Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30]>C(OCCO)C>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(=O)O)c3C)c2cc1OC
Yield: 24.7 %

Procedure:
Using an analogous procedure to that described in EXAMPLE 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 196.5 mg (1.3 mmol) of 3-amino-2-methylbenzoicacid to give 89.6 mg (24.7%) of the product as a gray solid, m.p. 242-245° C., mass (electrospray, m/e): M+H 364.0.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]1)=[O:19])[CH2:12][CH2:11][CH2:10]2>>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][C:29]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)=[O:19])[CH2:12][CH2:11][CH2:10]2
Reactant: O=S(=O)(O)Cl
Reactant: C[C@H](C(=O)N1CCN(c2ccccc2)CC1)N1CCCc2cc(F)ccc21
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)N1CCCc2cc(F)ccc21
Temperature: 25 °C

Procedure:
After cooling chlorosulfonic acid (5.5 ml, 3 eq) to 0° C. under N2, (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperazin-1-yl)propan-1-one (1 g, 2.72 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (250 ml), followed by an extraction with CH2Cl2 (3×100 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was used without further purification for next step. LCAMS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=466.3; tR=3.49 min.
Reaction SMILES: [C:1]([C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[CH:4]=1)#[N:2].[NH4+].[OH-:28].OO>>[C:1]([C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[CH:4]=1)(=[O:28])[NH2:2]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(C#N)cc3c(=O)[nH]ncc(n1)c23
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(C(N)=O)cc3c(=O)[nH]ncc(n1)c23

Procedure:
To the compound from Example 24 is added a NH4OH and H2O2 in alcoholic solution to yield the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.OC1C=C(C=CC=1[C:32]([O:34][CH3:35])=[O:33])N.ClC1N=C(Cl)C(F)=CN=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:32]([O:34][CH3:35])=[O:33])=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: COC(=O)c1ccc(N)cc1O
Agent: Fc1cnc(Cl)nc1Cl
Product: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(O)c3)n2)cc1O
Yield: 41 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-primidinediamine, 3-hydroxy-4-methoxycarbonylaniline (500 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis-[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (105 mg, 41%). 1H NMR (DMSO-d6): δ 3.90 (s, 3H), 3.93 (s, 3H), 7.31 (dd, J=2.4, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.7 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 8.28 (d, J=3.6 Hz, 1H), 9.72 (s, 1H, NH), 9.82 (s, 1H, NH), 10.77 (s, 1H, OH), 10.80 (s, 1H, OH); 19F NMR (282 MHz, DMSO-d6): δ−161.74; LCMS: ret. time: 31.47 min.; purity: 96.03%; MS (m/e): 428.99 (MH+).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[S:28]1[CH2:32][CH:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH:30][CH2:29]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:30]2[CH:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:32][S:28][CH2:29]2)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)C1CSCN1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CSCC2C(=O)OCC)cc1

Procedure:
One-tenth mole of 4-(hexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[N:3]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[N:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: COc1nc(Cl)ccc1C(N)=O
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C(N)=O
Temperature: 110 °C
Yield: 38.6 %

Procedure:
A mixture of 6-chloro-2-methoxy-nicotinamide (7.15 g, 38.3 mmol), 2-bromo-5-hydroxy-benzaldehyde (11.5 g, 57.5 mmol) and K2CO3 (15.9 g, 115 mmol) in dimethylformamide (60 mL) was heated to 110° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with H2O (800 mL) and extracted with ethyl acetate (6×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (50-80% ethyl acetate/hexanes) to give the title compound as a light brown solid (5.19 g, 39% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Li]CCCC.[C:18](=[O:20])=[O:19]>CCOCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500 mL three-neck flask fitted with magnetic stirrer, nitrogen lines and a 125 mL addition funnel was charged with 200 mL of dry ether (newly opened can) and 6-bromo-2-naphthol (15.6 g, 70 mmol). The atmosphere was replaced with nitrogen and a solution of 15 mL of 10M n-BuLi in 100 mL of ether (150 mmol) was added via the addition funnel over a 30 minute period. The solution became pale yellow with a precipitate. After stirring for 20 minutes more, dry ice was added until the solution became quite cold (<-25° C.) and green in color. The solution was warmed to room temperature and quenched by the addition of 200 mL of water. The two-phase system was transferred to a separatory funnel, the layers separated and the ether solution extracted with 100 mL of saturated NaHCO3 solution. The combined aqueous layers were washed with 100 mL of ether and neutralized by careful addition of 12N HCl. The pale blue solid was filtered and dried in the air to give 10.3 g (76%): mp 238-241° C. (dec.); lit. mp 240°-241° C.; reference: S. V. Sunthankar and H. Gilman, J. Org. Chem., 16, 8 (1951). ##STR26##
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1[CH:16]=[CH:15][C:14](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1.[CH:32](N(CC)C(C)C)(C)C>>[CH2:32]([C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 16.0 g (116.6 mmol) of 2-fluoro-4-hydroxybenzonitrile and 50.0 g (140.0 mmol) of N-phenyltrifluoromethanesulfonimide in 250 mL of dichlorormethane is added N,N-diisopropylethylamine and the mixture is stirred for 16 hr at room temperature. The mixture is then washed with 10% aqueous sodium bisulfate. The organic portion is separated and the aqueous portion is extracted three times with dichlorormethane. The combined organic portions are dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (silica gel, 50% chloroform/hexane) of the residue affords 26.7 g (85%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:3][O:4][C:5](=[O:35])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.[C:42]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][C:54]1[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=1)(=[O:45])[CH:43]=[CH2:44]>ClCCl>[C:42]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][C:54]1[CH:62]=[CH:61][C:57]([C:58]([O:1][C@H:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:3][O:4][C:5](=[O:35])[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:34])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[O:59])=[CH:56][CH:55]=1)(=[O:45])[CH:43]=[CH2:44]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OC[C@H](O)c3ccccc3)cc2)cc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OC[C@H](OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.4 %

