Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([OH:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cc(Br)ccc2OCc2ccccc2)cc1

Procedure:
A solution of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ol (7.00 g), potassium carbonate (3.80 g) and benzyl bromide (3.27 ml) in DMF (10 ml) was stirred at 60° C. for 5 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane→hexane:ethyl acetate=10:1) to give the title compound (8.31 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:4][C:3]1=[O:13].C(N(CC)CC)C.[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:38][CH2:39][CH2:40]Br)[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]>C(C(C)=O)C(C)C>[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:38][CH2:39][CH2:40][CH:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:5]43[O:4][C:3](=[O:13])[N:2]([CH3:1])[C:6]4=[CH2:7])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Reactant: CC(=O)c1ccc2c(c1)N(CCCBr)c1ccccc1S2
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=C1N(C)C(=O)OC12CCNCC2CCCN1c2ccccc2Sc2ccc(C(C)=O)cc21
Reaction time: 6 h
Yield: 84.5 %

Procedure:
A mixture containing 7.3 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 9 ml of anhydrous triethylamine, 22.0 g of 3-(2-acetyl-10H-phenothiazin-10-yl)-propyl bromide and 80 ml of methyl isobutyl ketone is refluxed under argon while stirring for 6 hours. After cooling down the organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained is purified by chromatography on a silica gel column by using first chloroform and then ethyl acetate as eluating agent. After combining the ethyl acetate eluate is evaporated under reduced pressure and the residue is recrystallized from ethanol to give the title compound in 84.5% yield, m.p.: 105°-106° C.
Reaction SMILES: [C-]#N.[Na+].[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].[N:17]1C=CC(C)=C[CH:18]=1>[Cu]I>[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([C:18]#[N:17])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: Cc1ccncc1
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 155 °C

Procedure:
A 250-mL, four-necked flask equipped with a mechanical stirrer and condenser was charged with copper(I) iodide (1.97 g, 10.3 mmol), sodium cyanide (95% purity, 3.30 g, 64.0 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (10.0 g, 40.9 mmol), 4-picoline (distilled prior to use) (1.16 g, 12.5 mmol) and oxygen-free anisole (20 mL), and then purged with nitrogen, after which time the reaction mixture was maintained under a nitrogen atmosphere. The reaction mixture was heated at about 155° C. for 12 h and then allowed to cool to room temperature overnight. Toluene (20 mL) was added to the solid-containing reaction mixture, the mixture was heated at about 100° C., and then water (60 mL) was added over 20 minutes with stirring. The reaction mixture was stirred for 1 h at 85° C., cooled to room temperature, and then filtered. The solid collected was washed with water (3×mL) and toluene (1×20 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (7.34 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=[O:14])=[CH:5]2.[OH-].[K+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2cc(F)c(F)cc2c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A suspension of 37.7 g of ethyl 6,7-difluoroquinoline-3-carboxylate in a mixture of 20 cm3 of ethanol and 160 cm3 of a 1 N aqueous potassium hydroxide solution was stirred for 4 hours, at a temperature of 20° C. 600 cm3 of water was added to the solution and the insoluble material was extracted twice with 400 cm3 of diethyl ether. The aqueous solution was neutralized with 161 cm3 of a 1 N aqueous hydrochloric acid solution. The precipitate obtained was dewatered, washed 3 times with 150 cm3 of water, and dried under vacuum at a temperature of 50° C. 30 g of 6,7-difluoroquinoline-3-carboxylic acid was obtained in the form of white crystals, which melted at 290° C.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:15]([F:16])=[CH:14][C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])([O:3]CC)=[O:2].[OH-].[Na+]>CO>[CH3:11][C:10]1[C:9]2[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:15]([F:16])[C:8]=2[O:7][C:6]=1[C:1]([OH:3])=[O:2]
Reactant: CCCc1cc(F)c2oc(C(=O)OCC)c(C)c2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(F)c2oc(C(=O)O)c(C)c2c1O
Yield: 87 %

