Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1nc(-c2ccc(F)cc2)cs1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a stirred solution of ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoate (0.900 g, 3.07 mmol) in 1:1:1 THF/ethanol/water (15 mL) was added lithium hydroxide monohydrate (0.451 g, 10.7 mmol). After overnight stirring, the reaction was concentrated and redissolved in water (80 mL). The solution was washed with ether (1×50 mL), acidified with the addition of 1 N HCl (15 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried (Na2SO4) and concentrated to afford 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid as a pale golden solid (0.808 g, 99%).
Reaction SMILES: Cl.[C:2]([C:12]1[CH:29]=[CH:28][C:15]([CH2:16][NH:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1)#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:30]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:35][CH2:36][C:37]([N:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:29][CH:28]=2)[C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCCCCCC#Cc1ccc(CNc2cccc(C(=O)OC)c2)cc1
Agent: Cl
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCC2CCCC2)c2cccc(C(=O)OC)c2)cc1

Procedure:
The titled compound was prepared following the procedure G using methyl 3-[(4-dec-1-yn-1-ylbenzyl)amino]benzoate hydrochloride and 3-cyclopentylpropanoyl chloride as a pale yellow oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.99 (d, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.38 (m, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.09 (m, 3H), 4.88 (s, 2H), 3.93 (s, 3H), 2.39 (t, J=7.0 Hz, 2H), 2.06 (m, 2H), 1.61-1.30 (m, 21H), 0.95 (m, 2H), 0.89 (t, J=6.8 Hz, 3H). M+ (ESI): 502.4. HPLC, Rt: 6.32 min (Purity: 99.9%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:23]([C:20]1[CH:21]=[N:22][C:17]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1)[S:32]([CH3:31])(=[O:34])=[O:33])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.89 g, 2.9 mmol), triethylamine (0.61 mL, 4.4 mmol) and N,N-dimethylaminopyridine (catalytic amount) in 20 mL of dichloromethane is cooled to 0° C. and methanesulfonyl chloride (0.30 mL, 3.5 mmol) is added dropwise under nitrogen. The cold bath is removed and the solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of water, and the organic layer is dried (sodium sulfate). The solvent is removed under reduced pressure and the residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound as a white solid; mp 168°-169.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:7][S:8][N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[C:51]2[C:46]([CH:47]=[CH:48][N:49]=[CH:50]2)=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:50]1[C:51]2[C:46](=[CH:45][CH:44]=[C:43]([O:1][CH2:2][CH2:3][O:4][C:5]3[C:6]([N:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][S:8][N:9]=3)[CH:52]=2)[CH:47]=[CH:48][N:49]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCOc2ccc3ccncc3c2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The title compound was prepared according to the procedure of Example 218, Step 3 starting from the product of Example 218, Step 2 (100 mg, 0.30 mmol), triphenylphosphine (102 mg, 0.39 mmol), 7-hydroxyisoquinoline (57 mg, 0.39 mmol) and diethyl azodicarboxylate (61 μl, 0.39 mmol) except that the reaction mixture was stirred at room temperature for 5 days. It gave an orange oil (0.34 g) of low purity (63% by HPLC). It was used directly in the following step without further purification.
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[N+:39]([O-:41])=[O:40])(=O)C1C=CC=CC=1.C[O-].[Na+]>>[C@H:11]1([N:34]2[CH:38]=[CH:37][N:36]=[C:35]2[N+:39]([O-:41])=[O:40])[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@H](n2ccnc2[N+](=O)[O-])[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1nccn1[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 46.9 %

Procedure:
1-(2',3',5'-tri-O-benzoyl-α-D-arabinofuranosyl)-2-nitroimidazole (557 mg, 1 mmol) was added to 5 ml of 0.05 M methanolic sodium methoxide. The mixture was stirred at 0° C. for 2.5 hours. The precipitate of 1-(mono-benzoyl-α-D-arabino furanosyl)-2-nitroimidazole was filtered off and the filtered solution was purified by preparative TLC using chloroform:methanol (5:1) to give 115 mg (46.9%) of the title product as pale yellow needles, mp 160° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:44]([O:47][CH:48](Br)[CH3:49])(=[O:46])[CH3:45].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([O:30][CH:48]([O:47][C:44](=[O:46])[CH3:45])[CH3:49])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) in N,N-dimethylformamide (30 ml) was added cesium carbonate (0.47 g). The mixture was stirred for 30 minutes at 25° C., and 1-bromoethyl acetate (1.35 g) was added dropwise thereto at 0°-3° C. After stirring for 1 hour, the reaction mixture was poured into ethyl acetate (200 ml) and the insoluble material was filtered off. The filtrate was washed with water (200 ml×2), an aqueous solution of sodium bicarbonate (100 ml×1) and a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was pulverized with diisopropyl ether to give 1-acetoxyethyl 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (0.63 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=5)[C:31]([CH3:40])=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=5)[C:31]([CH3:40])=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To 2 mL of a chloroform solution containing 109 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 67 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-6-methoxyquinolin-2(1H)-one as a pale yellow oil.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:33][N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[Sn](CCCC)(CCCC)CCCC>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:11]2[C:12]3[C:13]([C:35]4[N:34]([CH3:33])[CH:38]=[CH:37][CH:36]=4)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:27][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(-c3nnn(C)n3)cc12
Product: Cn1nnc(-c2cc(-c3cccn3C)c3c(Sc4ccc(Cl)cc4)c4n(c3c2)CCC4CC(=O)O)n1

