Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18]>>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][C:12]=1[F:18]
Reactant: N#Cc1cccnc1F
Reactant: Oc1cnc(Cl)c(F)c1
Product: N#Cc1cccnc1Oc1cnc(Cl)c(F)c1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 6-chloro-5-fluoro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 250 (M)+, 252 (M+2)+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:18][O:19][C:20]([CH:22]1[CH:26]([C@@H:27]([CH3:30])[CH2:28]I)[CH2:25][N:24]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:23]1)=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:18][O:19][C:20]([C@@:22]12[CH2:28][CH:27]([CH3:30])[CH:26]1[CH2:25][N:24]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23]2)=[O:21]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@@]12CC(C)C1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A 0.5 M solution of potassium hexamethyldisilazide in toluene (28 mL, 14.0 mmol) was added dropwise to a solution of 4-[(R)-2-iodo-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (5.0 g, 11.5 mmol) in anhydrous tetrahydrofuran (100 mL) in an argon atmosphere at −78° C. After completion of dropwise addition, the mixture was stirred at the same temperature for 30 minutes. An ammonium chloride solution was added, and the mixture was heated to room temperature. After extraction with ethyl acetate, drying over magnesium sulfate, and filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to give 3.2 g (91%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[CH:35][C:27]=2[CH:24]2[CH2:23][CH2:22][NH:21][CH2:26][CH2:25]2)[NH:31][C:30]1=[O:36]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 30.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 3-methyl-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 30.2%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(CO)cc3)CCC2)cc1
Yield: 92.5 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 290 mg (1.9 mmol) of 4-hydroxymethylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:4) gave 255 mg (92%) of 1-[2-(4-hydroxymethylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a solid: mp 82°-85° C; NMR (CDCl3) d 2.04 (m, J=7 Hz, 2H), 2.45 (s, 3H), 2.88 (t, J=7 Hz, 4H), 4.64 (s, 2H), 7.08 (s, 4H), (m, 2H), 7.15-7.25 (m, 4H).
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:14])([F:13])[CH:7]=[CH:8][C:9]([F:12])([F:11])[F:10].[H][H]>>[F:5][C:6]([F:14])([F:13])[CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10]
Reactant: [H][H]
Reactant: FC(F)(F)C=CC(F)(F)F
Solvent: O=[N+]([O-])O
Product: FC(F)(F)CCC(F)(F)F
Reaction time: 2.5 h
Yield: 99 %

Procedure:
In a 20 1 stainless steel autoclave, which had previously been conditioned using 10% strength nitric acid and was equipped with closed circuit heating and an anchor stirrer, 10.0 kg of 1,1,1,4,4,4-hexafluorobutene were heated from 0 to 30 C. over a period of 10 minutes in the presence of 250 g of catalyst (5% by weight of metallic palladium on activated carbon) at a pressure of 20 bar of hydrogen. After reaching this temperature, the hydrogen consumption was compensated for by repeated pressurization with fresh hydrogen at pressures between 20 and 30 bar. After about 2.5 hours the conversion was 87%. 1,1,1,4,4,4-Hexafluorobutane had been formed in a yield of greater than 99% of theory.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:20][C:21]1[C:37]([O:38][CH3:39])=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:20][C:21]2[C:37]([O:38][CH3:39])=[CH:36][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31](=[O:32])[N:33]([CH3:34])[CH3:35])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:6][CH:7]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Br
Temperature: 120 °C
Yield: 45.9 %

