Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[F:12].CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:32](N1CCOCC1)=[O:33]>O.C1COCC1>[CH3:14][O:13][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:12])=[C:6]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:32]=[O:33]
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(F)c(C(OC)OC)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=O)c(F)c(C(OC)OC)c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To 15 ml of a THF solution containing 3.665 g of 2-dimethoxymethyl-1-fluoro-4-methoxybenzene [CAS No. 883576-30-5] and 3.48 g of N,N,N′,N′,N″-pentamethyldiethylenetriamine, 7.1 ml of n-butyllithium (2.66 M, hexane solution) was added dropwise at −74° C. The resulting mixture was stirred at −60° C. for 3 hours, and then 3 ml of N-formylmorpholine was added thereto. The temperature of the reaction mixture was slowly allowed to rise to room temperature. Then, water was added to the reaction mixture while cooling on ice, and then the mixture was extracted with a mixture of hexane and t-butylmethyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product of 3-dimethoxymethyl-2-fluoro-5-methoxybenzaldehyde.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=[C:25]2[CH3:34]>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:34][C:25]1[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([F:21])[CH:23]=2)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(=O)n(C)c2ccc(F)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)cc(CBr)c2cc(F)ccc21
Temperature: 70 °C
Yield: 38.9 %

Procedure:
2,2′-Azobis(2-methylpropionitrile) (AIBN, 17.2 mg, 0.105 mmol) and N-bromosuccinimide (NBS, 97.7 mg, 0.549 mmol) were added to a suspension of 6-fluoro-1,4-dimethylquinolin-2(1H)-one (100 mg, 0.523 mmol) in CCl4 (10 mL) at 70° C. After 1 h an additional 2 eq. of NBS and 0.4 eq. of AIBN were added and the mixture heated at 70° C. for 1 h. The mixture was concentrated and the residue purified by preparative TLC to give desired the title compound (55 mg, 31%) as white solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1
Reactant: CN1CCNCC1
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1CCN(C2=Nc3ccccc3C(O)(c3ccccc3)C2(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (0.7g., 0.0025 mole) was dissolved in dry dioxan (10 ml.). Triethylamine (0.5g) followed by N-methylpiperazine (1.92g.) were added and the mixture stirred for 4 hours. The mixture was then evaporated down to a white solid residue which was recrystallised from isopropyl alcohol to give the title compound (0.60g., m.p. 268° - 269° C) [Found: C, 75.6; H, 8.1; N, 12.15% C22H27N3O requires C, 75.6; H, 7.8; N, 12.0%].
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C1COCC1>[O:19]1[CH2:8][CH:12]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccnc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: c1cncc(C2CO2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
The title compound was prepared by following general procedure 3. Sodium hydride 50% dispersion in oil (1.64 g, 34.2 mmol, 1.8 equiv.) was taken into DMSO (12 mL) and heated at 65° C. for 1 h. THF (36 mL) was added at the same temperature and heated for 10 min. The reaction mixture was cooled to 0° C. and trimethylsulfonium iodide (3.81 g, 18.6 mmol, 1 equiv.) was added, followed by nicotinaldehyde (2 g, 18.6 mmol, 1 equiv.) and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 3-(oxiran-2-yl)pyridine (1 g).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].[CH3:30][NH2:31].C1COCC1.[BH4-].[Na+]>CO>[CH3:3][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:31][CH3:30])=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:1]
Reactant: CN
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Reaction time: 1 h

