Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]([F:27])([F:26])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([I:24])[C:15]=1[OH:25])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3](=[O:5])(=[O:4])[O:25][C:15]1[C:16]([I:24])=[CH:17][C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:19][C:14]=1[CH2:13][NH:12][C:10](=[O:11])[C:9]([F:8])([F:26])[F:27]
Reactant: CC(C)(C)c1cc(I)c(O)c(CNC(=O)C(F)(F)F)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Oc1c(I)cc(C(C)(C)C)cc1CNC(=O)C(F)(F)F
Reaction time: 72 h

Procedure:
To a solution of N,N-dimethylsulfamoyl chloride (17.4 g., 0.12 mole) in dry methylene chloride (75 ml.) maintained under a nitrogen atmosphere is added slowly and with good stirring a solution of 2,2,2-trifluoro-N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethyl]acetamide (8 g., 0.02 mole) and triethylamine (12.12 g., 0.12 mole) in dry methylene chloride (200 ml.) at 20°-25° C. The resulting reaction mixture is stirred at 20°-25° C. under nitrogen for 72 hours. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and water. The phases are separated and the organic phase is washed successively with 2N hydrochloric acid, water and saturated brine, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves the intermediate 2-(2,2,2-trifluoroacetamidomethyl)-4-(1,1-dimethylethyl)-6-iodophenyl N,N-dimethylsulfamate as a tan oil (10.3 g., 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].I[CH2:12][C:13]([CH3:17])(C)[CH2:14]I.[OH-].[K+].[CH3:20]S(C)=O>>[CH3:12][C:13]1([CH3:17])[CH2:14][CH2:20][C:8]1([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]#[N:10]
Reactant: N#CCc1ccccc1Cl
Reactant: CS(C)=O
Reactant: CC(C)(CI)CI
Agent: [K+]
Agent: [OH-]
Product: CC1(C)CCC1(C#N)c1ccccc1Cl
Reaction time: 1 h

Procedure:
A mixture of 2-chlorophenylacetonitrile (26.5 g), 1,3-diiodo-2,2-dimethylpropane (56 g) and dimethyl sulphoxide (300 ml) was added dropwise to a stirred suspension of powdered potassium hydroxide (40 g) in dry dimethylsulphoxide (300 ml). The mixture was stirred for one hour, then poured onto ice/water and extracted with ethyl acetate. The extracts yielded an oil which was distilled under vacuum to give 2,2-dimethyl-1-(2-chlorophenyl)cyclobutane carbonitrile, (b.p. 116°-120° C./1 mbar) which was recrystallised from petroleum ether (b.p. 60°-80° C.) m.p. 65°-69° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)#[N:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:25]([O:36][CH3:37])(=[O:35])[C:26]1[CH:34]=[CH:33][C:31]([OH:32])=[C:28]([O:29][CH3:30])[CH:27]=1>C(#N)C>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:32][C:31]2[CH:33]=[CH:34][C:26]([C:25]([O:36][CH3:37])=[O:35])=[CH:27][C:28]=2[O:29][CH3:30])=[CH:12][CH:11]=1)#[N:9]
Reactant: ClCCCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)c(OC)c1
Temperature: 82 °C
Reaction time: 20 h

Procedure:
To a solution of 1-bromo-5-chloropentane (3794 g, 20.45 mol) in acetonitrile (38 L) is added 4-cyanophenol (2437 g, 20.45 mmol) and powdered powdered potassium carbonate (2827 g, 20.45 mol). This suspension is heated with stirring under nitrogen at 96° C. bath temperature (82° C.-internal) for 20 hours. Additional powdered potassium carbonate (2827 g, 20.45 mol.) is then added to the hot reaction mixture followed by potassium iodide (3397 g, 20.45 mol) and methyl vanillate (3725 g, 20.45 mol). The reaction mixture is heated under nitrogen for another 3 days until TLC shows no intermediate chloro compound present. The bath is removed and stirring stopped. The reaction mixture is filtered hot through a filter crock and into another 20 gallon reactor. The filtrate is stirred and cooled with an ice bath to 10° C. for 3 hours and the product filtered, washed with diethyl ether (4×1 L) and dried in vacuo (50° C., 3 mm Hg) to give methyl 4-[5-(4-cyanophenoxy)-pentoxy]-3-methoxybenzoate, mp 105°-107° C., HPLC indicating a purity of 99.8%.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]([F:9])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][NH2:50])[CH:44]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:10]2[N:49]([C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)[N:50]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(Br)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2cccnc2)n1

