Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.25 mmol), 4-chlorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in dioxane (2.0 mL) at 20° C. was added K2CO3 (40 mg, 0.28 mmol) in water (0.6 mL). The resulting reaction mixture was stirred at 100° C. for 15 h under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (38 mg, 0.10 mmol) as a yellow solid. MS: [M+H]+=380. 1H NMR (CD3OD): δ 7.73 (d, J=1.8 Hz, 1H), 7.50 (q, 4H), 6.93 (d, J=1.9, 1H), 3.71 (d, J=1.8, 2H), 2.12 (m, 1H), 0.90 (d, J=1.7, 6H).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[CH:14]2)[N:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[N+:32]([O-])=O)[N:5]=1)([CH3:3])[CH3:2].[Cl-].[NH4+]>C1COCC1.CO.O.[Fe]>[NH2:32][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[N:6]1[C:7]2[C:12](=[C:11]([N:13]3[CH:17]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:15]=[CH:14]3)[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]1)[C:28]#[N:29]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2[N+](=O)[O-])c2cccc(-n3cnc(-c4cccnc4)c3)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nn(-c2ccc(C#N)cc2N)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 80 °C
Yield: 88.9 %

Procedure:
A solution of compound (10a) (470 mg), iron powder (584 mg) and ammonium chloride (470 mg) in THF (3.5 mL), methanol (3.5 mL) and water (3.5 mL) was stirred under heating at 80° C. for 2 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling, filtered, and the filtrate was concentrated. Water was added to the obtained residue to precipitate a solid, which was collected by filtration and dried to obtain compound (10b) (390 mg, yield 89%) as a milky white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: COc1ccc(B(O)O)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OC)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4-methoxyphenylboronic acid.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Li].O>CCOCC>[OH:1][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:2]1
Reactant: c1ccc2c(c1)CC1OC1C2
Reactant: [Li]c1ccccn1
Solvent: CCOCC
Solvent: O
Product: OC1Cc2ccccc2C(c2ccccn2)C1
Temperature: -20 °C

Procedure:
A solution of 25 g of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene in 250 ml ether is added to a solution of 2-pyridyl lithium (prepared from 2-bromopyridine and butyllithium) cooled to -20° C. After addition, the mixture is allowed to come to room temperature over several hours, then cooled again and treated with water. The separated, dried organics are taken to dryness, and the product purified by chromatography in neutral alumina.
Reaction SMILES: [C:1](/[C:3](/[CH3:15])=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([CH:3]([CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(/C=C(\C)C#N)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CC(C)C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-[(1E)-2-cyanoprop-1-en-1-yl]benzoate (108 mg, 537 μmol) in ethanol (4 mL)/tetrahydrofuran (1 mL) was added 10% palladium-carbon (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 4 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(2-cyanopropyl)benzoate as a colorless oil.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:33])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)=[O:43])=[CH:37][CH:36]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:33])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:47]([C:44]4([C:42](=[O:43])[NH:41][C:38]5[CH:37]=[CH:36][C:35]([F:34])=[CH:40][CH:39]=5)[CH2:45][CH2:46]4)=[O:48])=[CH:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reaction time: 15.5 h
Yield: 70.4 %

