Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.CO[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C(=COC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a flask maintained under reduce pressure, p-methoxyaniline (35.1 g, 280 mmol) and diethyl 2-(methoxymethylene)malonate (73.97 g, 340 mmol) were stirred at 100° C. for two h. The crude mixture was used without further purification.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]([CH3:23])([CH3:22])[C:8](=[O:21])[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11].C(O)C>ClCCl>[Cl:4][CH:9]([C:8](=[O:21])[C:7]([CH3:23])([CH3:22])[CH3:6])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)C(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Sulfuryl chloride (54.1 g, 0.4 mol) was added dropwise with vigorous stirring over a 60 minute period to a solution of N-[4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline, prepared as above (109 g, 0.378 mol) in dichloromethane (600 mL) at -10° C. The reaction mixture was maintained at this temperature for 3 hours after the addition had been completed. After this time, the mixture was allowed to warm to 0° C. and ice (approximately 50 mL) was added, with stirring. The organic layer was separated and washed with 50% saturated aqueous sodium chloride solution (2×500 mL), then dried over magnesium sulfate. Evaporation of the solvent afforded a brown oil which was stirred with ethanol (150 mL) to induce crystallization of the product. The resultant mixture was stored at 0° C. overnight. The solid product was removed by filtration, washed with cold ethanol and dried to afford N-[2-chloro-4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (104.2 g, 85.4% yield) as a white crystalline solid which melted at 64.5°-65.5° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 29.5 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 3-Chlorobenzaldehyde (39.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 31.23 mg (30%) of the title compound. (300 MHz, DMSO-d6) 13.42 (s, 1H), 8.19 (s, 1H), 8.10 (d, J=8 Hz, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.62-7.53 (m, 2H), 7.32 (d, J=9 Hz, 1H), 7.25 (s, 1H), 6.39 (s, 2H), 5.18 (t, J=17 Hz, 9 Hz, 1H), 2.87 (s, 1H), 2.91 (s, 1H), 2.81 (d, J=8 Hz, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=414 (M+H), HPLC: 2.73 min. (G Method)
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH3:2].[CH2:16]([O:18]CC)C.C([Li])CCC.CN(C=O)C>O>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:11]=1[CH:16]=[O:18])[CH3:2]
Reactant: CCOCC
Reactant: CCOCOc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOCOc1cc(C(F)(F)F)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4.0 g of 1-ethoxymethoxy-3-trifluoromethylbenzene and 160 ml of diethyl ether was added dropwise 16 ml of n-butyllithium (1.6 N, n-hexane solution) under a nitrogen atmosphere at −70° C. This mixture was stirred at room temperature for 3 hours. Subsequently, 5.5 ml of DMF was added to this mixture at −70° C., and the temperature was returned to room temperature. The reaction mixture was added to water. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.90 g of 2-ethoxymethoxy-4-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]1>>[N:14]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C1=CCNCC1
Product: N#Cc1ccc(N2CC=CCC2)c2ccccc12
Yield: 25.5 %

Procedure:
The title compound (7 mg, 26% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 1,2,3,6-tetrahydropyridine (39 mg, 0.468 mmol).
Reaction SMILES: [CH2:1](OC(N1C[C@H](OC(C)(C)C)C[C@H]1C(O)=O)=O)[C:2]1[CH:7]=CC=C[CH:3]=1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][CH:42]=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][C:42]([C:2]([CH3:7])([CH3:3])[CH3:1])=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)c1cnc([C@@H]2C[C@H](N)CN2C(=O)OCc2ccccc2)o1

Procedure:
(2S,4S)-4-Amino-2-(5-tert-butyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C19H26N3O3 [(M+H)+] 344, obsd. 344.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]2[C:29]=1[CH:30]([C:44]1[C:52]([OH:53])=[CH:51][C:47]3[O:48][CH2:49][O:50][C:46]=3[CH:45]=1)[C:31](=[O:43])[N:32]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]2[C:29]=1[C:30]([C:44]1[C:52]([OH:53])=[CH:51][C:47]3[O:48][CH2:49][O:50][C:46]=3[CH:45]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (94%) as a gummy solid: MS (ES+) m/z 439.3 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Cl[CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH2:12]([O:11][C:9]([C:8]1[S:5][C:3]([CH:2]([CH3:6])[CH3:1])=[N:4][C:14]=1[CH3:16])=[O:10])[CH3:13]
Reactant: CC(C)C(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(C(C)C)nc1C
Yield: 93.8 %