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 36) (100 mg, 0.254 mmol) was dissolved in methanol (3 mL) and 2M methylamine in THF (0.254 mL, 0.507 mmol) was added. The yellow solution was stirred under nitrogen at room temperature for 135 minutes at which point sodium borohydride (15.35 mg, 0.406 mmol) was added. The reaction was stirred for 1 h then left sitting overnight. The reaction was quenched with sat. aqueous sodium bicarbonate solution (1 mL) and EtOAc (8 mL) was added. A white solid was filtered off (bond elut reservoir) and found to be the desired product (34 mg). The filtrate was partitioned and the organic layer dried. Concentration of the organic layer gave 67 mg of a colourless residue which was applied to a silica 12+S Biotage column and purified eluting with a gradient of 1-5% methanolic ammonia in DCM. Concentration of the product containing fractions gave another batch of the desired product (52 mg).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:13]2[CH2:14][CH2:15][N:10]([C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]2)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1
Reactant: CC(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
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: CC(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of 1-methylethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)-amino]-1-piperidinyl}propanoate (Int. B5) (80 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (67 mg, 1 equiv), HATU (400 mg, 5 equiv), DIPEA (0.22 ml, 1.5 equiv) and DMF (2.0 ml) was stirred at room temperature for 30 min. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain 1-methylethyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate (25 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([C:11]2[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=2[C:13]#[N:14])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH3:20].CCOC(C)=O>CO>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([S:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:10])[C:12]=1[C:13]#[N:14]
Reactant: N
Reactant: Cc1cc(C)cc(S(=O)c2cccc(F)c2C#N)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(S(=O)c2cccc(N)c2C#N)c1
Temperature: -78 °C
Yield: 59.2 %

Procedure:
2-[(3,5-Dimethylphenyl)sulfinyl]-6-fluorobenzonitrile (Example 19) (0.4 g, 1.5 mmol) was dissolved in 40 ml of methanol and chilled to -78° C. Condensed ammonia (20 ml, 15.4 g, 905 mmol) was added and the mixture was heated to 150° C. in a sealed Parr bomb for 24 h. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.24 g (61%) of 2-amino-6-[(3,5-dimethylphenyl)sulfinyl]benzonitrile: mp 190°-191° C.; NMR (Me2SO-d6, 200 MHz) δ 2.32 (s, 6H), 6.48 (br s, 2H), 6.90 (apparent d, 1H), 7.11 (apparent d, 1H), 7.20 (m, 1H), 7.32 (m, 2H), 7.52 (apparent t, 1H); mass spec (CI) M+ +1=271. Anal. Calc. for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; S, 11.86. Found: C, 66.71; H, 5.27; N, 10.32; S, 11.84.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[NH2:23][C:24]1[C:39]([Cl:40])=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:29])=[C:26]([O:41][CH3:42])[CH:25]=1.O>CN(C)C=O>[ClH:20].[NH2:23][C:24]1[C:39]([Cl:40])=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:19][CH2:18][CH2:17][CH2:16][S:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:14])=[O:15])[CH2:36][CH2:37]2)=[O:29])=[C:26]([O:41][CH3:42])[CH:25]=1
Reactant: O=S(=O)(CCCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Reaction time: 7.5 h
Yield: 13.4 %

Procedure:
Potassium carbonate (0.87 g) and 4-phenylsulfonylbutyl chloride (0.40 g) were added to a solution (15 ml) of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.52 g) in dimethylformamide, and the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained oil was treated with hydrochloric acid-ethanol and the obtained crystals were recrystallized from ethyl acetate to give 0.10 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-phenylsulfonylbutyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14]CC2C=CC=CC=2)[CH:11]=[C:10]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H][H]>[Pd]>[Cl:1][C:2]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Product: OCCCCOc1c(Cl)cc(O)cc1Cl

Procedure:
This compound was prepared in a manner analogous to that of Step A of this example, using 12.2 grams (0.036 mole) of 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butan-1-ol and 0.5 gram (catalyst) of 10% palladium on carbon and a theoretical amount of hydrogen gas in a Parr Hydrogenator. The yield of the subject compound was 9.3 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>C1COCC1>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH:29]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])=[CH:31][CH:32]=1
Reactant: N#CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C=CCCCCCC#N)cc1
Yield: 71.1 %

