 mg, 0.5 mmol), (Chem. Berichte, 1903, 36, 4016), to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (61 mg, 33%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:25]=1)#[N:30]
Reactant: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.2 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 524 mg of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane at room temperature. After stirring at room temperature for 17 hours the solution was washed with sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:4) for the elution. There were obtained 240 mg of 2-(6-cyano-2,2-dimethyl-2H1-benzopyran-4-yl)pyridine N-oxide of melting point 187°-189° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Yield: 95.4 %

Procedure:
Treatment of ((2R)-8-(biphenyl-2-yl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (1.36 g, 2.79 mmol) with platinum (IV) oxide (84% Pt, 0.35 g) in ethanol (40 mL) and ethyl acetate (10 mL) according to the procedure described for Example 69, Step 8 provided 1.30 g (96%) of ((2R)-8-(biphenyl-2-yl)-6-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as an off-white solid. MS (ESI) m/z 489.2 ([M+H]+); m/z 506.2 ([M+NH4]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([F:54])[CH:43]=1>C(Cl)Cl>[CH3:49][O:48][C:46](=[O:47])[C:45]1[CH:50]=[C:51]([O:52][CH3:53])[C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:43][C:44]=1[F:54]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 15 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μmol, Eq: 1.00), was combined with CH2Cl2 (3 ml) to give a clear solution. DIPEA (242 mg, 327 μl, 1.87 mmol, Eq: 3.5) and diphenylphosphenic chloride (316 mg, 255 μl, 1.34 mmol, Eq: 2.5) were added and the reaction was stirred at RT for 5 minutes. Methyl 4-amino-2-fluoro-5-methoxybenzoate (107 mg, 535 μmol, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([OH:23])[CH2:19][C:20]([OH:22])=O)=[CH:12][CH:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[S:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C)C=O>[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH:18]([OH:23])[CH2:19][C:20]([N:56]2[CH2:57][CH2:58][S:54][CH2:55]2)=[O:22])=[CH:14][CH:15]=1
Reactant: O=C(O)CC(O)CCc1ccc(-c2ccccc2)cc1
Reactant: C1CSCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(O)CCc1ccc(-c2ccccc2)cc1)N1CCSC1
Reaction time: 0.08 h
Yield: 47.2 %

Procedure:
Diisopropylethylamine (32 μL, 0.19 mmol) was added to a stirred solution of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid (Example 1, 25 mg, 93 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.19 mmol) in dimethylformamide (1 mL) at room temperature under nitrogen. After stirring for 5 minutes, thiazolidine (11 μL, 0.14 mmol) was added then stirring was continued for a further 2 hours. The volatiles were removed by evaporation under reduced pressure and the residue partitioned between dichloromethane (5 mL) and water (5 mL). The phases were separated and the organic phase evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1:1 ethyl acetate: 40–60 petroleum ether) to give the title compound (15 mg, 47%) as a white solid. LC/MS: 3.22 min; z/e 342, calcd (M+1) 342.