Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:29])[C@@H:12]([NH:21]C(OC(C)(C)C)=O)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:29])[C@@H:12]([NH2:21])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
2-((2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.65 g, 1.54 mmol) was mixed in dichloromethane (5 mL) in an ice-bath. Trifluoroacetic acid (5 mL) was added and the solution was stirred for 2 hours. The reaction mixture was evaporated and the residue was precipitated with ether. The mixture was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave 2-((2S,3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.35 g, 71%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:6][CH2:7][CH:8]([NH:15][C:16]([CH:18]2[N:22]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:21][CH2:20][S:19]2)=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: C1CCCNCC1
Product: O=C(NC(CCN1CCCCCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and azepane, the title compound was obtained in 99.1% purity by HPLC.
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[CH3:4][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2][CH2:1][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of 2.47 g of the above farnesyl bromide in 20 ml of dry dimethyformamide (DMF) at room temperature under argon was treated with 1.83 g (9.9 mmol, 1.1 eq.) of potassium phthalimide and stirred for 3 hours at room temperature. The solvent was removed under reduced pressure, the residue was triturated with 150 ml of ethyl ether, and the precipitate was filtered off. The ethereal solution was washed with 50 ml of H 0 and 50 ml of brine, dried over MgSO4 and evaporated to yield 2.96 g of crude title compound as a milky oil. Purification by flash chromatography on 300 g of Merck 9385 silica, eluted with 7:93 ethyl acetate:petroleum ether afforded 2.56 g (81%) of the desired product as a colorless oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=1>>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals, m.p.=109-111° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]([F:58])([F:57])[CH2:34][NH:35][C:36]([C:38]1([CH2:52][CH2:53][CH2:54][CH2:55]Br)[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:45][C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH2:55][CH2:54][CH2:53][CH2:52][C:38]4([C:36](=[O:37])[NH:35][CH2:34][C:33]([F:58])([F:57])[F:32])[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[O:45][C:44]5[C:39]4=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(Cc2ccccc2)CC3)CC1
Product: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5Oc5ccccc54)CC3)ccc2CCN1Cc1ccccc1

Procedure:
Step (b) of Example 97 was repeated, except that the compound prepared in step (a) of Example 97 and the compound prepared in step (a) of Example 96 were used. Thus, the title compound was prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>C(Cl)Cl>[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCN
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (Fluka, 1.00 g; 4.51 mmol) in DCM (30 mL) was treated with 2-methoxyethylamine (Fluka, 1.9 ml; 22.6 mmol). After 2 hours, the organic solvents were evaporated in vacuo, the residue was taken up in EtOAc and extracted with a saturated NH4Cl solution. The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as a pale yellow solid (1.077 g, 92%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[C:2]=1[CH:13]=[O:14].O[C:16]1[C:25]2[C:20](=CC=CC=2)[C:19](O)=[CH:18][CH:17]=1>>[CH:16]1[C:25]2[C:13](=[O:14])[C:2]3[C:3](=[CH:4][C:5]4[C:10]([CH:1]=3)=[CH:9][C:8]3[C:7](=[CH:10][CH:1]=[CH:2][CH:3]=3)[CH:6]=4)[C:11](=[O:12])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(O)c2ccccc12
Reactant: O=Cc1cc2ccccc2cc1C=O
Product: O=C1c2ccccc2C(=O)c2cc3cc4ccccc4cc3cc21
Temperature: 120 °C

Procedure:
To a flame-dried flask was added 2,3-naphthalenedicarboxaldehyde (1 molar equivalent (0.29 g, 1.57 mmol)) and 1,4-dihydroxynaphthalene (1 molar equivalent (0.25 g, 1.57 mmol)) these reagents were flushed with nitrogen for 15 minutes before anhydrous pyridine (5 ml) was added. The resulting solution was stirred at 120° C. with stirring for 24 hours. On cooling, the solid product was filtered off and washed successively with methanol (10 ml), 10% copper sulphate solution (10 ml), water (10 ml) and acetone (10 ml) and dried in vacuum oven. The product was an orange/brown solid (0.14 g, 29%) and was greater than 90% pure by HPLC. 1H NMR (D8-THF) δ 9.09 (2H, s, H—Ar), 8.87 (2H, s, H—Ar), 8.38 (2H, m, H—Ar), 8.15 (2H, m, H—Ar), 7.87 (2H, m, H—Ar) and 7.61 ppm (2H, m, H—Ar).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=1)[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2C[C@H]1CCCN1
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (230 mg, 0.44 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring over 10 min. The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 0.185 g (crude) of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Reaction time: 0.13 h