Procedure:
This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-anisaldehyde (2.72 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the products (3.26 g, 71%) as a colorless liquid (bp: 143-146° C./0.05 torr). IR: 2285 cm-1 ; 1H-NMR: 1.50 (m, 6H), 2.30 (m, 4H), 3.80 (s, 3H), 5.50 (m, 1H), 6.30 (d, 1H), 7.05 (q, 4H).
Reaction SMILES: C1(C)C=CC(S)=CC=1.[OH:9][C:10]1[C:21]([OH:22])=[CH:20][C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]=1[S:23][C:24]1[CH:29]=[CH:28][C:27](C)=[CH:26][CH:25]=1.[N+:31](C1C=CC(S)=CC=1)([O-:33])=[O:32]>CO>[OH:9][C:10]1[C:21]([OH:22])=[CH:20][C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Cc1ccc(Sc2c(O)c(O)cc3c2CCN(C)CC3)cc1
Agent: Cc1ccc(S)cc1
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3ccc([N+](=O)[O-])cc3)c2CC1

Procedure:
Similarly, reaction of 1 g. (0.0075 mole) of p-toluenethiol and 2 g. of the dione in 200 ml. of methanol as described above gave 7,8-dihydroxy-3-methyl-6-(p-tolylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 105°-114° C. and reaction of 1.65 g. (0.0011 mole) of p-nitrothiophenol and 2.3 g. of the dione in 200 ml. of methanol gave 7,8-dihydroxy-3-methyl-6-(p-nitrophenylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 165°-170° C.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7](Br)[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:17][C:18]([F:38])([F:37])[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[N:25]=[CH:24]2)=[O:20]>CCOCC.C1COCC1>[CH2:1]([N:4]1[CH:8]=[C:7]([C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:25]=[CH:24]3)([OH:20])[C:18]([F:37])([F:17])[F:38])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C=CCn1cc(Br)c(C#N)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c(C#N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a chilled (−78° C.) solution of 1-allyl-4-bromo-1H-pyrazole-3-carbonitrile (116.6 mg, 0.550 mmol) in dry ether (2 mL) was added n-BuLi (190 pt, 2.5 M in hexanes, 0.475 mmol). After 2 minutes a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.500 mmol) in THF (2 mL) was added. After 15 minutes, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO2 (0-50% ethyl acetate in hexanes, gradient) to give 152 mg (69%) of the title compound. MS m/z 422.96 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:19]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl>ClCCl.C(O)(C)C>[ClH:1].[NH2:19][CH:8]1[CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=2)[C:16]2[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(N)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl [1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (15 mg, 0.038 mmol) was dissolved in dichloromethane (1.5 mL) and 5 M hydrochloric acid in isopropanol (0.3 mL) was added. The reaction mixture was stirred for 3 h at room temperature. The solvent and the excess hydrochloric acid were evaporated in vacuo. Yield: 11 mg (0.033 mmol, 87%, colorless solid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.B(F)(F)F.[CH3:16][CH2:17]OCC>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 15-(trifluoromethyl)pentadecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 4-[15-(trifluoromethyl)pentadecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the product as a white solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:27](OC)([O:30]C)[O:28]C.Cl>C1COCC1.CCCCCC>[C:16]1([C:11]2[C:12]3[C:7]([N:8]=[CH:9][CH:10]=2)=[C:6]2[C:15]([C:2]([B:27]([OH:30])[OH:28])=[CH:3][CH:4]=[N:5]2)=[CH:14][CH:13]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Temperature: -39 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-7-phenyl-1,10-phenanthroline (1.42 g) is dissolved in THF solvent (15 mL). The mixture is cooled to −39° C. and added over a period of 20 minutes to an n-hexane solution of n-BuLi (1.5 M; 3.12 mL) which has been cooled to −78° C. The reaction mixture is stirred for 30 minutes, followed by the addition of trimethyl borate (0.49 mL) in THF at −39° C. is added over a period of 20 minutes. The reaction mixture is maintained at −78° C. for one hour, then allowed to warn to room temperature over a day. The reaction mixture is acidified with cold 2N HCl extracted with ether. The organic layer is extracted with 1 N NaOH and filtered. To the filtrate is added 2 N HCl at 0° C. to yield a precipitate, which is filtered, washed, dried and re-crystallized from ethanol to give the desired product.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[OH-].[NH4+:17].O>CN1C(=O)CCC1>[NH2:17][C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)OC(=O)c1cc(F)c(F)c(F)n1
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)c1cc(N)c(F)c(F)n1
Reaction time: 8 h
Yield: 68 %

