Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9]CC(C)(OC2CCCCO2)C)=[CH:4][N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH:23]1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:3]1[C:4]2[N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH:23]3[C:28](=[O:30])[NH:9][C:5]=2[CH:6]=[N:7][CH:2]=1
Reactant: CC(C)(CNc1cnc(Cl)nc1Cl)OC1CCCCO1
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cncnc2N2CCOCC12
Temperature: 95 °C
Reaction time: 4 h
Yield: 24.6 %

Procedure:
To a mixture of 2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine (315 mg, 0.982 mmol) and morpholine-3-carboxylic acid hydrochloride (247 mg, 1.47 mmol) in DMSO (6 ml) was added diisopropylethylamine (0.686 ml, 3.93 mmol), and the reaction mixture was stirred at 95° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude residue was chromatographed by silica gel (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-5-2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (96.2 mg, 0.242 mmol, 25% yield) as a pale yellow oil which was used in the next reaction without further purification. MS [M+H] found 397.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([CH:13]=O)=O.[BH4-].[Na+].O>C(O)C>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[CH2:13][NH:4][CH2:1][CH2:2][NH:3]1
Reactant: O=CC(=O)c1cccs1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1csc(C2CNCCN2)c1
Reaction time: 1.5 h

Procedure:
A solution of ethylenediamine (4.1 g, 0.068 mol) in ethanol (25 ml) is added dropwise to a solution of 2-thienylglyoxal hydrate [prepared by the procedure of F. Kipnis and J. Ornfelt, J. Amer. Chem. Soc. 68, 2734 (1946)] (10.0 g, 0.063 mol) in ethanol (250 ml) at 0° C. under an atmosphere of dry nitrogen. The cooling bath is removed and the reaction mixture stirred for an additional 1.5 h. Sodium borohydride (4.5 g, 0.126 mol) is added all at once, and a cooling bath used to control the exothermic reaction. Stirring is continued for an additional 18 h. Water (25 ml) is added, and the ethanol removed under reduced pressure. The remaining aqueous solution is extracted with methylene chloride (3×100 ml) and the extracts dried with potassium carbonate. Removal of the solvent under reduced pressure gives 2-(2-thienyl)piperazine as an off-white solid. An analytical sample is obtained by addition of an ethereal solution of the base to an ethereal solution of oxalic acid dihydrate. The resulting precipitate is washed with diethyl ether and methanol, and the free base (m.p. 81°-83° C.) is obtained with a saturated solution of potassium carbonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)([Cl:14])=O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)cnc1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)cnc1Cl

Procedure:
To 15 g (0.069 mole) of 5-bromo-2-hydroxy nicotinic acid was added 75 ml of thionyl chloride and 3 ml of dimethylformamide. The mixture was heated to reflux for 30 minutes. After cooling, the excess thionyl chloride was removed by rotary evaporation and the residue poured into water (1 liter) with vigorous agitation. The precipitate was collected and the mother liquor condensed to 1/2 the volume, yielding additional precipitate. The precipitates were combined and crystallized from toluene giving 6 g (37%) of material. The product was recrystallized from toluene, m.p. 174°-177° C.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[CH2:23]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:23]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:22][C@H:11]([C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)[C@@H:10]2[CH2:9][C@@H:8]3[CH2:7][CH2:6][N:5]2[CH2:4][C@@H:3]3[CH:2]=[CH2:1])=[O:35])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](OC(=O)c1ccc(OCCCCCC)cc1)c1ccnc2ccccc12
Yield: 72.3 %

Procedure:
Example 9 was performed as Example 1 except for substitution of 2.91 g of cinchonidine, 2.0 g of 4-n-hexyloxy-benzoic acid, 2.33 g of N,N′-Dicyclohexyl carbodimide (DCC), 1.32 g of N,N-(dimethyl amino)-pyridine (DMAP) and 80 ml of dichloromethane into a round-bottom flask. After filtering and condensing, the residue was subjected to recrystallization from methanol, giving (R)-1-(4-quinolyl)-1-[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 4-(hexyloxy)benzoate, as a white solid having a melting point about 70° C. in a 72.3% yield. The optical properties of the resulting compound were tested as in Example 1. The compound exhibited a specific rotation [α] of +57.59 and a helical pitch P of 5.1 μm, with helical twisting power of 19.7 μm−1.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N:15]=[C:16]=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:21]([CH3:40])[CH:20]=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH:15][C:16]([NH:18][C:19]3[CH:39]=[CH:38][C:22]([O:23][C:24]4[C:29]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=5)=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:21]([CH3:40])[CH:20]=3)=[O:17])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)cc1N=C=O
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Solvent: Cc1ccccc1
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Nc3cc(C4CCCCC4)ccc3OC)cc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-cyclohexyl-2-isocyanato-1-methoxy-benzene (56 mg, 0.24 mmol) in toluene (3.0 mL) was added {4-[2-(4-amino-2-methyl-phenoxy)-pyridin-3-yl]-pyrimidin-2-yl}-methyl-amine (46 mg, 0.15 mmol). The mixture was stirred overnight at RT, concentrated and purified by preparative TLC (50% EtOAc/CH2Cl2) to yield N-(5-cyclohexyl-2-(methyloxy)phenyl)-N′-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)urea. MS m/z=539 [M+1]+. Calc'd for C31H34N6O3: 538.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][C@@H:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][C@@H:56]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNC[C@H](O)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(C[C@H](O)c2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.8 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 5 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[(R)-2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 24 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 80 mg light yellow solid (43%). MS (ISP) 495.4 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>O.CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C(O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 4-(tert-butyl)benzyl bromide (2.240 g, 9.861 mmol), 2-hydroxyphenylacetic acid (1.00 g, 6.572 mmol), potassium carbonate (3.996 g, 28.918 mmol), chloroform (6 ml) and methanol (6 ml) was refluxed for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.007 g, 51.4%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.NC(N)=O.[CH3:16][N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31].S(=O)(=O)(O)O>O>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([C:21]2[CH:22]=[CH:23][C:18]([N:17]([CH3:24])[CH3:16])=[CH:19][CH:20]=2)[C:33]2[CH:34]=[CH:35][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][C:29]=2[C:30]([OH:32])=[O:31])=[CH:5][CH:4]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Yield: 9.8 %

