Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON1CCN(C2C=CC=CC=2)CC1.C1(CC(O)=O)C2C=CC=CC=2CCCO1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=O)[CH2:45][CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.[ClH:58]>CCOCC.CO>[ClH:58].[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCN(C(=O)CC3OCCCc4ccccc43)CC2)cc1
Agent: CON1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=C(O)CC1OCCCc2ccccc21
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(N2CCN(CCC3OCCCc4ccccc43)CC2)cc1

Procedure:
Step 5--Following the general procedure of EXAMPLE 50 and making non-critical variations p-methoxyphenylpiperazine is acylated with (1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)acetic acid (CXXIII, 619 mg) and the resulting amide, 1-(4-methoxyphenyl)-4-(1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)acetyl piperazine (CXXIV, 1.07 g) is reduced according to the general procedure described in EXAMPLE 50 (making non-critical variations) to give crude product. This crude material is dissolved in ether (30 ml) and methanol (3 ml) and treated with gaseous hydrochloric acid resulting in the formation of a salt. This crude salt is recrystallized from methanol/ethyl acetate to give the title compound, mp 217.0°-219.0° (uncorrected, decomp.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH:12]([CH3:14])[CH3:13])(=[O:4])=[O:3].[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][CH2:7][CH:8]([OH:11])[CH2:9][O:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH:12]([CH3:14])[CH3:13])[CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1cc(O)ccc1S(C)(=O)=O
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc(S(C)(=O)=O)c(C(C)C)c1

Procedure:
Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-3-isopropylphenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-3-ISOPROPYLPHENOXY]-2-PROPANOL.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:36])=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:26][CH:27]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(S(=O)c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1,8 g of methyl (p-chlorophenoxy)[p-(p-chlorophenylthio)phenyl]acetate in 10 ml of dichloromethane is added dropwise a solution of 0.891 g of 83% m-chloroperbenzoic acid in 10 ml of dichloromethane. The mixture is chilled overnight, filtered and the filtrate washed with 10% sodium sulfite solution, saturated sodium bicarbonate and sodium chloride solutions. After drying (MgSO4), the solvent is removed under reduced pressure to give a gum. Crystallization from dichloromethane-zepane given 1.65 g of product as white crystals, mp 134°-144° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH:24]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccc2ccccc2n1
Product: O=C(C=Cc1ccc2ccccc2n1)c1ccc2ccccc2c1

Procedure:
Synthesised according to example 1.59.1 using quinoline-2-carbaldehyde (3.0 g, 19.09 mmol) and 1-(naphthalen-2-yl)ethanone (3.25 g, 19.09 mmol); yellow solid; yield: 4.95 g (84%);
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)[OH:2].O1CCOCC1.[OH-].[K+].[CH3:20][N:21]([S:25][N:26]([CH3:28])[CH3:27])[C:22](F)=[O:23]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.O>[CH3:27][N:26]([CH3:28])[S:25][N:21]([CH3:20])[C:22]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)=[O:23]
Reactant: CN(C)SN(C)C(=O)F
Reactant: CC1(C)NC(=O)CSC1=NO
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)SN(C)C(=O)ON=C1SCC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 5.8 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, 200 ml dioxane, 2.1 g powdered potassium hydroxide and 0.1 g dicyclohexyl-18-crown-6, was charged to a stirred flask and 5.3 g of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride was added at 30° C over a 1-minute period. The reaction mixture was stirred overnight at room temperature and then added to cold water and stirred for 5 minutes. The resulting mixture was extracted with methylene chloride. The methylene chloride layer was washed thoroughly with water and then dried with magnesium sulfate. The methylene chloride was stripped from the product under reduced pressure and the crystalline residue was recrystallized from ethylene acetate to provide 7.0 g of 2-[O-(N-Dimethylaminosulfenyl-N-methylcarbamoyl)oximino]-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 165°-167° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1C=CC=CC=1>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: c1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol (100 mg, 0.4 mmol) in benzene (3.0 mL) at 0° C. was added PBr3 (30 μL, 0.4 mmol). The reaction was heated at reflux for 1 hour. After cooling to room temperature the reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material did not require further purification (115 mg, 94%). MS (Q1) 350 (M)+
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:14](=[O:15])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6]1.C1(C)C=CC(S([Cl:25])(=O)=O)=CC=1>>[Cl:25][CH2:2][CH2:3][CH2:4][N:5]1[C:14](=[O:15])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1n(CCCO)nc2n1CCCCC2
Product: O=c1n(CCCCl)nc2n1CCCCC2