Procedure:
600 mg (1.30 mmol) of the compound of Example 2A is reacted analogously to the synthesis of the compound of Example 20A with 208 mg (1.43 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 406 mg (86% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C@H:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20])=[CH:13][CH:12]=1.C1C=CC=CC=1>O.CCOCC>[Cl:1][C:15]1[CH:16]=[C:11]([O:10][CH3:9])[CH:12]=[CH:13][C:14]=1[NH:17][C@H:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(N[C@H](C(=O)O)C(C)C)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(N[C@H](C(=O)O)C(C)C)c(Cl)c1

Procedure:
A mixture of N-chlorosuccinimide (1.17 mmole), m-phenoxybenzyl ester of N-(p-methoxyphenyl)valine (1.23 mmole) and benzene (20 ml) is refluxed under nitrogen for about 60 hours. The reaction is worked up in water/ether. The ether layer is washed with water and brine and dried over sodium sulfate. The crude product is purified by preparatory TLC eluting with 15% ether/hexane to give the m-phenoxybenzyl ester of N-(2-chloro-4-methoxyphenyl)valine, MS m/e 439 (M+, 7.4), 212 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][S:10]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(F)cc1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(C=Cc1ccc(F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
163 g of 2-(4-fluorophenyl)ethenesulfonyl chloride were dissolved in 1.5 l of toluene and, at RT, 69.64 g of phenol were added. Subsequently, at RT, 103 ml of triethylamine were added dropwise, during which the temperature rose to 44° C. The mixture was then stirred at RT for 90 minutes, left to stand for 16 hours and stirred at RT for a further 2 hours. The solvent was then removed in vacuo, and the crude product was taken up in 2.5 l of EA. Washing 3 times with 750 ml of a saturated aqueous NaHCO3 solution was followed by washing 3 times with 750 ml of 2 N aqueous HCl solution each time. After drying over Na2SO4, the solvent was removed in vacuo. The product was then stirred in 350 ml of HEP for 1 hour and, on cooling, the product crystallized and was washed with HEP and dried under medium vacuum. 145.0 g of white crystals were obtained, mp 108° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[OH:10]O.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)C>[C:12]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N+:3]=1[O-:10])(=[O:14])[CH3:13]
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CC(=O)OC(C)=O
Reactant: OO
Solvent: CCO
Product: CC(=O)Nc1nc(Cl)cc(N)[n+]1[O-]
Temperature: 40 °C
Yield: 38 %

Procedure:
5.0 g (0.035 mole) of 2,6-diamino-4-chloropyrimidine are dissolved in 70 ml of anhydrous ethyl alcohol. 7 ml of a 70% aqueous hydrogen peroxide solution and 14 ml of acetic anhydride are dropped into it while stirring at a temperature of 40° C. in half an hour. The mixture is stirred at 60° C. for further two hours, then it is cooled and the flaky crystals are filtered out, washed with ethanol and dried. Thus 2.67 g (38%) of 2-acetamido-4-chloro-6-aminopyrimidine-1-oxide are obtained.
Reaction SMILES: [F:1][C:2]([C:25]([F:28])([F:27])[F:26])([O:6][C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:3]([NH2:5])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([C:25]([F:26])([F:27])[F:28])([O:6][C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:3]#[N:5]
Reactant: NC(=O)C(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F)C(F)(F)F
Temperature: 200 °C
Yield: 55 %

Procedure:
80 g of the thus prepared crude perfluoro (2-methyl-3,8-dioxa-9-decenamide) and 30 g of phosphorus pentoxide were mixed together and pulverized, and charged into a glass flask having a net capacity of 300 ml. Then, the flask was heated to 200° C. Low boiling components formed in the course of the reaction were removed from the flask by distillation through a cooling pipe. Crude residues were distilled in the presence of a small amount of phosphorus pentoxide, whereby 60 g of perfluoro (2-methyl-3,8-dioxa-9-decenonitrile) was obtained (total yield: 55% ).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[N:6]([CH2:16][CH2:17]O)[C:7](=[O:15])[NH:8]2.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:17][CH2:16][N:6]1[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[NH:8][C:7]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)n(CCO)c(=O)c2c1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(=O)n(CCCl)c(=O)c2c1OC

