Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][S:18][C:19](=[O:22])[CH2:20][CH3:21])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:19]([S:18][CH2:17][CH:16]([CH3:23])[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([OH:33])=[O:5])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:25])=[O:24])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
The 1-(3-propanoylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester obtained was dissolved in a mixture of anisole (10 ml) and trifluoroacetic acid (20 ml). The solution was allowed to stand at room temperature for one hour and concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel with chloroform-methanol (98:2) to give 1-(3-propanoylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine. The diastereomeric mixture thus obtained was dissolved in a proper amount of diethyl ether. The solution was seeded with crystals of the title compound and stored in a refrigerator. The precipitated crystals were collected and recrystallized repeatedly from diethyl ether/petroleum ether to give the title compound, m.p. 107°-114° C. [α]D20 =-81.1° (c=1.00, ethanol)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: CC(C)(C)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, white solid (61 mg, 68%), MS (ISP) m/z=358.5 [(M+H)+], mp 215° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(F)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 56 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (94 mg, 0.681 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 152 mg of a white solid (56%), mp 222.7-223.8° C. (discolors). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 7.89 (dt, J=5.6, 8.1 Hz, 1H); 7.76 (dd, J=1.6, 7.3 Hz, 1H); 7.67 (d, J=7.4 Hz, 1H); 7.56 (d, J=8.1 Hz, 1H); 7.47 (t, J=7.1 Hz, 1H), 7.41-7.53 (m, 2H); 7.37 (dd, J=8.7, 11 Hz, 1H); 4.38-4.52 (m, 2H). 13C NMR (DMSO-d6) ppm: 160.9 (d, J=264 Hz), 157.6, 156.8, 154.1, 151.5, 149.6, 149.0, 143.6, 136.4 (d, J=11 Hz), 133.9, 132.2, 131.7, 131.6, 130.5, 130.2, 128.8, 123.6, 114.4 (d, J=20 Hz), 110.2, 32.0. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.5C2H6O: C, 54.61; H, 3.27; Cl, 7.68; N, 18.19; S, 6.94. Found: C, 54.37; H, 3.26; Cl, 7.89; N, 18.26; S, 6.55.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.F[C:19]1[C:20]([CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:20]([CH:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:33])[CH3:32])[CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of 4-(benzo[d]thiazol-2-ylamino)phenol (91 mg, 0.38 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (56 mg, 0.25 mmol), and cesium carbonate (123 mg, 0.38 mmol) in DMSO (0.85 mL) was heated at 80° C. for 16 h. After cooling to RT, the reaction mixture was partitioned between Teac and brine. The aqueous layer was back extracted with Teac (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% Teac in hexane, then 3% MeOH in Teac, followed by reverse-phase preparative HPLC using a Germini C18 5 uM column, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 15 min, then neutralize with Si carbonate resin, to provide 1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl) as a white solid. MS (ESI, pos. ion) m/z: 445.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1([F:45])[CH2:10][CH2:11][N:12]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=2/[C:15]/1=[CH:16]/[C:17]([N:19]1[CH2:24][CH2:23][C:22](=[N:25][OH:26])[CH2:21][CH2:20]1)=[O:18]>O1CCCC1.C(OCC)(=O)C>[F:45][C:9]1([F:8])[CH2:10][CH2:11][N:12]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=2/[C:15]/1=[CH:16]/[C:17]([N:19]1[CH2:20][CH2:21][C:22](=[N:25][O:26][CH2:4][C:5]([NH2:7])=[O:6])[CH2:23][CH2:24]1)=[O:18]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NO)CC2)c2ccccc21
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NOCC(N)=O)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Sodium hydride (47 mg) and 58 mg of bromoacetamide were added to a solution of 150 mg of (Z)-4,4-difluoro-5-{2-[4-(hydroxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine in 10 ml of tetrahydrofuran, and the mixture was stirred at 0° C. for three hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform-methanol). The resulting residue was crystallized from diethyl ether to give 110 mg of (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperidin-4-ylidene)aminoxy]acetamide as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 3-tert-butoxycarbonylaminopropanoic acid (2 g, 10.6 mmol.) and HOSu (1.22 g, 10.6 mmol.) in 40 mL DCM/Dioxane (2:1) was cooled in an ice bath. To this solution was added DCC (2.4 g, 11.6 mmol.), and the mixture was stirred at room temperature for 1 h. To the resulting mixture was added benzylamine (1.7 g, 15.8 mmol.), the mixture was stirred for 4 h at room temperature. The solid that formed in the mixture was removed by filtration and washed with EtOAc. The filtrate and washings were combined and washed with 1N HCl and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford 3-tert-butoxycarbonylamino-N-benzylpropionamide (2.4 g, 82%). 