Procedure:
A mixture of 38.0 ml of water, 17.4 g (0.1 mole) of 85.5 percent 4-dimethylaminobenzaldehyde, 6.0 g (0.1 mole) of urea, 12.6 g (0.1 mole) of N,N-dimethylaniline, 18.2 g (0.11 mole) of 3-dimethylaminobenzoic acid and 14.6 ml (0.273 mole) of concentrated sulfuric acid was maintained at a temperature in the range of 90° to 95° C. for approximately two and one-half hours with stirring. Slowly, 240.0 ml of water was added to the reaction mixture and the resulting mixture was stirred for approximately eight hours. The mixture was filtered to remove the insolubles and the filtrate was added with stirring to a solution of 30.0 ml of concentrated ammonium hydroxide dissolved in 150.0 ml of water. The pH of the resultant mixture was adjusted to 11.0 by gradually adding 21.6 g of 90 percent potassium hydroxide. After stirring approximately one-half hour, the mixture was filtered retaining both the filtercake and the filtrate. The filtrate was adjusted to a pH of approximately 4.8 by slowly adding glacial acetic acid. The solid which formed was collected by filtration, washed with water and dried in vacuo to obtain 4.1 g of 2-[bis(4-dimethylaminophenyl)]methyl-5-dimethylaminobenzoic acid (Formula II: Y=4--N(CH3)2 ; R=R1 =R2 =R3 =CH3), a solid.
Reaction SMILES: C(Cl)Cl.[OH2:4].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1.C(OO)(=[O:14])C>[Ru].C(OCC)(=O)C>[CH3:5][C:6]1([OH:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:4]
Reactant: CC(=O)OO
Reactant: CC1=CCCCC1
Reactant: O
Agent: [Ru]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(O)CCCCC1=O
Reaction time: 2 h

Procedure:
In a 50 ml flask equipped with a thermometer, a dropping funnel, and a stirrer were charged 7 ml of methylene chloride, 7 ml of water, 2 mmole of 1-methyl-1-cyclohexene, and 0.1 mmole of each of ruthenium catalysts shown in Table 2 below. To the mixture was added dropwise a 30% ethyl acetate solution of 1.52 g (6 mmole) of peracetic acid at room temperature over 2 hours while stirring on a magnetic stirrer. After the addition, the stirring was further continued at room temperature for 2 hours. The reaction mixture was extracted three times with 20 ml portions of methylene chloride. The extract was washed with 30 ml of a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residual crude product was purified by silica gel column chromatography using a 5:1 (by volume) mixture of n-hexane and ethyl acetate as an eluent to obtain 2-methyl-2-hydroxy-1-cyclohexanone. The percent yield of the product is shown in Table 2.
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].CN([CH:23]=[O:24])C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:23][O:24][N:3]([CH3:6])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h