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na2CO3 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh3)4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71%). Analytical Data: LCMS: 573.35 (M+1)+; HPLC: 99.5% (@254 nm) (Rt; 3.999; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[CH:16][CH:17]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: OB(O)c1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1c2cc(-c3ccnc4ccccc34)sc2C(=O)NC1(C)C
Yield: 29.2 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), quinolin-4-ylboronic acid (173 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained yellow solid (62 mg) was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (47.2 mg, 29%) as a pale yellow solid:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([OH:22])=O)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)n1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(6-Methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.27 g (12.7 mmol) of N,O-dimethylhydroxylamine hydrochloride, 9 mL (6.5 g, 64.7 mmol) of triethylamine and 9.2 mL (9.83 g, 15.5 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 50 mL acetonitrile to give 2.30 g of the product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])=[O:4]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methoxycarbonyl chloride (5.7 g) in dichloromethane (60 ml) was added dropwise over a period of 30 minutes to a solution of 2-nitromethylene-tetrahydro-2H-1,3-thiazine (6.4 g) and triethylamine (10.4 ml) in dichloromethane (60 ml) at -20° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature over a period of 60 minutes and was then washed with 2% hydrochloric acid. The organic phase was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was triturated with ethyl acetate to yield the required product as a crystalline solid m.p. 93°-95° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[O:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])[CH:2]=[CH2:3]
Reactant: NNC(N)=O
Reactant: C=CCOC(=O)N[C@H](C=O)CCC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@H](C=O)CCC(=NNC(N)=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of (207a) (2.39 g, 8.8 mmol), in MeOH (20 ml) was added sodium acetate (0.72 g, 8.8 mmol) and semicarbazide (0.98 g, 8.8 mmol) stirred overnight, concentrated and diluted with CH2Cl2 (100 ml), washed with water, dried and concentrated. Flash chromatography (2% MeOH in CH2Cl2) afforded (208a) (2.10 g, 73%) as an oil: [α]D20 -21 (c 2.55°, CH2Cl2); 1H NMR (CDCl3) δ 9.98 (1H, s), 7.27 (1H, d), 5.8 (1H, m), 5.5 (1H, d), 5.35-5.19 (2H, m), 4.58 (2H, m), 4.14 (1H, m), 2.37 (2H, t), 2.09 (1H, m), 2.0-1.75 (2H, m); Anal. Calcd for C14H24N4O5 : C, 51.21; H, 7.37; N, 17.06. Found: C, 50.2; H, 7.3; N, 16.1
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:6]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:8]2=[O:24])[C:5](=[O:25])[N:4]1CC1C=CC(OC)=CC=1OC.[S:37](Cl)([CH3:40])(=[O:39])=[O:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[S:37]([O:1][CH2:2][C@H:3]1[C@@H:6]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:8]2=[O:24])[C:5](=[O:25])[NH:4]1)(=[O:39])(=[O:38])[CH3:40]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2C(=O)[C@H](n3c(-c4ccccc4)c(-c4ccccc4)oc3=O)[C@@H]2CO)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)OC[C@@H]1NC(=O)[C@@H]1n1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Yield: 73 %

Procedure:
When cis-2-hydroxymethyl-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine is reacted according to Example 13 except that mesyl chloride is substituted for p-toluenesulfonyl chloride, cis-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxo-2-azetidinylmethyl mesylate is obtained; 73% yield, mp 185°-8° from ethyl acetate-hexane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)(=[O:28])=[O:27])=[CH:4][CH:5]=1
Reactant: NCc1ccc(CO)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(CO)cc1)c1ccccn1
Yield: 85 %