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (see Example 32) and 1-methyl-2-(tributylstannyl)-1H-pyrrole, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([CH:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[OH:21][CH:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][N:1]([CH2:20][CH:19]([OH:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: NCCCc1ccc(C(N)=O)s1
Reactant: c1ccc(C2CO2)cc1
Solvent: CCO
Product: NC(=O)c1ccc(CCCN(CC(O)c2ccccc2)CC(O)c2ccccc2)s1

Procedure:
750 mg of 5-(3-aminopropyl)-2-thiophenecarboxamide and 0.47 ml of (±)-phenylethylene oxide were heated to boiling for 4 hours in 4.7 ml of ethanol. After evaporation of the solvent in vacuo, the residue was chromatographed on silica gel with ether/methanol. There were obtained 400 mg of 5-[3-[bis-(β-hydroxyphenethyl)amino]propyl]-2-thiophenecarboxamide; UV: ε277 =11250.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Br:21]>>[Br:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Br:21]
Reactant: Fc1ccc(Br)c(Br)c1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(Br)c(Br)c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dibromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21]COC)[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10](CCl)[CH2:9]1)=[O:7])(C)(C)C.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+].[Cl:39]C(OC)=O>O>[Cl:39][CH:10]1[C:11]2[C:16](=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]=2[OH:21])[N:8]([C:6]([O:5][CH3:1])=[O:7])[CH2:9]1
Reactant: COC(=O)Cl
Reactant: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N1CC(Cl)c2c1cc1ccccc1c2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A solution of 28 (11 mg, 29.1 μmol) was treated with 1.0 mL of 3.6 N HCl/EtOAc and the resulting solution was stirred for 30 min at 25° C. The solvent was removed by a stream of N2 and the residual salt was dried under vacuum. This salt was suspended in 0.6 mL of anhydrous THF and treated with NaHCO3 (5.4 mg, 64.1 μmol, 2.2 equiv) and ClCO2CH3 (4.5 μL, 58.2 μmol, 2.0 equiv) and the mixture was stirred for 3 h at 25° C. Upon completion, the reaction mixture was diluted with 10 mL of H2O extracted with EtOAc (3×10 mL), dried (Na2SO4) and concentrated in vacuo. Flash chromatography (SiO2, 1.5×15 cm, 0-40% EtOAc/hexane gradient) provided pure 32 (5.5 mg, 65%) as a white solid: 1H NMR (CDCl3, 400 MHz ) δ7.86 (d, J=8.2 Hz, 1H), 7.86 (br s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.42 (m, 1H), 7.35 (m, 1H), 5.80 (s, 1H), 4.11 (m, 2H), 4.01-3.87 (m, 5H), 3.63 (app t, J=9.4 Hz, 1H); IR (film) νmax3379, 2956, 1673, 1435, 1372, 1283, 1218 cm−1; FABHRMS (NBA/NaI) m/z 291.0656 (M+, C15H14ClNO3 requires 291.0662).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8]
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
To a solution of 25 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5. mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 20 mL (0.15 mol) of benzenesulfonyl chloride in 50 mL of CH2Cl2 dropwise over fifteen minutes. The addition funnel was rinsed with an additional 25 mL of CH2Cl2, and the cloudy, colorless mixture was allowed to warm to room temperature with stirring overnight. The solution was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, 1× with brine, then dried (MgSO4), filtered, and concentrated to a pale yellow solid. This material was recrystallized three times from ethyl acetate/hexanes to give 38.2 g (0.142 mol, 95%) of N-(benzenesulfonyl)-Proline methyl ester (MW=269) as broad white needles (TLC vs. 2:1 hexanes/ethyl acetate, Rf=0.35). M/z=270.2 (M+H+). N-(benzenesulfonyl)-Proline: To a solution of 38.2 g (0.142 mol) of the above methyl ester in 500 mL methanol was added 140 mL (0.28 mol) of freshly-prepared 2M aqueous LiOH with stirring to give a colorless solution. This was stirred overnight, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1N HCl and CH2Cl2 (200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white solid. This was recrystallized twice from ethyl acetate/hexanes to give 34.7 g (0.136 mol, 96%) of the title compound as fine white needles. M/z=256.2 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:16])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH3:15])[CH:2]=[CH2:3].[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(OC(=O)C)(=O)C>O>[C:17]([O:16][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][C:11](=[O:14])[O:12]2)=[CH:7][CH:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=CCc1c(OC(C)=O)ccc2c(C)cc(=O)oc12
Reaction time: 4 h
Yield: 94 %