Procedure:
In the manner described in Reference Example 10-3), 2-(3-hydroxypropyl)-2,5,6,7,8,9-hexahydro-3H-1,2,4-triazolo-[4,3-a]azepin-3-one was treated with p-toluenesulfonyl chloride to obtain the entitled compound as an oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C(#N)C.C(OCC)(=O)C>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C1CCc2ccccc2C12CCNCC2
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C12CCN(CCCOc1cccc3[nH]ccc13)CC2

Procedure:
A solution of 1-chloro-3-(1H-indole-4-oxy)propane, 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4′-piperidine] and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 37% overall yield. FDMS m/e=388 (M+ of free base).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:37](O)=[O:38])=[CH:32][CH:33]=[C:34]([CH3:36])[CH:35]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:37]([C:31]3[C:30]([C:27]4[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=4)=[CH:35][C:34]([CH3:36])=[CH:33][CH:32]=3)=[O:38])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)O)c(-c2ccc(C(C)C)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirred solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (4.15 g), 4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid (3.81 g), HOBt (2.36 g), and Et3N (1.97 g) in CH2Cl2 (50 mL) was added EDCl (3.72 g) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3, with brine and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was crystallized from diisopropyl ether to give the title compound (4 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=1[C:49]1[C:53]([CH2:54]O)=[C:52]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[C:43]=1[C:49]1[C:53]([CH2:54][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:52]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Temperature: 90 °C
Yield: 42 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (154 mg, 0.550 mmol), triphenylphosphine (144 mg, 0.550 mmol) and {3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methanol (150 mg, 0.500 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.550 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution). A second purification was done by chromatography (silica gel, 2% methanol in dichloromethane) to afford methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate as a white solid (118 mg, 42%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=8 Hz, 2H), 7.63-7.51 (m, 3H), 6.92 (d, J=8 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.94 (s, 3H), 3.27-3.22 (m, 1H), 1.73-1.66 (m, 2H), 1.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4]([Cl:31])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)Cl)C(C)(C)C)c2C1
Reaction time: 2 h

Procedure:
To a solution (S)-3,3-dimethyl-2-(7-methyl-3-phenyl-5,6,7,8-tetrahydroimidazo [1,5-a]pyrazine-1-carboxamido)butanoic acid (Compound 281) (0.11 g. 0.30 mmol) in DCM was added oxalyl chloride (0.08 g, 0.60 mmol) followed by a catalytic amount of DMF. The resulting mixture was stirred for 2 h and the solvent was evaporated, toluene (2 mL) was added and the mixture was concentrated again. The resulting product (Intermediate 23A) was dried under vacuum and then used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:17]([C:24]([OH:26])=O)[CH2:18][O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[NH2:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl>C(OCC)(=O)C>[NH:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:17]([C:24]([NH:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:26])[CH2:18][O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
2.75 ml of triethylamine and 2.63 ml of chloroformic acid isobutyl ester are added to 5.9 g of Z-Ser(But)-OH in 20 ml of ethyl acetate at -10°C. After 10 minutes, 4.0 g of H-Leu-OMe-HCl and 3.05 ml of triethylamine are added. After stirring for 11/2 hours in an ice bath, the mixture is extracted by shaking with phosphoric acid and sodium bicarbonate solution and after drying over sodium sulphate the ethyl acetate is evaporated completely. 8.2 g of a waxy mass are obtained. Melting point (after crystallisation from hexane): 56°-58°C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].IC1C=CC(C(O)=O)=CC=1[N+]([O-])=O.S(Cl)(Cl)=O.[Cl:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]([C:49]([F:52])([F:51])[F:50])[C:33]=1[NH2:34]>>[Cl:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:40]([F:42])([F:43])[F:41])[C:44]([F:45])([F:47])[F:46])[CH:36]=[C:35]([C:49]([F:50])([F:51])[F:52])[C:33]=1[NH:34][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Agent: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1ccc(I)c([N+](=O)[O-])c1