Procedure:
Isopropyl 4,5,6-trifluoropicolinate (17.52 g, 80 mmol) was dissolved in NMP (175 g) in a 500 mL flask equipped with a stirring bar. The mixture was blanketed with nitrogen and then ammonium hydroxide (10.70 g 176 mmol, 28% in water) was added to the flask dropwise at room temperature, and the reaction was stirred overnight. To the reaction was added water (190 mL) and the resulting slurry was cooled in an ice bath and stirred for 5 hours. The solid was collected by filtration and the cake washed with water. Vacuum drying provided the isopropyl 4-amino-5,6-difluoropicolinate as an off-white solid (11.7 g, 68% yield, 96% HPLC purity): mp 167-168° C.; 1H NMR (THF-d8, 300 MHz) δ 7.25 (d, 1H, J=6 Hz), 6.07 (s, 2H), 5.01 (m, 1H, J=6 Hz), 1.20 (d, 6H, J=6.3 Hz); 13C NMR (THF-d8, 75 MHz, 1H decoupled) δ 162.9 (s), 151.5 (dd, J=228 Hz, 12 Hz), 146.1 (dd, J=9 Hz, 6 Hz), 140.4 (dd, J=17 Hz, 5 Hz), 134.5 (dd, J=251 Hz, 32 Hz), 111.9 (m), 68.4 (s), 21.0 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[F:11].[CH2:12](I)C>C(O)C.O>[F:11][C:3]1[CH:4]=[C:5]([S:8][CH2:9][CH3:12])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#CSc1ccc(N)c(F)c1
Reactant: CCI
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7 mL) was added dropwise to a solution of Na2S.9H2O (714 mg, 2.97 mmol) in water (1.5 mL) and the resulting mixture stirred at 50° C. for 1 hour. A solution of ethyl iodide (510 mg, 3.27 mmol) in ethanol (1 mL) was then added and the reaction stirred at 50° C. for a further 6 hours. The mixture was diluted with water (30 mL) and extracted with Et2O (4×10 mL), then the combined Et2O extracts washed with water (3×20 mL), saturated NaCl (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a pale yellow oil which was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to afford 2-fluoro-4-ethylthioaniline as a colourless oil (470 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J=11.3, 2.0 Hz, 1 H), 7.01 (ddd, J=8.2, 2.0, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.81 (br s, 2 H), 2.80 (q, J=7.3 Hz, 2 H), 1.24 (t, J=7.3 Hz, 3 H). Step B: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]-benzoic acid
Reaction SMILES: N1C=CC=CC=1O.C([Zn][CH2:11][CH3:12])C.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH:13]([OH:20])[CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Agent: Oc1ccccn1
Product: CCC(O)c1ccccc1

Procedure:
A dry Schlenk flask under argon was charged with 0.05 equiv. of the pyridinyl alcohol. The flask was evacuated twice and flushed with argon. Then, 5 mL of freshly distilled toluene were added followed by 1.5 equiv. of neat diethylzinc while stirred. After stirring for 20 min at room temperature, 1.0 equiv. of benzaldehyde (10) was added at the given temperature (see Table). The proceeding of the reaction was monitored by thin layer chromatograpy. After full conversion of the aldehyde, the reaction was quenched by careful addition of 10 mL of 2 M HCl, and the resulting mixture was extracted three times with 25 mL of dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/methyl tert-butylether=10:1) followed by Kugelrohr distillation to give 1-phenylpropanol (11) as a colorless oil. The enantiomeric excess of 11 was determined by HPLC on a stationary phase [CHIRALCEL OD, n-heptane/iso-propanol=98:2, 1 0 mL/min; tR=17.2 min (R); 21.5 min (S)], and the absolute configuration was determined by correlation of the optical rotation with the values reported in the literature (Soai, K.; Ookawa.; Kaba, T.; Ogawa, K.; J. Arn. Chem. Soc. 1987, 109, 7111).