Procedure:
A crude product of [4-(4-aminophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (820 mg) was dissolved in N,N-dimethylformamide (15 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (830 mg), triethylamine (0.519 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.65 g) were added in this order under a nitrogen atmosphere at room temperature, followed by stirring for 15.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The resultant organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white foam (845.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:37]([N:39]([CH2:42][CH2:43]Cl)[CH2:40][CH3:41])[CH3:38]>>[CH2:37]([N:39]([CH2:42][CH2:43][O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:29])([F:30])[F:28])=[CH:24][C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH2:40][CH3:41])[CH3:38]
Reactant: Cc1cc(C(F)(F)F)n(C)c(=O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-20 pyridinyl]-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester can be prepared from N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine and 2-[(N,N-diethyl)amino]ethyl chloride hydrochloride using the general procedure described in example 39.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 g (3.43 mmol) of 4-(benzyloxy)-3-bromobenzaldehyde [Lit.: R. Baker et al., J. Chem. Soc. Chem. Commun. 14, 1102-1104 (1987)] is initially charged in 10 ml of tetrahydrofuran. At 0° C., 0.04 g (1.03 mmol) of sodium borohydride is added. The reaction mixture is stirred at room temperature for 3 hours. Saturated ammonium chloride solution is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried with sodium sulphate and the solvent is removed under reduced pressure. This gives 0.98 g (97% of theory) of [4-(benzyloxy)-3-bromophenyl]methanol.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14]C2C=CC=CC=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CO.O.Cl>[O:1]([C:8]1[CH:9]=[C:10]([NH:14][NH2:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: c1ccc(Nc2cccc(Oc3ccccc3)c2)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: NNc1cccc(Oc2ccccc2)c1
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To a solution of 3-phenoxy-phenylaniline (2.32 g, 12.5 mmol) in methanol (5 mL), water (10 mL) and concentrated HCl (3 mL) at 0° C. was added in rapid drops a solution of sodium nitrite (0.87 g, 12.7 mmol) in water (2 mL). The reaction was stirred 10 min then treated in rapid drops with a 0° C. solution of tin chloride dihydrate (6.77 g, 30 mmol) in concentrated HCl (25 mL). The reaction was stirred for 1 h, then adjusted to ˜pH 7 with 6N NaOH and sodium bicarbonate, then filtered through Celite, washing with 1:3 methanol: dichloromethane. The filtrate was separated, the aqueous phase was extracted with 1:3 methanol:dichloromethane (2×). The combined organic layer was dried over sodium sulfate, evaporated, then purified by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes to provide (3-phenoxy-phenyl)-hydrazine (1.78 g, 71% yield) as an orange oil. 1H-NMR (CDCl3, 500 MHz) 7.30 (m, 2H), 7.14 (t, 1H), 7.08 (t, 1H), 7.00 (m, 2H), 6.52 (m, 1H), 6.47 (m, 1H), 6.45 (m, 1H) 5.2 (br 1H), 3.5 (br 2H) ppm; MS (FIA) 201.1 (M+H); HPLC (method A) 2.887 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: COc1ccc(C(=CN(C)C)C(C)=O)cc1

Procedure:
35 g of 3-(4-methoxyphenyl)-2-propanone and 70 ml of dimethylformamide dimethyl acetal are heated at 70° C. for 3 hours. The reaction mixture is then evaporated to dryness in vacuo, and the residue is induced to crystallise with petroleum ether and the crystals are filtered off with suction. 43 g of 4-dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one are obtained. Melting point 51° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]=[N+:26]=[N-:27])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([Sn:32]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]#[CH:34])[CH2:29][CH2:30][CH3:31]>O1CCOCC1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:34]=[C:33]([Sn:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(N=[N+]=[N-])cc32)n1)c1ccccc1
Solvent: C1COCCO1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccc3ncn(-c4ccnc(N[C@@H](C)c5ccccc5)n4)c3c2)nn1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution containing 95 mg of 2-[(S)-1-phenylethylamino]-4-[6-azidobenzimidazol-1-yl]pyrimidine and 386 μL tributyl-ethynylstannane in 2 mL 1,4-dioxane was stirred at 100° C. for 48 hours under 1 atm of nitrogen. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 139 mg of the title compound. RF: 0.4 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, CD3OD): δ0.91 (t, J=7.4 Hz, 3H), 1.25 (t, J=8.1 Hz, 2H), 1.39 (m, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.65 (m, 2H), 5.22 (q, J=7.1 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 7.0-7.4 (m, 5H), 7.76 (m, 1H), 7.85 (d, J=8.7 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.50 (s, 1H), 8.91 (m, 2H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 673.2 (M+1).
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[C:47]([C:51]1[CH:56]=[CH:55][C:54]([C:57](=[O:62])[CH2:58][CH2:59][CH2:60]Cl)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>>[C:47]([C:51]1[CH:52]=[CH:53][C:54]([C:57](=[O:62])[CH2:58][CH2:59][CH2:60][N:44]2[CH2:45][CH2:46][N:41]([C:33]3[CH:34]=[C:35]([F:40])[C:36]([O:38][CH3:39])=[CH:37][C:32]=3[F:31])[CH2:42][CH2:43]2)=[CH:55][CH:56]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)cc1F
Yield: 79.8 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 1-(4-tert-butylphenyl)-4-chlorobutan-1-one (239 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate) to provide 1-(4-tert-butylphenyl)-4-[4-(2,5-difluoro-4-methoxyphenyl)piperazin-1-yl]-butan-1-one (343 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])[CH3:30].C(COC)OC.C(=O)(O)[O-].[Na+]>O.[Pd].C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:19][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:11]=[CH:12][C:7]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([C:29](=[O:31])[CH3:30])[CH:37]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cccc(-c2ccccc2)c1OCc1ccccc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Yield: 98.2 %