Procedure:
A solution of 2-methylpropanethioamide (3.1 g, 30 mmol) and ethyl 2-chloroacetoacetate (3.29 g, 20 mmol) in ethanol (40 mL) was heated at reflux for 3 h. The reaction mixture was evaporated to dryness and the residue was taken up in dichloromethane (50 mL) and the solution was washed with saturated sodium bicarbonate solution (2×25 mL). The aqueous layers were back-washed with dichloromethane (25 mL), then the combined dichloromethane layers were dried (MgSO4), filtered and concentrated under vacuum. The residue was purified using a Waters Prep 500 apparatus (silica gel dual column; 10% ethyl acetate/hexanes). Evaporation of the appropriate fractions afforded 2-(1-methylethyl)-4-methylthiazole-5-carboxylic acid ethyl ester (4.0 g, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14](N)[CH2:15][CH2:16][CH3:17].N>O1CCOCC1>[CH2:14]([NH:1][C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: NC1=NS(=O)(=O)c2cccc(Cl)c21
Reactant: CCCCN
Agent: N
Solvent: C1COCCO1
Product: CCCCNC1=NS(=O)(=O)c2cccc(Cl)c21
Reaction time: 2 h

Procedure:
A solution of 2.17 g of the 3-amino-4-chlorobenzo[d]isothiazole-1,1-dioxide prepared according to Example II and 2 ml of n-butylamine in 15 ml of dioxane was boiled for approx. 2 hours, ammonia escaping. After distilling off the solvent, the residue was stirred with water, sucked off, washed successively with water and petroleum ether and dried. The desired product was obtained in a yield of 2.4 g, melting-point 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[NH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[NH2:19]>CO>[ClH:1].[N:23]1[CH:24]=[CH:25][C:20]([NH:18][NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[N:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cnc2ccncc2c1Cl
Reactant: NNc1ccncc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cnc2ccncc2c1NNc1ccncc1

Procedure:
A solution of 2.36 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylate and 1.53 g of 4-hydrazinopyridine hydrochloride in 37 ml of methanol is stirred for 19 hours at room temperature, then refluxed for 4 hours. The reaction mixture is then cooled in an ice bath, and solid is collected by filtration, washed successively with methanol and ether to yield ethyl 4-[2-(4-pyridyl)hydrazino]-1,6-naphthyridine-3-carboxylate hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][OH:10])[C:2]=1[NH:1][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11]
Reactant: Nc1c(Cl)cccc1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To the crude (2-amino-3-chlorophenyl)methanol(1.08 g, 6.88 mmol) in CH2Cl2 (15 mL) was fast dropwise added trimethylacetyl chloride (0.89 mL, 7.23 mmol), followed by DIEA (2.4 mL, 13.8 mmol) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 1 hr. Normal aqueous work-up to afford the expected product as a white solid (1.58 g, 95% yield), which was pure enough to be used in next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9 H), 3.35 (s, 2 H), 4.36 (d, J=6.29 Hz, 1 H), 7.06-7.22 (m, J=7.81, 7.81 Hz, 1 H), 7.29-7.33 (m, 2 H), 7.58 (s, 1 H); Mass spec. 242.08 (MH+), Calc. for C12H16ClNO2 241.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:18][O:19][CH:20]([O:26][CH3:27])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+].[Na]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:21]([CH:20]([O:26][CH3:27])[O:19][CH3:18])[C:22]2=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1cccnc1Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CC(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1cc2cccnc2n(-c2cc(Cl)cc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A solution of 42.7 g of 2-(3,5-dichlorophenyl)aminonicotinaldehyde, prepared in Example 29, in 500 ml of tetrahydrofuran containing 35.6 g of methyl 3,3-dimethoxypropionate, and a solution of sodium methylate prepared from 5.5 g of sodium in 100 ml of methanol, are stirred for 24 h at room temperature. The reaction mixture is subsequently concentrated under vacuum, water is then added and the crystals formed are filtered off, washed carefully with water and dried to give 44.25 g of 1-(3,5-dichlorophenyl)-1,2-dihydro-3-dimethoxymethyl-2-oxo-1,8-naphthyridine in the form of white crystals melting at 190° C. Yield 75.7%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.28 mL, 0.28 mmol) was added to a solution of {5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 139-(1); 50 mg, 0.09 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for five hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=5:2) to give the target compound as a colorless oil (22 mg, 45%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of Mg (1.7 g, 0.07 mol) in dry ether (25 mL) was added a solution of benzyl bromide (10 mL, 1.5 equ.) in dry ether (25 mL) drop-wise and allowed to stir at RT for 1 h. By the time all magnesium was dissolved and the reaction mixture was cooled to 0° C. To this was added a solution of benzophenone (10 g, 0.05 mol) in dry ether (25 mL) and allowed to stir at RT for 5 h. The progress of the reaction was followed by TLC and when it was ready the reaction mixture was quenched with saturated NH4Cl solution, extracted with ether (100 mL), washed with brine, dried and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (10% ethyl acetate in pet. ether) to give the title compound (9.6 g, 65%) as a white solid. TLC: Pet. ether/EtOAc, 9:1, Rf=0.4
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: O=C=Nc1ccccc1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (600 mg) was suspended in toluene (15 ml), and the suspension was heated to reflux for dissolution, after which phenyl isocyanate (292 μl) was added dropwise and the mixture was heated to reflux for 30 minutes. After cooling, the precipitated solid was filtered out, washed with ether and ethyl acetate and dried to obtain 760 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:21])[N:14]([CH3:20])[N:15]=[C:16]([CH3:19])[C:17]=1[OH:18])[CH3:2].C(Cl)(Cl)Cl.Cl[CH2:27][N:28]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:29](=[O:33])[O:30][CH2:31][CH3:32]>C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:21])[N:14]([CH3:20])[N:15]=[C:16]([CH3:19])[C:17]=1[O:18][CH2:27][N:28]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Reactant: CCOC(=O)N(CCl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(COc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC)c1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a mixture of 0.30 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-3(2H)-pyridazinone [compound (II-1-2)] and 5 mL of chloroform, 0.22 mL of triethylamine and 0.52 mL of ethyl N-chloromethyl-N-phenylcarbamate were added, followed by stirring at room temperature for 13.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 0.27 g of 4-(2,6-diethyl-4-methylphenyl)-5-(N-ethoxycarbonyl-N-phenylaminomethoxy)-2,6-dimethyl-3(2H)-pyridazinone [compound (I-6-1)].
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C(C)C)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C(C)C)nc2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[methyl(1-methylethyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (363 mg) in DMF (5 mL) was added potassium tert-butoxide (124 mg) at 0° C., and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (270 mg, 82%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 74475.7 %

