Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[NH:30][CH:29]=1)([OH:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO.O>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[C:28]3[CH2:27][C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Reactant: O=C(O)Cc1c[nH]c2ccc(B(O)O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2ccc3[nH]cc(CC(=O)O)c3c2)n1
Temperature: 130 °C
Yield: 16.9 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (493 mg, 1.408 mmol) and 3-carboxymethyl-1H-indol-5-yl boronic acid (370 mg, 1.689 mmol) in toluene (9 mL), EtOH (4.5 mL) and water (1 mL) is added Cs2CO3 (1.146 g, 3.52 mmol) and degassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium (0) (81.3 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 15 minutes. To the reaction mixture is added 1N hydrochloric acid to adjust pH to about 2. This mixture is extracted three times with EtOAc (40 mL). The combined, extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to give (5-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-indol-3-yl)-acetic acid [116 mg, 17%, Example 52] as a solid. LC/MS: RT=2.57 minutes, MS: 489 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □12.18 (1H, s), 11.05 (1H, s), 8.18 (1H, s), 7.24-7.76 (7H, m), 6.6 (1H, s), 3.87 (3H, s), 3.7 (2H, s), 3.6 (2H, m), 3 (2H, m). IC50=0.4 nM
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[C:15]=[S:16])[CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cnco1
Yield: 94 %

Procedure:
3-Methoxy-4-(5-oxazolyl)aniline, 1D, (3.50 g, 18.4 mmol) and 1,1′-thiocarbonyldi-2(2H)-pyridone (4.41 g, 18.4 mmol) in dichloromethane (100 mL) were stirred at rt for 3 h. The solvent was evaporated under vacuum, and the residue was subjected to a short column (30% AcOEt/hexane) to afford 34A (4.02 g, 94% yield) as white flakes.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH2:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CCCCc1ccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)cc1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinoline -5(6H)-one was reacted with 4-butylbenzoyl chloride according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4, 7,8-hexahydro-1-(4-butylbenzoyl)-quinoline5(6H)-one (22) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][CH:33]=[N:32]1.C(O)CCC>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][N:32]=[CH:33][CH:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1ccns1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCCCO
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ccns2)C1
Temperature: 110 °C

Procedure:
A solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(244 mg, 0.839 mmol) in dry dichloromethane (DCM) (2098 μl) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (175 mg, 0.923 mmol) was added and the resulting mixture was stirred for ¾ hours. After this time, 5-isothiazolecarbohydrazide (I84) (153 mg, 1.069 mmol) was added and the resulting mixture was stirred at room temperature for 60 hours (over the weekend). 1-Butanol (2098 μl) was added and the reaction mixture was heated to 110° C. for 2 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between DCM (approx 40 ml) and NaHCO3 (saturated aqueous solution approx. 20 ml). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to give a pale yellow coloured solid. The solid was purified using MDAP to give a white coloured solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14](=[O:34])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)[C:6]=2[CH:35]=1.[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38]>CC(C)=O.C(#N)C>[CH3:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][C:6]=2[C:7]=1[C:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)=[O:34].[ClH:40]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Solvent: CC(C)=O
Solvent: CC#N
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: Cl
Temperature: 12.5 °C

Procedure:
Under a temperature range from room temperature to reflux temperature, preferably reflux temperature, 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran is reacted with methanesulfonyl chloride in a mixture of acetone and acetonitrile solvent to provide a crude dronedarone hydrochloride, wherein an ratio of acetone and acetonitrile used is in the range of 0˜5:1 (v/v), preferably 0.2˜3:1 (v/v), more preferably 0.5˜1:1 (v/v), and an amount of methanesulfonyl chloride used is in the range of is 1 to 5 equivalents, and preferably 1.5 to 4 equivalents, and more preferably 2 to 3 equivalents relative to the compound A to obtain a reaction mixture. When the reaction is terminated, the reaction mixture is cooled to −40 to 50° C., preferably −15 to 40° C., more preferably −10 to 35° C. to obtain crude dronedarone hydrochloride. Then the crude dronedarone hydrochloride can be purified to obtain highly pure dronedarone hydrochloride. If desired, the obtained dronedarone hydrochloride can be converted to highly pure dronedarone via alkaline solvent, or further converted to other pharmaceutically acceptable salts of dronedarone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[N:38]#[C:39]Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:39]#[N:38])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: N#CBr
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of 3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (197 mg, 0.45 mmol) in CH2Cl2 (4.5 mL) was treated with K2CO3 (93 mg, 0.67 mmol) and cyanogen bromide (100 mg, 0.94 mmol). The reaction mixture was stirred at room temperature for 1 hour and heated at reflux for 18 h. The mixture was cooled at room temperature and filtered on celite. The filtrat was washed with AcOH (1N) and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (2% MeOH/CH2Cl2) to provide 3-[(1-cyano-piperidin-4-yl)-(4-methyl cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (154 mg, 74% yield) as pale yellow foam.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].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.[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([OH:73])[CH2:55][C@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[C:68]([Cl:70])[CH:67]=[CH:66][C:65]=2[F:71])=[CH:60][CH:59]=1)[CH3:51]>C(Cl)Cl>[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([OH:73])[CH2:55][C@H:56]([NH:72][C:9]([C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[NH:5][N:6]=1)=[O:11])[CH2:57][C:58]1[CH:59]=[CH:60][C:61]([C:64]2[CH:69]=[C:68]([Cl:70])[CH:67]=[CH:66][C:65]=2[F:71])=[CH:62][CH:63]=1)[CH3:51]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
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
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 25 °C
Yield: 14.6 %