Procedure:
A mixture of 5,6-dimethoxy-3-hydroxyethylquinazolin-2,4-dione (2.0 g, 7.51 mM) and thionyl chloride (0.76 ml, 10.45 mM) in CHCl3 (20 ml) was heated at reflux for 4 hours under nitrogen with vigorous mechanical stirring. Trituration of the solid reaction mixture followed by drying afforded crude product as an off-white solid. The crude product was recrystallized from MeOH (100 ml) and dried to afford the title compound as a white solid; 0.86; (A); mp 118°-120° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.C([Li])CCC.CN([CH:30]=[O:31])C>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([CH:8]=1)[CH:30]=[O:31])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(F)c(C=O)c1
Temperature: -60 °C
Reaction time: 0.67 h
Yield: 94.6 %

Procedure:
To a solution of 1-ethyl-4-fluorobenzene (10 g, 80.6 mmol) and PMDTA (17 mL) in THF (60 mL) cooled to −78° C. was added 1.6 M n-butyl lithium (56 mL, 89 mmol) dropwise and the mixture stirred for 40 min at −60° C. Mixture cooled to −78° C. and added DMF (16 mL, 202 mmol) before allowing the mixture to warm to 23° C. Quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). Organic layer was washed with H2O and brine before concentrating to afford 11.6 g of Intermediate 311.2. 1H-NMR (CDCl3)=1.18 (t, 3 H), δ 2.58 (q, 2 H), δ 7.04 (t, 1 H), δ 7.35 (m, 1 H), δ 7.62 (m, 1 H), δ 10.31 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.C([Cl:23])(=O)OCC.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2/[CH:42]=[CH:43]/[C:44]2[CH:49]=[CH:48][N+:47]([O-:50])=[CH:46][CH:45]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl.CO>[ClH:23].[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]([N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2/[CH:42]=[CH:43]/[C:44]2[CH:45]=[CH:46][N+:47]([O-:50])=[CH:48][CH:49]=2)[S:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[O:10])[CH2:5][CH2:6]1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1
Reactant: O=C(O)CN1CCOCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(C(=O)CN2CCOCC2)c2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1
Product: Cl
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Morpholinoacetic acid (5.18 g) prepared in the same manner as Reference Example 1 was dissolved in methylene chloride (230 ml), and triethylamine (4.86 g) was added thereto. To the mixture was added dropwise ethyl chlorocarbonate (5.21 g) under ice-cooling, and the mixture was stirred for thirty minutes at room temperature. To the mixture was added (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)amino)phenyl)ethenyl)pyridine 1-oxide (7.65 g) and the mixture was further stirred for three hours at room temperature. The reaction solution was washed with water, dried over magnesium sulfate and concentrated. The resultant residue was dissolved in acetonitrile. To the solutuion was added hydrochloric acid-methanol and the mixture was stirred over night at room temperature. The precipitated crystals were filtered off, washed with acetonitrile and further with ether and the crude crystals were obtained. The recrystallizaion from methanol yielded the objective compound (8.16 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][O:10]2)=[CH:5][C:4]=1[F:18].[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[Br-:1].[F:18][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[CH2:2][P+:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:10][CH2:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC1COc2cc(CBr)c(F)cc2C1
Solvent: CC#N
Product: CCCCCC1COc2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c(F)cc2C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.0 g (34.9 mmol) of 7-bromomethyl-6-fluoro-3-pentylchroman and 9.20 g (35.1 mmol) of triphenylphosphine are dissolved in 70 ml of acetonitrile, and the mixture is stirred overnight at room temp. The batch is subsequently cooled to 0° C., and the precipitated (6-fluoro-3-pentylchroman-7-ylmethyl)triphenylphosphonium bromide is filtered off with suction and dried in vacuo.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[I:8][C:7]1[C:2]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[S:9][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)=[CH:24][CH:23]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1I
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-fluoro-3-iodopyridine (1.674 g, 7.51 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (2.73 g, 11.26 mmol) and cesium carbonate (4.16 g, 12.76 mmol) in N-methyl-2-pyrrolidinone (10 mL) was degassed and heated to 120° C. After 3 h 30 min, the reaction was cooled to 23° C., diluted with EtOAc (200 mL) and washed with water (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0-1% methanol/dichloromethane), affording the product as an off-white solid. MS (ESI, pos. ion) m/z: 445.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)CCC>O>[ClH:1].[ClH:1].[C:19]1([C@H:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: C[C@H](N)c1ccccc1
Solvent: CCCCO
Solvent: O
Product: C[C@@H](Nc1nnc(Cc2ccncc2)c2ccccc12)c1ccccc1
Product: Cl
Temperature: 110 °C
Reaction time: 40 h