3-tert-Butoxycarbonylamino-N-benzylpropionamide was dissolved in cooled HCl/MeOH (20 mL) and the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed to afford 3-amino-N-benzylpropionamide hydrochloride (1.8 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=[O:14])[C:9]=2[CH3:18])=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)noc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylate (63 mg, 0.24 mmol) in tetrahydrofuran (1.5 mL) was added a solution of lithium hydroxide hydrate (10 mg, 0.24 mmol) in water (1.5 mL). After stirring for 20 minutes, the reaction mixture was acidified with 1M HCl and extracted with dichloromethane three times. The combined dichloromethane extracts were washed with brine, dried over magnesium sulfate, and evaporated to obtain 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylic acid (55 mg, 0.23 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:36][CH2:37][CH:38]1[O:40][CH2:39]1)(=O)C(C)=C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[OH:36][CH2:37][CH:38]([OH:40])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(O)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(OCC(O)CO)cc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a reaction vessel equipped with a stirrer, a thermometer, a condenser, and a dropping funnel, 11.75 g of 4-hydroxy-4′-(di-p-tolylamino)stilbene, 4.35 g of glycidyl methacrylate, and 8 ml of toluene are contained, and the mixture is heated to 90° C. Further, 0.16 g of triethylamine is added thereto, and the mixture is agitated for 8 hours at 95° C. Next, 16 ml of toluene and 20 ml of a 10% aqueous solution of sodium hydroxide are added thereto, and the mixture is further agitated for 8 hours at 95° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (300 mg, 1.692 mmol) in pyridine (5 mL), stirred in air at room temperature, was added 4-acetylbenzene-1-sulfonyl chloride (370 mg, 1.692 mmol) in one charge. The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand overnight. The solvent was evaporated in vacuo then redissolved in methanol and passed through an aminopropyl (NH2) SPE cartridge, eluting with methanol, followed by 2M ammonia/methanol. The product containing fractions were combined and passed through a sulphonic acid (SCX) SPE cartridge eluting with methanol, followed by 2M ammonia/methanol. The product containing fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by flash (Si) chromatography (using a 0-50% ethyl acetate-cyclohexane gradient) to give the required product (282 mg) as a yellow gum. LCMS (M+1) 360, RT 1.35 mins.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[C:22]([C:32](O)=[O:33])=[N:23][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:22]1[C:21]([CH3:20])=[N:25][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=1)=[O:33]
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1nn(-c2ccccc2)nc1C

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid. MS: 445.4 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.C(Cl)(Cl)Cl>O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]2
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Clc1ccc2c(c1)CCN2
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccccc1N1CCc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
A solution of 32.3 g of 1-fluoro-2-nitrobenzene and 92.2 g of 5-chloroindoline are stirred at 120° C. under N2 overnight (20 hours). The mixture is cooled, and stirred vigorously in a two phase chloroform and water system. The undissolved material is filtered off and the organic phase is then separated, washed with 3 N--HCl, water, dried over Na2SO4, and concentrated to an oil which is dried further in vacuo at 90° C. This is taken up in isopropyl ether and refrigerated overnight to provide 5-chloro-1-(2-nitrophenyl)indoline, m.p. 85°-89° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][NH:21][CH2:22][CH:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH:23]3[CH2:22][NH:21][CH3:20])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CNCC1COCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3CNC)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-(methylaminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[3-(methylaminomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:12][O:11][C:10]1([O:13][CH3:14])[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COC(OC)OC
Reactant: O=C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC1(OC)CCNCC1
Reaction time: 24 h

Procedure:
Into 9 ml of methanol were dissolved 0.69 g of 4-piperidone hydrochloride monohydrate, 0.74 ml of trimethyl orthoformate and 86 mg of p-toluenesulfonic acid monohydrate, and the reaction was conducted at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent. The residue was dissolved into 2 ml of N,N-dimethylacetamide and admixed with 1.4 ml of triethylamine to give a solution of 4,4-dimethoxypiperidine.