Procedure:
A mixture of 31 (3.18 g, 7.8 mmol), 3-acetylphenylboronic acid (1.6 g, 9.76 mmol, 1.25 equiv.), glyme (5 mL), bis(triphenylphosphine)palladium(II) dichloride (25 mg) and sodium bicarbonate (2.1 g) in water (40 mL) was kept at reflux under nitrogen for 11 hr with additional palladium catalyst (2×30 mg) added after 3 and 7 hr. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2×800 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (120 g) with 2% ethyl acetate in heptane (4 L) to afford 32 (2.9 g, 100%).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[CH2:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.Cl>CN(C)C=O>[CH2:1]([N:7]([CH2:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CCCCCCNc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of N-hexyl-4-phenyl-1,3-thiazol-2-amine (390 mg) in N,N-dimethylformamide (1.0 mL) was added sodium hydride (60%, oil, 50 mg) at room temperature and the mixture was stirred at room temperature for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:19 to 1:1 by volume ratio) to give the title compound (260 mg, yield 48%) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].[CH:14](O)([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-hydroxy-4-methoxybenzoate (3.00 g, 16.5 mmol), isopropanol (1.9 mL, 24.8 mmol) and triphenylphosphine (5.40 g, 20.6 mmol) in ethyl acetate (70 mL) was added, dropwise, diethyl azodicarboxylate (3.9 mL, 25 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated. The resulting yellow oil was taken up in 1:1:1 tetrahydrofuran/methanol/1 N aqueous sodium hydroxide (120 mL) and heated at reflux. After 4 hours additional 1 N aqueous sodium hydroxide (10 mL) was added and the mixture was stirred at room temperature overnight. The reaction was then concentrated to remove organic solvents and diluted with water. After washing several times with ethyl acetate, the solution was stirred and acidified with 1 N aqueous hydrochloric acid (50 mL). The resulting precipitate was filtered off, rinsed with water and vacuum oven dried to afford 2.83 g (82%) of product as a white solid: 1H NMR (DMSO-d6) δ 12.64 (s, 1H), 7.53 (dd, J=8.4, 1.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.55 (sept, J=6.0 Hz, 1H), 3.71 (s, 3H) ppm.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[Cl:30][C:31]1[C:32]([C:44](O)=[O:45])=[N:33][CH:34]=[C:35]([O:37][CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])[CH:36]=1>>[Cl:30][C:31]1[C:32]([C:44]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:45])=[N:33][CH:34]=[C:35]([O:37][CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])[CH:36]=1
Reactant: O=C(O)c1ncc(OC[C@H]2CC2(F)F)cc1Cl
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ncc(NC(=O)c2ncc(OC[C@H]3CC3(F)F)cc2Cl)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 3-chloro-5-(((1R)-2,2-difluorocyclopropyl)methoxy)pyridine-2-carboxylic acid, and in the same manner as in Step A of Example 4 and Step D of Example 83, the title compound was obtained.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:25]2[CH:24]=[CH:23][C:22]3[O:17][CH2:18][CH2:19][O:20][C:21]=3[CH:26]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc3c(c1)OCCO3)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[C:26]2[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH:31]([OH:34])[CH2:32][CH3:33])[C:18]=1[C:35]([NH:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=[O:36].[C:43](O)(=[O:46])[CH2:44][CH3:45].C(NC1CCCCC1)(NC1CCCCC1)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:16][C:17]1[C:26]2[C:21](=[C:22]([C:27]([F:29])([F:28])[F:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH:31]([O:34][C:43](=[O:46])[CH2:44][CH3:45])[CH2:32][CH3:33])[C:18]=1[C:35]([NH:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=[O:36]
Reactant: CCC(=O)O
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: CCC(=O)OC(CC)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
1.24 g of dicyclohexylcarbodiimide were added to a suspension of 2 g of 4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-8 trifluoromethyl-3-quinoline carboxamide [prepared as in Step C of Example 10 of Belgian Patent No. 896,941]and 0.4 ml of propionic acid in 20 ml of methylene chloride After stirring for 5 minutes, 0.30 g of 4-dimethylamino-pyridine were added and the mixture stood for an hour with stirring at ambient temperature The dicyclohexylurea formed was filtered off and the organic phase was washed with N hydrochloric acid, then with an aqueous solution of sodium bicarbonate, then with water, followed by drying and concentrating to dryness under reduced pressure The residue was taken up in 15 ml of ether, filtered, dried under reduced pressure to obtain 2.2 g of 4-hydroxy-2-[1-(1-oxopropoxy)-propyl]-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide melting at 216° C. which was identical to that obtained in Example 2.