Procedure:
To a stirred solution of 3-acetyl-1H-pyrazole-5-carboxylic acid (50.9 mg, 330 mol), HATU (125 mg, 330 μmol), and DIPEA (104 μL, 0.6 mmol) in DMF (0.6 mL, 7.7 mmol), was added (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (110 mg, 300 μmol). The resulting mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organics were dried over Na2SO4, and the solvent removed. Half of material was then purified by preparative HPLC to yield the title compound (22 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C25H25ClFN3O5, 502.15. found 502.1.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1>C1C=CC=CC=1.CCCCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:25])=[CH:19][CH:18]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCC
Product: CCCCCCC(=N)NC(=S)Nc1ccc(F)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 1.6 g. sodium in 200 ml. dry acetone, 12.3 g. heptanamidine hydrochloride, and 11.6 g. 4-fluorophenyl isothiocyanate (b.p. 48° C./0.025 mm.; prepared from 4-fluoroaniline) in 50 ml. dry acetone there was obtained 1-(4-fluorophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 75°-76° C. (from benzene-n-pentane); hydrochloride (17.1 g.), m.p. 155° C. (from acetonitrile).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:19]([CH3:33])[C:20]([C:31]#[N:32])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:19]([CH3:33])[C:20]([C:31]#[N:32])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3nccs3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3nccs3)nc2c1C#N
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (48.4 μl, 0.382 mmol) and triethylamine (53.2 μl, 0.382 mmol) were added to a dimethyl sulfoxide (1 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(1,3-thiazol-2-yl)-1,3-benzoxazole-4-carbonitrile (I-186) (64.0 mg, 0.191 mmol), followed by stirring in an oil bath at 100° C. for 3 hours.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:14])[CH2:6]1.[CH3:15]I.O>CCCCCC.C1COCC1.[Cl-].[Na+].O>[CH3:15][O:3][CH2:4][C:5]1[CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:14])[CH:6]=1
Reactant: O=C1CC(CO)Cc2sccc21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COCC1=CC(=O)c2ccsc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.2 g, 5 mmol), was washed with hexane and then suspended in THF (6 mL) under a nitrogen atmosphere at 0° C. 6-(Hydroxymethyl)-6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.745 g, 4.1 mmol) was dissolved in THF (4 mL) and added drop-wise to the sodium hydride suspension. After 10 min methyl iodide (0.71 g, 0.31 mL, 5 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 3 hr. Water and saturated brine solution (2 mL, 1:1) were added and the product was extracted into dichloromethane (×3). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The crude residue was purified on silica gel using a gradient elution of 0-50% ethyl acetate in iso-hexane to afford the title compound (0.109 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 50%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[OH:19][CH2:20][CH:21]1[NH:26][CH:25]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:24][N:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:22]1>C(Cl)Cl.O.C(=O)(O)[O-].[Na+]>[CH3:39][O:38][C:36]([N:23]1[CH2:24][CH:25]([C:27]2[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=2)[N:26]([C:2]([O:4][CH2:5][CH:6]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:3])[CH:21]([CH2:20][OH:19])[CH2:22]1)=[O:37]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)N1CC(CO)NC(c2cc(F)c(F)c(F)c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CC(CO)N(C(=O)OCC2c3ccccc3-c3ccccc32)C(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
9-Fluorenylmethyl chloroformate (958 mg) was added to a mixed solution of methyl 3-hydroxymethyl-5-(3,4,5-trifluorophenyl)piperazine-1-carboxylate (867 mg) in methylene chloride (20 mL) and saturated sodium bicarbonate water (20 mL), and the reaction solution was stirred at room temperature for 14 hours. The organic layer was separated from the reaction solution. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->ethyl acetate) to obtain 916 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1C=CC(O)=N[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25](C)[C:26](=[O:28])[CH3:27]>C(OCC)(=O)C>[Cl:10][C:11]1[CH:16]=[CH:24][N:25]=[C:26]([O:28][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:27]=1
Reactant: CC(=O)N(C)C
Reactant: Oc1ccc(Cl)cn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Temperature: 25 °C
Yield: 8 %