Reaction SMILES: N1CCOCC1.C([O:10][C:11]([C@H:13]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:14]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])C=C>O1CCCC1.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>[C:11]([C@H:13]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:14]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]([O:17][CH3:18])=[O:16])([OH:12])=[O:10]
Reactant: C=CCOC(=O)[C@H](CC(C)C)[C@H](OCc1ccccc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COC(=O)[C@@H](OCc1ccccc1)[C@@H](CC(C)C)C(=O)O
Reaction time: 0.5 h
Yield: 121.2 %

Procedure:
0.39 ml of morpholine and 0.05 g of tetrakis(triphenylphosphine)palladium(0) were added to a stirred solution of 0.15 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-benzyloxy-5-methylhexanoate in 5 ml of tetrahydrofuran under a nitrogen atmosphere. After stirring the mixture for 0.5 hour the solvent was evaporated. The residue was dissolved in dichloromethane and washed in succession with 2M aqueous hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was dissolved in diethyl ether and filtered. The diethyl ether solution was evaporated to give 0.16 g of methyl 3(R)-carboxy-2(S)-benzyloxy-5-methylhexanoate in the form of a yellow oil.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[I:9][C:10]1[CH:11]=[N:12][NH:13][CH:14]=1.Cl[CH2:16][CH:17]1[O:21][C:20](=[O:22])[NH:19][CH2:18]1>O1CCOCC1.ClCCl>[I:9][C:10]1[CH:11]=[N:12][N:13]([CH2:16][CH:17]2[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:14]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C1NCC(CCl)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1NCC(Cn2cc(I)cn2)O1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Potassium phosphate tribasic (6.6 g, 31 mmol), 4-iodo-1H-pyrazole (2.0 g, 10 mmol), and 5-(chloromethyl)oxazolidin-2-one (2.8 g, 21 mmol) were suspended in dioxane (0.10 L, 0.10 M). The reaction vessel was heated to 110° C. for 48 hours, then cooled to room temperature and diluted with dichloromethane (0.25 L). The organics were washed with H2O (2×0.20 L) and were concentrated under reduced pressure. The residue was suspended in methanol:hexanes for 3 hours at ambient temperature with stirring. The precipitate was filtered to afford 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one. MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H). The racemic compound, thus obtained, was resolved by chiral super critical fluid chromatography (IC column, 1:4 Isopropanol/CO2) to afford (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (early eluting enantiomer): MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H); and (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (late eluting enantiomer), MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.O>[CH3:7][N:6]1[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[C:3]([CH:9]=[O:10])[C:4]([CH3:8])=[N:5]1
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1nn(C)c(N2CCN(C)CC2)c1C=O
Temperature: 122.5 °C
Yield: 28.7 %

Procedure:
To a solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (25.4 g, 0.16 mol) in HMPA (25 mL) and water (25 mL) was added 1-methylpiperazine (40 g, 0.4 mol, 2.5 equiv), and the mixture was heated at 120-125° C. for 25 h. When the reaction was completed, the reaction mixture was poured into water (500 mL), and potassium carbonate was added to make the medium strongly alkaline. The mixture was extracted with dichloromethane (5×100 mL). The combined organic extracts were washed twice with water and dried with sodium sulfate, and the solvent evaporated. The residue was purified chromatographically on silica gel with gradient elution from dichloromethane to methanol, affording 10.2 g (29%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.26 (s, 3H), 2.44 (m, 4H), 3.16 (m, 4H), 3.59 (s, 3H), 9.88 (s, 1H). LC-MS (API-ES) calcd for C11H18N4O: 222.15, found (M+H+): 223.1 m/z.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[Cl:1][C:2]1[N:7]=[C:6]([O:22][CH2:21][CH2:20][O:19][CH3:18])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Reactant: COCCO
Agent: [Na]
Product: COCCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of 44.6 g (0.176 mol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine from Example 1 in 300 ml of 2-methoxyethanol at 0°-5° was added dropwise over 2 hours a solution of 4.25 g (0.177 g-atom) of sodium metal in 250 ml of 2-methoxyethanol. The solution was stirred for 30 minutes at 5°, concentrated and the resulting oil dissolved in 500 ml of ethyl acetate. The solution was washed with water, dried over sodium sulfate, filtered and concentrated to give 40.4 g (0.137 mol, 78%) of 2-chloro4-(2-methoxyethoxy)-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine: m.p. 50°-52°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:15](=O)([O:21]C(OC(C)(C)C)=O)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH:3]1[CH2:6][N:5]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:4]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN(C)C1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of N,N-dimethylazetidin-3-amine (Intermediate 28, 100 g, 1.0 mol) and triethylamine (487 mL, 3.5 mol) in CH2Cl2 (500 mL) was added tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (326 g, 1.5 mol) at 0° C. The mixture was then stirred at r.t. for 5 h. The mixture was then washed with water (4×500 mL) and the organic solution were dried (Na2SO4) and concentrated in vacuo. Purification by FCC gave the title compound (62 g, 31%).