Procedure:
To a solution of 2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (1.0 gm, 3.6 mmoles) in methanol (100 mL) was added 2N sodium hydroxide (10 mL) and the resulting solution was refluxed for a period of 4.5 hours. The reaction mixture was concentrated in vacuo. The residue was acidified with 3N hydrochloric acid and then extracted with ethylacetate. The organic phase was dried (Na2SO4), concentrated in vacuo, and 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofurancarboxylic acid (0.79 gm; 88%) was isolated by filtering the solid after suspending in hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C:49]1[CH:54]=[C:53]([O:55][C:56]2[CH:61]=[C:60]([F:62])[C:59]([NH2:63])=[CH:58][C:57]=2[F:64])[N:52]=[CH:51][N:50]=1>CN(C)C=O>[NH2:48][C:49]1[CH:54]=[C:53]([O:55][C:56]2[C:57]([F:64])=[CH:58][C:59]([NH:63][C:14]([C:11]3([C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:60]([F:62])[CH:61]=2)[N:52]=[CH:51][N:50]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1cc(Oc2cc(F)c(N)cc2F)ncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (378 mg) in N,N-dimethylformamide (3 ml) were added triethylamine (0.236 ml) and HATU (644 mg) at room temperature under a nitrogen atmosphere, followed by stirring for 30 min. To the resultant mixture was added 4-amino-6-(4-amino-2,5-difluorophenoxy)pyrimidine (270 mg) in N,N-dimethylformamide (3 ml) at room temperature, followed by stirring for 6 hr. Triethylamine (0.079 ml) and HATU (215 mg) were added again and the resultant mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and a 1N aqueous solution of sodium hydroxide (10 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (10 ml, twice) and brine (10 ml), dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2 to 1:4). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale brown powder (199 mg, 40%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[Cl:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([CH:29]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[C:20]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:21][CH:22]=[C:23]([CH:29]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: CCNC(=O)c1cnc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)c1cnc(-c2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
2.44 g of Na2CO3 (23.0 mmol), 1.15 g of 4-formylphenylboronic acid (7.67 mmol), and 0.21 g of Pd(PPh3)4 were added to 1.68 g of 5,6-dichloro-N-ethyl-nicotinamide (5) (7.67 mmol) prepared in Example 2 dissolved in 30 mL of 1,2-dimethoxyethane and 30 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, concentrated about 50% under reduced pressure to extract the aqueous layer with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 5-chloro-N-ethyl-6-(4-formyl-phenyl)-nicotinamide 1.78 g (yield 80%).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.Cl>[ClH:12].[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: CCC(CC)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added 4-nitrophenyl chloroformate (201 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×20 ml) and water (3×20 ml) and dried (MgSO4). The organic solution was concentrated to yield an oil that was dissolved in a 0.5 N HCl solution (15 ml). The acidic solution was concentrated and re-evaporated twice with acetonitrile to give 290 mg (81%) of the title compound as a solid. M.p. 251–253° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.Cl.[C:10]([NH:14][NH2:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>C(O)C>[C:10]([NH:14]/[N:15]=[C:2](\[CH3:4])/[C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)/C(C)=N/NC(C)(C)C
Yield: 71.3 %

Procedure:
To a solution of ethyl pyruvate (20.22 g, 174.1 mmol) in ethanol (150 mL) was added t-butyl hydrazine hydrochloride (21.7 g, 174 mmol) and N,N-diisopropylethyl amine (33.4 mL, 192 mmol). After stirring at reflux for 18 hours, the reaction was cooled and the volatiles were removed under reduced pressure. The resultant golden oil was taken up in 300 mL ethyl acetate and washed with 200 mL water and 300 mL saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to yield (E)-ethyl 2-(2-tert-butylhydrazono)propanoate (23.1 g) as a clear pale yellow oil. +APCI (M+H) 187.3; 1H NMR (400 MHz, CDCl3, δ): 5.51 (br. s., 1H), 4.25 (q, J=7.2 Hz, 2H), 1.89 (s, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.28 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])(=[O:23])C.[Na+]>>[OH:23][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: O=c1c(CO)c(-c2ccc(O)cc2)oc2ccccc12
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.50 g, 1.5 mmol) and sodium acetate (1.24 g, 15.0 mmol) in ACOH (20 mL) was heated to reflux for 15 h. AcOH was removed and the residue was poured into water and extracted with EtOAc (100 mL). The organic phase was further washed with brine and dried over sodium sulfate. The residue was mixed with potassium carbonate (0.52 g) and MeOH (10 mL) and stirred for 2 h. AcOH (1.0 mL) was added and MeOH was removed. The residue was poured into water and the solid was washed additionally with water and hexane to give 3-(hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.265 g, 62.6%). MS (ES) m/z: 269.94 (M+1), 268.94 (M); Mp. 234-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)c1cc2cc(O)ccc2o1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 1-(5-hydroxy-1-benzofuran-2-yl)ethanone (1.15 g, 6.53 mmol) in DMF (10 mL) were added tert-butyldimethylchlorosilane (1.07 g, 7.18 mmol) and imidazole (666 mg, 9.80 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 7:3) to give the title compound (1.76 g, yield 98%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:8]([CH2:10][CH3:11])=O)[CH3:7]>>[CH3:7][CH:6]=[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][CH3:11]
Reactant: C1CCNC1
Reactant: CCC(=O)CC
Product: CC=C(CC)N1CCCC1
Reaction time: 170 h
Yield: 69.3 %