Procedure:
Using the above procedure J: Reaction of (4-aminomethyl-phenyl)-methanol (255 mg, 1.86 mmol, N,N-diisopropylethylamine (294 μL, 1.69 mmol), and pyridine-2-sulfonyl chloride (300 mg, 1.69 mmol) for 10 minutes at room temperature gave the title compound (400 mg, 85%) white solid. 1H NMR (300 MHz, CDCl3) δ 4.26 (br s, 2H), 4.66 (br s, 2H), 5.28 (br s, 1H), 7.23-7.30 (m, 4H), 7.49-7.51 (m, 1H), 7.90-7.92 (m, 1H), 7.99 (d, 1H, J=4.8 Hz), 8.68 (d, 1H, J=4.5 Hz).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.CCOC(C)=O>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)=[O:27])[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCC(=O)N2CCN(CC(=O)O)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Dissolve {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester (66) (100 mg, 0.25 mmol) in MeOH (2.0 mL) at it and add 2M aqu NaOH (260 μL, 0.52 mmol). Stir the reaction mixture for 1 h under reflux. Add dropwise 1M aqu. HCl (550 μL, 0.55 mmol), extract the mixture with EtOAc (3 times) and remove solvent obtain {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]piperazin-1-yl}-acetic acid (67) (88 mg, 95%) as a brown sticky solid. No further purification. 1H NMR (400 MHz, CDCl3/CD3OD 9+1): 2.54 (br.t, 2H); 2.78 (t, 2H, J=7.5 Hz); 2.83-3.10 (br.m, 2H); 3.24 (s, 2H); 3.43-3.62 (br.m, 2H); 3.68 (s, 3H); 3.73 (s, 6H); 3.74-3.85 (br.m, 4H); 6.34 (s, 2 H).
Reaction SMILES: [Na].[C:2]1([CH:8]([OH:11])[CH2:9][SH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([CH:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13]>C1(C=CC(O)=CC=1)O.C(O)C>[C:2]1([CH:8]([OH:11])[CH2:9][S:10][CH:14]([CH:12]=[CH2:13])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CS)c1ccccc1
Reactant: C=CC(Cl)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: C=CC(SCC(O)c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 104.8 %

Procedure:
To 125 ml of absolute ethanol was added 5.7 g (0.247 moles) of sodium metal. After the sodium had dissolved, the solution was cooled to 0° to 5° C. and 38 g (0.247 moles) of 1-phenyl-2-mercaptoethanol was added dropwise. After addition, the reaction was stirred at 0° to 5° C. for 1 hour and then 37.7 g (0.247 moles) of vinylbenzyl chloride was added dropwise. After the addition was complete, 0.5 g of hydroquinone was added and the mixture was refluxed for 2 hours. The mixture was cooled and the sodium chloride was removed by filtration. The solvent was evaporated and the residue was added to 100 ml of water. The aqueous mixture was extracted with three 100 ml portions of ether and the combined ethereal extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to leave 70 g of the product as a crude oil. Due to its high boiling point, the product was used without further purification in the synthesis of the following sulfone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]=[C:18]([C:27]([O-:29])=O)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C(OC(C)C)(C)C>CO>[CH3:30][O:31][CH2:32][CH2:33][NH:34][C:27]([C:18]1[N:17]=[C:16]([NH:15][C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]=1)=[O:29]
Reactant: Cc1ccc2nc(C(=O)[O-])nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: COCCN
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a suspension of 15.0 g of ethyl 4-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino-6-methylquinazolin-2-carboxylate in 15 ml of methanol, 7.89 g of 2-methoxyethylamine was added, and the mixture was stirred at 50° C. for 15 hours. After the reaction solution was cooled to room temperature, 45 ml of diisopropyl ether was added thereto, and the mixture was stirred at 0° C. for 30 minutes. The deposited crystal was collected by filtration, washed with diisopropyl ether and dried under reduced pressure, whereby 12.2 g of a desired compound was obtained as a white powder.