Procedure:
To a solution of 4-fluorobenzaldehyde (3.6 g, 29 mmol) in N,N-dimethylacetamide (25 mL) was added 5-chloro-2-pyridinol (4.1 g, 32 mmol) and K2CO3 (4.1 g, 30 mmol) at room temperature under argon. The mixture was heated to reflux for 4 h, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography to yield the title compound as a white solid (0.59 g, 2.5 mmol, 8%). 1H NMR (CDCl3): δ 9.99 (s, 1H), 8.16 (s, 1H), 7.94 (d, J=7.7, 2H), 7.27 (d, J=7.7, 2H), 7.71 (d, J=8.6, 1H), 6.99 (d, J=8.6, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].N1C=CC=CC=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: ON=Cc1ccc(Cl)cc1

Procedure:
4-Chlorobenzaldehyde (45.6 g; 0.325 mol), hydroxylamine hydrochloride (27.9 g; 0.401 mol) and pyridine (64 mL; 0.791 mol) in methylene chloride (600 mL) were stirred overnight at room temperature. The reaction mixture was poured into aqueous hydrochloric acid (2N; 300 mL) and extracted. The organic layer was washed with additional aqueous hydrochloric acid (2×300 mL), water (300 mL), dried (MgSO4), filtered and evaporated to yield oxime 1a as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][N:9]=[C:8]([CH3:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.IC[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].[CH3:29]C([N-]C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][N:9]=[C:8]([CH2:12][CH2:29][CH:17]3[CH2:16][CH2:15][CH2:20][CH2:19][N:18]3[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: COc1cccc2c(C)noc12
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c(CCC3CCCCN3C(=O)OC(C)(C)C)noc12
Yield: 61.8 %

Procedure:
The procedure described in Example 1d was followed using 7-methoxy-3-methyl-1,2-benzisoxazole (0.30 g, 1.84 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.60 g, 1.85 mmol), and 1M LDA (1.9 mL, 1.9 mmol) in dry THF (2 mL). After purification, the title compound (0.41 g, 62%) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 4-(5-bromo-2-chloro-benzyl)-phenol (9.01 g, 30.28 mmol) dissolved in N,N-dimethylformamide (100 mL) and cooled to 0 degrees Celsius (ice bath) was added imidazole (4.53 g, 66.6 mmol) and 4-dimethylaminopyridine (370 mg, 3.03 mmol). tert-butylchlorodimethylsilane (6.85 g, 45.4 mmol) was added and the ice bath was removed. The reaction mixture was allowed to stir at room temperature overnight (˜16 hours), water (400 mL) was added and the resulting mixture was extracted with ethyl acetate (200 mL). The aqueous layer was extracted two additional times with ethyl acetate (200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (120 g silica gel column) and eluting with a gradient of 0 to 50% ethyl acetate in heptane. 12.4 g (99% yield) of product obtained as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 0.18 (s, 6 H), 0.97 (s, 9 H), 3.96 (s, 2 H), 6.77 (d, J=8.4 Hz, 2 H), 7.01 (d, J=8.4 Hz, 2 H), 7.17-7.30 (m, 3 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1CSc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(F)cc54)CC3)nc2N1
Yield: 23 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 54) (0.7 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (160 mg, 0.82 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21, (but the reaction mixture was refluxed overnight before reduction with sodium cyanoborohydride at room temperature for 2 hours) to give 76 mg (23%) of product.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil), which was stirred for 15 minutes at 0° C. Next, benzyl bromide (5.99 mL, 50.4 mmol) was added to this reaction mixture at 0° C., which was stirred for 3.5 hours at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (5.99 g, 66%).