Procedure:
0.56 g (2.7 mmole) of N,N-dicyclohexyl carbodiimide were added to a solution of 1.5 g (2.7 mmole) of (R)-4-(4-(6-acryloyloxyhexyloxy)benzoyloxy)cinnamic acid 2-hydroxy-2-phenyl-ethyl ester (21), 0.8 g (2.7 mmole) of 4-(6-acryloyloxy-hexyloxy)-benzoic acid (5) and 0.03 g (0.27 mmole) of 4-N,N-dimethylaminopyridine in 20 ml of dichloromethane, and cooled in an ice-water bath. After 3 h the ice-water bath was removed. The mixture was stirred at room temperature for two days. Then the mixture was filtered through a silica pad and the solvent was evaporated. After crystallization from ethanol, 1.2 g of the product (53%) were obtained with mp 97° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]1[CH:18]([CH3:20])[S:19][C:12]1=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2=[O:26].Cl.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1CCN2C(=NCCC2)CC1>O>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:38]1[CH2:39][CH2:40][N:35]([C:30]3[N:29]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]1)[N:13]1[CH:18]([CH3:20])[S:19][C:12]1=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2=[O:26]
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(c5ncccn5)CC4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 120 h
Yield: 96 %

Procedure:
To 16 ml of N,N-dimethylformamide were added 2.0 g (0.0064 mole) of ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]-thiazeto[3,2-a]quinoline-3-carboxylate, 3.0 g (0.0129 mole) of 1-(2-pyrimidinyl)piperazine dihydrochloride and 3.9 g (0.0256 mole) of 1,8-diazabicyclo[5.4.0]-7-undecene, and the mixture was stirred at room temperature for 5 days. The reaction mixture was added to water, and crystals precipitated were collected by filtration, washed with water and dried to obtain 2.8 g of ethyl 6-fluoro-1-methyl-4-oxo-7-[4-(2-pyrimidinyl)piperazin-1-yl]-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate as pale yellow powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH:11]=1)[NH2:10].[CH:20](O)=[O:21].C(OC(=O)C)(=O)C.O>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH2:2])=[CH:11][C:9]=1[NH:10][CH:20]=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Reactant: O=CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: NCCc1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 0.08 h

Procedure:
2.7 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, in 160 ml of chloroform is combined with 4 ml of a mixture of formic acid and acetic anhydride (3:5). After 5 minutes of agitation at room temperature, a small amount of water is added and the mixture completely evaporated. The residue is chromatographed on silica gel with methylene chloride/methanol 8:2. The thus-purified material is washed in methylene chloride with sodium bicarbonate solution. After evaporation, 1.5 g of 2-(4-benzyloxy-3-formylaminophenyl)ethylamine is obtained as a noncrystalline material.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1CCN2C(=NCCC2)CC1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[C:10]2[C:15]=1[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[N:4][C:3]=1[NH:9]2
Reactant: Cc1cnc(Nc2cc(Cl)ccc2OCC2CCN(C)CC2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cnc2[nH]c3c(OCC4CCN(C)CC4)ccc(Cl)c3c2c1
Temperature: 155 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a stirred solution of Compound 174 (450 mg, 1.06 mmol) in anhydrous and degassed DMF (3 mL), were added Pd(OAc)2 (59 mg, 0.26 mmol) and DBU (0.48 mL, 3.18 mmol), under nitrogen. After being stirred for 6 h. at 155° C. the reaction was quenched by addition of water (5 mL). The solid precipitates out was filtered and washed thoroughly with water. The residue was dried under vacuum and purified by flash chromatography to furnish Compound 175 (237 mg, 65%).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:14]([CH:22]1[CH2:27][O:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[O:24][CH2:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1C=CC=CC=1.N1C=CC=CC=1>O>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH:25]3[O:24][CH2:23][CH:22]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:27][O:26]3)=[CH:33][CH:32]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCC1COC(c2ccc(O)cc2)OC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCC1COC(c2ccc(OC(=O)c3ccc(CCCC)cc3)cc2)OC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.9 %