Procedure:
According to the method of 1-3 of Example 1, a target compound was prepared from 4-iodo-3-nitrobenzoyl chloride prepared from 4-iodo-3-nitrobenzoic acid and thionyl chloride, and 2-chloro-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCN(C)CC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3yl)isonicotinamide and N-methylpiperazine using method A. NMR; δH [2H6]—DMSO 10.31,(1H, s), 8.62,(1H, t), 8.24,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.64,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.23,(1H, s), 7.06,(1H, d), 3.55,(4H, m), 3.16,(2H, t), 2.40,(4H, t), 2.21,(6H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.74 min, MH+484.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3Br)ccc2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3-c3ccccc3OC)ccc2=O)c1
Temperature: 98 °C
Reaction time: 30 h
Yield: 30.2 %

Procedure:
A mixture of ethyl (3-{3-[5-(2-bromophenyl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (235 mg), (2-methoxyphenyl)boronic acid (114 mg), Na2CO3(159 mg), Pd(PPh3)4 (29 mg) in toluene (8 mL) and water (4 mL) was stirred under N2 gas atmosphere at 98° C. for 30 hours and cooled to ambient temperature. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The aqueous layer of the reaction mixture was acidified with 1M HCl aqueous solution and extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The filtrate and the residue of the first extract was combined and evaporated in vacuo. The residue was dissolved in EtOH (20 mL). To the solution was added concentrated H2SO4 (1.5 mL) at ambient temperature and refluxed for 1 hour. The reaction mixture was cooled to ambient temperature, neutralized with saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=60:40) to afford ethyl (3-{3-[5-(2′-methoxybiphenyl-2-yl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (75 mg) as a colorless oil.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:27])=[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]([CH3:41])([CH3:40])[C:36](OC)=[O:37]>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:27][C:35]([CH3:41])([CH3:40])[C:36](=[O:37])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:11]=2[CH:12]=1
Reactant: COC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ccc(Cl)cc32)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a N,N-dimethylformamide solution (23 ml) of tert-butyl 4-[(5-chloro-2-hydroxyphenyl)amino]piperidine-1-carboxylate (1.15 g) were added at room temperature cesium carbonate (5.73 g) and methyl 2-bromo-2-methylpropanoate (1.27 g), followed by stirring at 140° C. for 2 hours. After the reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(6-chloro-2,2-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)piperidine-1-carboxylate.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[F:9][C:10]([F:27])([F:26])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=1>CC(C)=O>[CH3:3][O:21][C:15]1[CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F

Procedure:
A mixture of methyl iodide (32.3 ml, 0.519 mol), potassium carbonate (14.4 g, 0.104 mol), and product of Step 2 (25.0 g, 0.086, 5 mol) in acetone (100 ml) was refluxed for 18 hours and concentrated. The residue was dissolved in ether and washed with water. The ether layer was worked up as usual. The crude product, a yellow solid (27.25 g), was recrystallized (chloroform petroleum ether) to afford white rods (22.95 g), yield--88%; mp 101°-103° C.
Reaction SMILES: [CH2:1]([OH:12])[C:2]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C@@H:6]([OH:9])[CH:7]=O)=O.[CH:13]([NH2:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:7]1[N:26]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:2]([CH2:1][OH:12])[C@@H:4]([OH:11])[C@H:5]([OH:10])[C@H:6]1[OH:9]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a -78° C. solution of 5-keto-D-glucose (Formula V, 4.00 g, 0.0225 mol) in 100 mL of methanol was added a cooled solution (-78° C.) of benzhydrylamine (3.29 g, 0.018 mol) and acetic acid (1.08 g, 0.018 mol) in 100 mL of methanol. Sodium cyanoborohydride (2.82 g, 0.0449 mole) was added, and the mixture was stirred at -78° C. for 2 h and then slowly warmed to ambient temperature. After 18 h, the solution was concentrated, saturated aqueous sodium carbonate was added, and the product was extracted into chloroform. The chloroform extracts were combined, dried (sodium sulfate), and concentrated to afford a yellow foam. Chromatographic purification on flash silica gel (5-10% gradient of methanol in chloroform) afforded 4.06 g (69%) of the title compound as a very pale yellow foam. 1H NMR and reversed-phase analytical HPLC showed that this substance was >95% stereochemically pure (ca. 4.5% of the iditol isomer). Recrystallization from MEOH afforded white needles, mp 101°-104° C. (corrected). Both 1H and 13C NMR in CDCl3 and D3CC(O)CD3 confirmed the structure.