Procedure:
Alcohol Compound 40 (48.8 g, 0.16 mmol) was added to a mixture of NaH (4.0 g, 0.17 mol) in dry THF (500 mL). After 5 min, MeI (10 mL, 0.17 mol) was added and, after another 3 hours, the mixture was quenched with H2O (150 mL), extracted into diethyl ether (500 mL), dried (MgSO4) and concentrated. Purification of the residue by silica-gel column chromatography [eluent: hexane/ethyl acetate, 90/10, v/v] yielded 1-O-benzyl-3-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (Compound 41) (37 g, 74%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:32])=[C:18]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[F:32][C:17]1[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])[N:7]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[NH:22][S:23]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: CC(C)CN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)CNc1nccc(-c2sc(C(C)C)nc2-c2cccc(NS(=O)(=O)c3cccnc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide (150 mg, 0.306 mmol) and isobutylamine (0.307 mL, 3.06 mmol). the title compound was obtained as a white solid (105 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.73 (dd, J=4.8, 1.0 Hz, 1H), 8.03-8.13 (m, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.53 (dd, J=8.1, 4.9 Hz, 1H), 7.31-7.41 (m, 1H), 7.09-7.33 (m, 3H), 5.67-5.93 (m, 1H), 3.14-3.25 (m, 1H), 2.84-3.09 (m, 2H), 1.69-1.87 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.81 (d, J=5.3 Hz, 6H). MS (ESI): 527.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([O:35][C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:26])[CH:34]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: N#Cc1ccc(O)cc1Cl
Product: CN1CCN(c2cc(N3CCc4ccc(Oc5ccc(C#N)c(Cl)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 17 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 2-chloro-4-hydroxybenzonitrile (Aldrich, Cat. No. 346071). LCMS (M+H)+: m/z=476.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[O:15][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2ccccc2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.7 %

Procedure:
To a solution of 4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (370 mg, 1.00 mmol), phenol (141 mg, 1.50 mmol) and Ph3P (393 mg, 1.50 mmol) in THF (6 mL) at room temperature was added DIAD (0.295 mL, 1.50 mmol) dropwise. The mixture was stirred at room temperature for 2.5 hours. Aqueous work-up and purification gave 4-[(4-bromophenyl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (213 mg, 48%).