Procedure:
2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50 mg, 0.161 mmol), 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (44 mg, 0.161 mmol) and camphorsulfonic acid (56 mg, 0.241 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 90 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 43 mg (51%) of a yellow foam. Compound 6: mp 225° C.; MS (ES+ calculated” 582; found: 583 M+H). 1H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 8.59 (d, J=8, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.49 (m, 3H), 7.10 (t, J=7 Hz, 1H), 6.65 (s, 1H), 6.29 (s, 1H), 3.88 (s, 3H), 3.29 (s, 2H), 3.16 (s, 3H), 3.05 (d, J=4, 3H), 2.99 (s, 3H), 2.89 (s, 2H), 2.77 (s, 2H), 2.71 (s, 6H), 1.66 (br s, 1H) ppm.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1.[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:25]=1[CH:26]=[O:27]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:25]=1[CH:26]([C:18]1[C:17]([Cl:21])=[CH:16][N:15]=[C:14]([Cl:13])[C:19]=1[Cl:20])[OH:27]
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2Cl)c(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
17.2 ml (26.7 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added to a diethyl ether (20 ml) solution of 2.7 g (26.7 mmol) of diisopropylamine at 0° C., followed by stirring for 1 hour. The solution was cooled to −78° C., a toluene solution of 4.8 g (26.7 mmol) of 2,3,5-trichloropyridine was dropwise added thereto, and then a toluene solution of 5.0 g (24.0 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde was dropwise added thereto, followed by stirring for 30 minutes. The temperature was recovered to room temperature, and stirring was carried out further for 1 hour. 30 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added for extraction. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 6.7 g (yield 72%) of amorphous (2,3,4-trimethoxy-6-methylphenyl)(2,3,5-trichloro-4-pyridyl)methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:29]3[C@H:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
N,N'-carbonyldiimidazole (2.43 g) is added to a solution, cooled to +5° C., of 2-dimethylaminophenylacetic acid (2.68 g) in dry dichloromethane (50 cc). The mixture is stirred for 90 minutes at +5° C. and a solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (4.9 g) and triethylamine (4.2 cc) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40:60 by volume) and collecting 125-cc fractions. Fractions 5 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of acetonitrile (40 cc) and isopropyl ether (200 cc). The crystals are drained, washed with isopropyl ether and dried. (3aR, 7aR)-7,7-Diphenyl-2-[2(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (2.58 g) is obtained in the form of white crystals, m.p. 190° C.; [α]D20 =-242° (c=1.18, chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[N:38](C(=O)C)[CH:39]=[CH:40][C:33]=12.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]5[NH:38][CH:39]=[CH:40][C:33]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)n1ccc2c(CN)ccnc21
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc2C(C)(C)C1

Procedure:
A mixture of 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.24 g), 1-(4-aminomethyl-pyrrolo[2,3-b]pyridin-1-yl)-ethanone (0.14 g), DIEA (0.8 mL) and IpOH (0.8 mL) was subjected to a MicroWave condition (170° C., 1000 s) twice. Evaporation of solvent yielded the crude compound, which was purified by chromatography through silica gel (15 g, 5% MeOH/CH2Cl2) to afford 4,4-dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.BrCC1CCCCO1>>[F:52][C:51]([F:54])([F:53])[C:48]1[O:47][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:50][CH:49]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (S)-(2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 53-56° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.74 (dd, J=2.1, 0.9 Hz, 1H), 6.50 (s, 1H), 6.38 (d, J=3.0 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (q, J=267 Hz), 112.8 (q, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: CC(C)=O.[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([CH:23]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>O.C(OCC)C>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:24][CH2:37][C:38]([F:41])([F:40])[F:39])=[C:17]([CH:23]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F

Procedure:
To a refluxing mixture of 100 ml of acetone, 10.3 g (0.0379 mole) of ethyl 5-benzyloxy-2-hydroxybenzoate and 10.5 g (0.0757 mole) of potassium carbonate is added dropwise over about 1 hour 13.2 g (0.0568 mole) 2,2,2-trifluoroethyl trifluoromethanesulfonate. The mixture is heated at reflux for another 16 hours then evaporated to provide a residue which is dissolved in water and diethyl ether. The layers are separated and the ether is washed with water, then saturated sodium chloride solution and dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the diethyl ether is removed by evaporation to provide the product, ethyl 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoate. The infrared spectrum of this material is consistent with the assigned structure.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.[C:17]1([N:23]2[C:27]([CH3:28])=[C:26](I)[N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][C:39](=O)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1.[Cu]I.O>[C:17]1([N:23]2[C:27]([CH3:28])=[C:26]([N:40]3[CH2:39][CH2:38][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH2:42][CH2:41]3)[N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cc1c(I)nnn1-c1ccccc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1
Temperature: 90 °C
Yield: 14.9 %