Procedure:
N,O-(Dimethyl)hydroxylamine hydrochloride (6.45 g, 65.8 mmol), triethylamine (20 ml, 145 mmol) and 4-dimethylaminopyridine (300 mg, 2.5 mmol) were suspended in 150 ml of DMF at 0° C. 4-Nitrobenzoyl chloride (10 g, 53.8 mmol) was added. After 1.5 hours at 0° C., the mixture was diluted with ethyl acetate, washed with 1M HCl and then sat. NaCl and dried over sodium sulfate. Filtration and evaporation gave the title compound as a light yellow solid (8.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12]>CN(C)C=O>[C:11]([NH:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(=O)NN
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
6-Chloronicotinoyl chloride (500 mg, 2.84 mmol) and acetohydrazide (232 mg, 3.12 mmol) were added to dimethylformamide (14.2 mL) at 0° C. The mixture was allowed to warm to room temperature and maintained at room temperature overnight. The reaction was then slightly concentrated in vacuo and diluted in acetonitrile. This mixture was directly purified via reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier). Fractions containing the desired product were lyophilized and free based using bicarbonate resin to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12]C([O-])(C)C.[K+].Cl[C:19]1[CH:24]=[CH:23]N=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=1.C([O-])([O-])=O.[K+].[K+].C[NH-]>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:19]2[CH:20]=[C:21]([CH:12]=[CH:23][CH:24]=2)[C:25]([NH:27][CH3:28])=[O:26])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: C[NH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1cccc(Oc2ccc(N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-amino-3-nitrophenol (0.6 g, 3.84 mmol, 1.2 eq) in DMSO (2.75 mL, 5×) was treated with KOt-Bu (0.44 g, 3.84 mmol, 1.2 eq), and the mixture was stirred at RT for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (0.55 g, 3.2 mmol, 1.0 eq), K2CO3 (0.24 g, 1.7 mmol, 0.53 eq), and heated at 110° C. for 16 h. HPLC showed N-methylamide <2%. To the stirred mixture was added water (about 30 mL) slowly, and the compound precipitated. The solid was filtered off (slow filtration) and washed with water (about 60 mL). The filtrant was dried in a vacuum oven over night to give the title compound as a brown solid.
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:17]O>>[F:2][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:17])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(O)c(F)c1

Procedure:
A commercial product, 3-fluoro-4-hydroxybenzoic acid hydrate (1.1 g) was dissolved in methanol (11 mL), and in an ice bath, thionyl chloride (0.77 mL) was added thereto, and heated under reflux for 2 hours. After the reaction, the reaction liquid was entirely concentrated to obtain the entitled compound (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:51][NH2:52]>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:51][NH2:52])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 20 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 200 ml of dimethylformamide was cooled to 0° C. under nitrogen and treated with 11.8 g of pentafluorophenol and 12.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for 2.5 hours at 0° C. and then treated with 19.8 g of hydrazine hydrochloride and 33 ml of triethylamine. The mixture was left to warm to room temperature and was then stirred overnight. Evaporation gave a residue which was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Evaporation gave a solid which was washed with ether/hexane (1:1) and dried to give 12.1 g of of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C)C=O.[F:12][C:13]([F:20])([F:19])[CH2:14]CC(O)=O>CCCCC>[F:12][C:13]([F:20])([F:19])[CH2:14][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C(Cl)CCC(F)(F)F
Yield: 76 %

Procedure:
101 ml of oxalyl chloride and 0.1 ml of dimethylformamide was added to a solution of thus obtained 131 g of the 4,4,4-trifluorobutyric acid in 1 liter of pentane, and the resultant solution was refluxed for three hours. Then the reaction solution was distilled to yield 112 g of 4,4,4-trifluorobutyryl chloride in a yield of 76%. (b.p. 103° C./760 mmHg)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromo-2-fluorobenzoic acid (1.0 mmol) and oxalyl chloride (2.0 mmol) are combined in dichloromethane (0.10 M), and 2 drops of dimethylformamide are added as a catalyst. The reaction is stirred at room temperature for 3 h. After this time, the reaction is concentrated in vacuo. Total conversion to the acid chloride is assumed.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(C)C.O.O.[F-].[K+]>CN(C=O)C>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[CH:5]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 5-[(trimethylsilyl)ethynyl]-2-hydroxybenzoate (100 g, 0.57 mol) and potassium fluoride dihydrate (150 g, 1.59 mol) in DMF (600 ml) was stirred for 4 h at room temperature. The solution was extracted with ether (3×400 ml) and the combined ether extracts were washed with 1M HCl (2×200 ml) and water (2×100 ml). The ether layer was dried with Na2SO4 and evaporated to dryness. Yield 66.5 g (93% ).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][CH2:37][OH:38])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: OCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-bromoethanol (0.621 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 80 mg (yield 90%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH2:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[CH3:16]>>[CH2:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[CH3:16]
Reactant: CCc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: CCc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-ethylaniline (60 μl, 0.243 mmol) similar to Example 13 and isolated as an tan oil (69 mg, 98%). 1H NMR (CDCl3): 8.81–8.79 (m, 1H), 8.48–8.45 (m, 1H), 7.84–7.78 (m, 1H), 7.42 (s, 1H), 7.37–7.29 (m, 2H), 7.18 (s, 1H), 7.16 (d, J=1.5 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 2.66 (q, J=7.5 Hz, 2H), 2.47 (s, 3H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28]>CO>[NH2:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][CH2:26][CH2:27][CH3:28])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][O:6][N:5]=[C:2]([CH3:4])[CH3:1])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Reactant: CC(C)=O
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
Acetone (444 mg, 7.65 mmol) was added to a solution of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.53 mmol), prepared as described in Parts A-C of Example 71, in methanol (7 mL), and the reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure and then further dried under high vacuum to provide 358 mg of acetone O-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxime as a white solid, mp 115-117° C.