Procedure:
A mixture of 4-n-butylbenzoyl chloride (0.98 g. 0.005 m), p-(5-n-octyl-1,3-dioxan-2-yl)phenol (1.37 g, 0.005 m), benzene (40 ml) and pyridine (2 ml) was stirred at room temperature for six hours. The resulting reaction mixture was poured into cold water. The organic layer was separated and washed with diluted hydrochloric acid solution, diluted potassium hydroxide solution and water, then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield p-(5-n-octyl-1,3-dioxan-2-yl)phenyl p-n-butylbenzoate (1.1 g. 51%) CN 65.5°-66.5° C., NL 141°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C[N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:42](N)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([C:4]1[N:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:12])=[O:8])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 636.4 %

Procedure:
Combined 6-chloronicotinic acid (20 g, 12.74 mmol) and HATU (72.6 g, 19.1 mmol) in DMF (200 mL) and added triethylamine (38.6 g, 38.2 mmol) drop wise, followed by benzylamine (16.36 g, 15.28 mmol) and stirred at room temperature overnight. Then the reaction mixture was poured into ice-water and stirred for 20 minutes to give a solid. The solid was collected by filtration, washed with water (30 mL×2), and dried under reduced pressure to give the title compound (20 g, 64%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.CO>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1)(=[O:5])[CH:4]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CCCc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 0.40 g of sodium hydroxide in 6 ml of water, a solution of 1.00 g of methyl 4-(4-acetylphenyl)butyrate in 2 ml of methanol was added under ice-cooling. Then, a solution of 0.48 g of benzaldehyde in 2 ml of methanol was added dropwise and stirring was continued at room temperature for 3 hours. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration, washed successively with water and n-hexane to yield 0.94 g of colorless crystals. Recrystallization from 80% aqueous methanol gave colorless needles, mp 111°~112° C.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[C:7]1(=[O:14])[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16]>C(O)C>[C:4]([C:3]1[CH:21]([C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:12]2[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]=2[NH:6][C:2]=1[CH3:1])#[N:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: C/C(N)=C\C#N
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Yield: 70 %

Procedure:
3-Aminocrotonitrile (0.91 g), 1,3-cyclohexanedione (1.25 g), and 3-nitrobenzaldehyde (1.70 g) were combined in ethanol (100 mL) and heated at reflux for 7 hours. Removal of solvent and chromatography (ethyl acetate) gave the title compound (2.40 g) as a yellow solid; mp 214°-216° C. NMR: 1.73-2.00 (m,2, CH2), 2.08 (s,3, CH3), 2.13-2.31 (m,2, CH2), 2.41-2.63 (m,2, CH2), 4.66 (s,1, CH), 7.61 (m,1, Ar), 7.68 (dd,1, J=7.7, 1.1 Ar), 7.98 (s,1, Ar), 8.07 (m,1, Ar), 9.66 (s,1, NH); MS: m/z=309(M). Analysis for C17H15N3O3 : Calculated: C, 66.01; H, 4.89; N, 13.58; Found: C, 65.78; H, 4.99; N, 13.45.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=2)[N:7]=1)[CH:9]1[CH2:25][CH2:24][C:12]2([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a suspension of tert-butyl 8-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.30 g, 0.79 mmol) in n-BuOH (4.0 mL) were added 1-methyl-1H-pyrazol-4-amine hydrochloride (0.21 g, 1.58 mmol) and DIPEA (0.41 g, 3.15 mmol). The mixture was stirred in a sealed tube at 150° C. overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a yellow solid (0.22 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:15](OC(=O)C)=[O:16].CO>CCOCC>[CH:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reactant: CC(=O)OC=O
Solvent: CO
Solvent: CCOCC
Product: O=CNc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (0.96 g, 4.44 mmol) was suspended in ether (50 ml). Acetic formic anhydride (1.0 g, 11.36 mmol) was added dropwise and the reaction mixture was stirred for 16 hours. The white precipitate was collected by filtration and triturated with ether (50 ml). There was thus obtained (4-formamidophenylsulphonyl)nitromethane (0.98 g, 90% yield), m.p. 192°-193° C. (after recrystallisation from aqueous methanol); microanalysis, found: C, 39.3; H, 3.1; N, 11.4%; C8H8N2O5S requires: C, 39.3; H, 3.3; N, 11.5%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:32])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl.O>[Cl:32][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCO3)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of N-(4-hydroxymethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (412 mg, 1.07 mmol) and pyridine (1 drop) in chloroform (5 ml) was dropwise added thionyl chloride (0.14 ml, 1.61 mmol), and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent was evaporated, and the resulting powder was washed with hexane-ethyl acetate (1:1) to give N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (380 mg, 88%) as colorless powder.