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 1.273 ml (10 mmol) (S)-1 phenylethylamine and 5 ml 1-butanol is stirred for 40 h at 110° C. After processing as described in Example 12 and equilibration for 65 hours at 20° C. and in room atmosphere, title compound is obtained with a water content of 10.53%;
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl.O>[N:12]1([C:10]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][CH:2]([O:1][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)=[O:24])[CH2:3][CH2:4]2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OCC1CCC(O)CC1)N1CCCC1
Reactant: O=C(Cl)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1CCC(COC(=O)N2CCCC2)CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-hydroxy-cyclohexylmethyl ester (1 mmol) in methylene chloride (5 mL) were added picolinoyl chloride (1.1 mmol) and triethylamine (1.5 mmol) and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (233 mg, 70% yield).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reaction time: 2.5 h

Procedure:
Concentrated sulfuric acid (30.00 mL) was cooled to −10° C. with an ice/salt bath. To this, 1,2,3,4-tetrahydro-quinoline (10.60 g, 75.60 mmol) and a solution of nitric acid (99.5%, 4.80 g, 75.60 mmol) in sulfuric acid (15.00 mL) were added simultaneously within 1 hour, so that the temperature of the reaction mixture does not exceed 10° C. The mixture was stirred then for 2.5 hours at −5° C., then poured over ice and treated with sodium carbonate (0.10 kg) until pH 8-9 was reached. The solid was filtered, washing with water, then dissolved in dichloromethane. The organic phase was washed with water, dried over magnesium sulphate and evaporated. 7-Nitro-1,2,3,4-tetrahydro-quinoline was obtained as a viscous brown oil, 13.70 g (85%), 84% purity.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=1>ClCCl>[Cl:3][CH2:13][C:12]1[C:7]([O:6][CH3:5])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ncccc1CO
Solvent: ClCCl
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Thionyl chloride (9.5 mL, 130 mmol) was added portionwise to a solution of (2-methoxy-pyridin-3-yl)-methanol (1.02 g, 7.3 mmol) in dichloromethane (36 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was carefully treated with saturated aqueous sodium hydrogen carbonate and the mixture was stirred for 5-10 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (sodium sulfate), filtered, and evaporated to give 3-chloromethyl-2-methoxy-pyridine (989 mg, 86%) as a light yellow oil.
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]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.[CH3:18][O-:19].[Na+].[Na].C(Cl)(Cl)Cl>CO>[CH3:18][O:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1cccc(-c2nc(C)cc(OC)n2)n1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (1 g) in methanol (10 ml), was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.11 g). After being left to stand at room temperature for two hours, the solution was concentrated under reduced pressure. To the residue obtained, was added chloroform (100 ml). The mixture was washed twice with water (30 ml each) and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain 4-methoxy-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (0.93 g, yield: 95 %).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14][C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[C:9]=2[F:20])[N:4]=1)C.[Cl-].ClC1N(C)CC[NH+]1C.N1C=C[CH:34]=[CH:33][CH:32]=1.C(C1C(C)=C([O:50]C(C2CC2)=O)C2C(=CC(F)=C(F)C=2)N=1)C>ClCCl.O>[CH3:1][C:3]1[C:12]([CH3:13])=[C:11]([O:14][C:15]([C:17](=[O:50])[CH2:19][CH2:18][CH2:32][C:33]#[CH:34])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[C:9]=2[F:20])[N:4]=1
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: c1ccncc1
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: C#CCCCC(=O)C(=O)Oc1c(C)c(C)nc2ccc(F)c(F)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 254.3 %

Procedure:
5-Hexynoic acid (starting material 2) (26.9 mg), 40.6 mg of 2-chloro-1,3-dimethylimidazolinium chloride and 37.9 mg of pyridine were stirred in dichloromethane (5 ml) at room temperature for one hr. Thereafter, 50 mg of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) prepared as described in Example 12 was added thereto, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with a saturated aqueous sodium hydrogencarbonate solution and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (10 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 77.8 mg of 2,3-dimethyl-4-(5-hexynoylcarbonyloxy)-5,6-difluoroquinoline (compound 58). 1H-NMR data are shown in Table 3.