Procedure:
584 g of pyrrolidine and 126.7 g of diethyl ketone are placed into a pear-shaped flask fitted with a Soxhlet attachment. In the Soxhlet there is contained 200 g of molecular sieve A4. The mixture is boiled for 170 hours at 150° C. bath temperature, and subsequently concentrated in a rotary evaporator. The residue obtained is distilled in a water-jet vacuum. There is obtained 142 g (70% of theory) of N-(3-pent-2-enyl)-pyrrolidine, b.p. 80° C./ 18 Torr. With the use of excess diethyl ketone, it is possible to attain a yield of 94%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[C:33]2([CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:35]2[CH2:36][CH2:37][C:33]3([CH2:31][CH2:32]3)[CH2:34]2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Reactant: C1CC2(CC2)CN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 17.9 %

Procedure:
In absolute anhydrous THF (15 mL) were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-formamide (180 mg, 0.41 mmol) and 5-azaspiro[2.4]heptane (59 mg, 0.61 mmol). The solution was cooled in an ice bath, and triethylamine (82 mg, 0.82 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h then was quenched with water. The reaction mixture was extracted with DCM. The organic phase was dried over sodium sulfate and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give the product as a solid (35 mg, 18% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:31][CH:32]=3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH:32]=3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-carboxylate (0.037 g, 0.065 mmol) in dichloromethane (1 mL) and the resulting solution was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15% methanol in dichloromethane) to give the title compound as a white solid (0.012 g, 0.025 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.39 (s, 1 H), 7.19-7.12 (m, 4 H), 6.20 (d, J=6.8 Hz, 1 H), 6.11-6.08 (m, 1 H), 4.82-4.74 (m, 1 H), 4.29-4.09 (m, 2 H), 3.98-3.70 (m, 2 H), 3.46-3.34 (m, 3 H), 2.70-2.48 (m, 3 H), 2.16-1.98 (m, 3 H), 2.00 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C25H27Cl2N4O [M+H]+ 469.2, found 469.4.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](C(=O)C)[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH2:4]1.Cl>C1COCC1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([S:8]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:23])[CH3:1])[CH2:4]3)(=[O:10])=[O:9])=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)N3CC[C@@H](N(C)C)C3)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(S(=O)(=O)c2ccc3c(c2)CCN3)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
(R)-1-(5-(3-(dimethylamino)pyrrolidin-1-ylsulfonyl)indolin-1-yl)ethanone was dissolved in THF. A 2 N HCl solution of equal volume was added, and the reaction mixture was stirred at 60° C. for 1 h. Volatiles were removed in vacuo, and the product that was precipitated was collected on a fritted glass funnel, washed with water, and was dried in vacuo at 45° C. overnight to obtain the title compound in 65% yield. 1H NMR (300 MHz, MeOD) δ ppm 2.02-2.22 (m, 1 H) 2.25-2.47 (m, 1 H) 2.88 (s, 6 H) 3.14-3.26 (m, 1 H) 3.28-3.33 (m, 2 H) 3.34-3.64 (m, 4 H) 3.82-4.01 (m, 2 H) 7.51-7.60 (m, 1 H) 7.87 (d, J=8.67 Hz, 1 H) 7.93 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=O.[OH-].[NH4+:17]>>[C:11]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=1)(=[O:13])[NH2:17]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnc2n(c1=O)CCC2
Yield: 96.6 %

Procedure:
10.4 g. of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 30 ml. of 30% by weight of ammonium hydroxide solution. The precipitated crystals are filtered after 2 hours. 8.7 g. of 3-carbamoyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained with a yield of 96.6%, which melts at 293° C. after recrystallization from dimethyl formamide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:26][CH2:25]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Agent: Cl
Product: CC(=O)NC1(c2ccc(CN3CCN(c4ncccn4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=145-146° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[O:28][CH2:29][CH2:30]O>CN(C)C=O.O>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[O:28][CH2:29][CH2:30][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc(S)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A stirred mixture of 1-(4-mercaptophenyl)ethanone (1.2 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.350 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthyloxy)ethanol (2.2 g). The mixture was heated at 60° C. for 2 hours and diluted with water and filtered. The solids were dissolve in dichloromethane, washed once with water, dried (Na2SO4), filtered and evaporated. Crystallization from dichloromethane-hexane provided 2.0 g of 1-[4-[[2-(2naphthalenyloxy)ethyl]thio]phenyl]ethanone, mp 151°-152° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][N:15](C(OC3C=CC=CC=3)=O)[CH2:16][C:3]=12.[ClH:26].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:26].[ClH:26].[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:3]=12
Reactant: O=C(Oc1ccccc1)N1CCCc2nc3ccccc3c(O)c2C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Oc1c2c(nc3ccccc13)CCCNC2

Procedure:
11-Hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline dihydrochloride was prepared by hydrolysis of 11-hydroxy-2-phenoxycarbonyl-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline with concentrated hydrochloric acid. Yield of the dihydrochloride: 65% of theory; m.p. 289° C. (decomp.).