Procedure:
In a nitrogen atmosphere, 2 g of tripotassium phosphate, 50 mg of copper(I) iodide and 1 ml of trans-1,2-diaminocyclohexane were successively added to a solution of 500 mg of 1-phenyl-5-methyl-4-iodo-1H-[1,2,3]triazole and 700 mg of 4-(tert-butyloxycarbonyl)piperazin-2-one in 10 ml of dioxane and the mixture was stirred for one night at 90° C. After addition of water, the product was extracted with ethyl acetate and the organic layer washed with water and dried over sodium sulfate. A borane methyl sulfide complex (0.1 ml) was added to the residue after evaporation of the solvent in vacuo and the mixture was stirred at room temperature for 1 hour. After addition of pyridine, the residue prepared by evaporation in vacuo was purified by a silica gel chromatography (hexane:ethyl acetate=3:1) to give 90 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:13]([F:16])([F:15])[F:14])=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([C:3]1[O:4][C:5]([C:13]([F:16])([F:15])[F:14])=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(CC)oc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc(C(=O)O)c(C(F)(F)F)o1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 45.4 %

Procedure:
To a solution of ethyl 2-ethyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylate (2.00 g, 8.43 mmol) in ethanol (10 mL) was added 8N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (800 mg, 45%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH:15]([C:17]([O:19]C)=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:24][O:23][C:21]([N:12]1[CH2:13][CH2:14][CH:15]([C:17]([OH:19])=[O:18])[CH2:16][CH:11]1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)=[O:22]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(S(C)(=O)=O)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(S(C)(=O)=O)cc1
Yield: 83.2 %

Procedure:
Dimethyl 2-(4-(methylsulfonyl)phenyl)piperidine-1,4-dicarboxylate (5.952 g, 16.75 mmol) was dissolved in acetonitrile (50 mL) and water (1.000 mL), then lithium bromide (11.64 g, 133.98 mmol) added. Triethylamine (9.29 mL, 66.99 mmol) was added and the reaction mixture heated under reflux for 1.5 h. MTBE (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (2×200 mL). The combined aqueous phases were acidified to pH 1 with 3 M HCl and extracted with MTBE (2×500 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo yielding 1-(methoxycarbonyl)-2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylic acid (4.76 g, 83%). MS m/z 342 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[CH:19]1([CH2:18][O:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(cc1OCC1CC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-cyclopropylmethoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 190.4 ([M+H]+, 100%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[N:32]=[C:31]5[C:26]([CH:27]=[CH:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[N:32]=[C:31]5[C:26]([CH:27]=[CH:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:16][CH2:17]3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4CC(O)CC5)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 7-{4-[4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one (1.20 g, 2.69 mmol) in methanol (10 mL) was added portionwise NaBH4 (0.41 g, 10.76 mmol). The reaction mixture was stirred at room temperature for 30 min and quenched with saturated NH4Cl solution and the compound was extracted with CH2Cl2 (2×20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (10% methanol in ethyl acetate) to afford the title compound (0.60 g, 50%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 7.72 (d, 1H), 7.63 (d, 1H), 7.12 (t, 1H), 6.91 (d, 1H), 6.85 (d, 1H), 6.59 (d, 1H), 6.52 (d, 1H), 4.23 (t, 2H), 4.13–4.08 (m, 1H), 3.25–3.20 (m, 1H), 3.02–2.83 (m, 6H), 2.61–2.47 (m 6H), 1.88–1.71 (m, 6H). ES MS: 449.26 (M+1)+ (Exact mass: 448.25).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6](O)[CH3:7])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([N:11]=[N+:12]=[N-:13])[CH3:7])=[CH:4][CH:3]=1
Reactant: C[C@@H](O)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@H](N=[N+]=[N-])c1ccc(F)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a cooled solution (−15° C.) of the product of Step 1 (23.5 g, 0.168 mol) in toluene (300 ml) was added diphenylphosporyl azide (55.4 g, 0.395 mol) followed by DBU (30.4 ml, 0.2 mol). After stirring overnight, the resulting biphasic solution was poured into 500 ml 1 N HCl. The aqueous layer was extracted with toluene and the combined organic layers were washed with water, 1 N HCl and dried over Na2SO4. After removal of solvent, 25 g of crude product was obtained and was carried on to next step without further purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].[OH-].[K+].O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:19][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Temperature: 150 °C
Yield: 54.8 %

Procedure:
5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (500.0 mg, 0.00315 mol), 3,4-dichlorophenol (565 mg, 0.00344 mol) and potassium hydroxide (265 mg, 0.00472 mol) were stirred in DMF (2.0 mL). Mixture was heated at 150° C. for 20 min using microwave. Water was added and resulting mixture was extracted with ethyl acetate. Organic layer was washed with brine twice, dried over MgSO4 and evaporated. The resulting oil was purified by column chromatography (10% to 20% ethyl acetate/heptane) to give 5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (492 mg, 54.7%) as white solid.