Procedure:
A solution of 8-allyl-7-hydroxy-4-methylcoumarin (61.0 g, 0.282 mol) and a few pinches of anhydrous sodium acetate in boiling acetic anhydride (480 ml.) was allowed to relux for four hours with magnetic stirring. The cooled brown mixture was then poured into water (1750 ml.) with magnetic stirring. The mixture was allowed to stir for half an hour. A brown precipitate was collected by filtration, washed with water, and dried in vacuo to obtain 7-acetoxy-4-methyl-8-allylcoumarin (68.5 g. 94% yield), mp. 98.8°-99.8° C. (lit.2 87°-87.5° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14]O)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14][O:19][C:16]3[N:11]=[CH:7][CH:3]=[CH:2][N:1]=3)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=NO)c1cnc(-c2cccnc2)s1
Agent: [Cs+]
Solvent: CC#N
Product: CC(=NOc1ncccn1)c1cnc(-c2cccnc2)s1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A suspension of 1-[2-(3-pyridyl)thiazol-5-yl]ethanone oxime (76 mg, 0.33 mmol) and cesium carbonate (330 mg, 1.0 mmol) in acetonitrile (10 ml) was stirred at ambient temperature and treated with 2-chlopyrimidine (60 mg, 0.5 mmol). The reaction was monitored by TLC and LC/MS until ca. 70% completion, and then concentrated in vacuo. The solid residue was stirred with ethyl acetate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with ethyl acetate:MeOH (95:5), to give isomer B of 1-[2-(3-pyridyl)thiazol-5-yl]-N-pyrimidin-2-yloxy-ethanimine (46 mg, 46%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[CH2:9][OH:10])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(Oc2ccc(C)cc2CO)cc1

Procedure:
A solution of 121 g. of 2-(4-methyl-phenoxy)-5-methyl-benzoic acid in 600 ml. of tetahydrofuran is slowly added dropwise, with cooling in an icebath, to 420 ml. of a 70% solution of sodium dihydro-bis(1-methoxyethoxy)-aluminate in benzene and stirred for an additional hour at room temperature. To the obtained clear solution, 800 ml. of 20% aqueous sodium hydroxide solution are carefully added dropwise. Then, the organic phase is separated. The aqueous phase is extracted three additional times with ether. The organic extracts are washed with saturated sodium chloride solution and the latter dried over sodium sulfate. After evaporation of the ether, there is obtained 2-(4-methyl-phenoxy)-5-methyl-benzyl alcohol as an oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]([NH:23][CH3:24])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]2[CH:16]=[N:15][C:6]3[C:7]4[N:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:5]=3[CH:4]=2)[CH2:32][CH2:33]1)[C:21]([NH:23][CH3:24])=[O:22]
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(F)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (50.00 mg, 0.232 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide (68.9 mg, 0.290 mmol) and (cyanomethyl)trimethylphosphonium iodide (90 mg, 0.372 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.202 mL, 1.162 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide 3-fluoro-N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.081 g, 0.186 mmol, 80.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.63 (m, 4 H) 2.75 (d, J=4.55 Hz, 3 H) 3.08-3.17 (m, 4 H) 3.63 (s, 2 H) 6.71-6.75 (m, 1 H) 7.02-7.10 (m, 2 H) 7.53-7.63 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.29 (q, J=4.29 Hz, 1 H) 8.33-8.38 (m, 1 H) 11.56 (br. s., 1 H). ESI-MS: m/z 435.4 (M+H)+. mp=288.0-294.5° C.
Reaction SMILES: C1(=O)[N:5]([C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][CH2:7]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][CH2:7]1
Reactant: O=C1Nc2ccccc2SC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@H]1CSc2ccccc2NC1=O
Yield: 62.6 %

Procedure:
A mixture of 3(R)-phthalimido-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (10 g), ethanol (500 ml) and hydrazine hydrate (6.2 g) is refluxed for 1 hour. After ethanol is removed by evaporation under reduced pressure, water (300 ml) is added, and the mixture is extracted with ethyl acetate (400 ml). The extract is washed with 0.1 N sodium hydroxide solution (100 ml×2) and water (100 ml) successively, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (3.75 g) as colorless leaflets.
Reaction SMILES: [CH:1]1[C:6](NC(CI)=O)=[CH:5][C:4]([C:12]([OH:14])=[O:13])=[C:3]([C:15]2[C:25]3[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=3[O:23][C:22]3[C:16]=2[CH:17]=[CH:18][C:19]([CH:21]=3)=[O:20])[CH:2]=1>CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH:1]1[CH:6]=[CH:5][C:4]([C:12]([OH:14])=[O:13])=[C:3]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([OH:20])=[CH:21][C:22]=3[O:23][C:24]3[C:25]=2[CH:26]=[CH:27][C:28]([CH:29]=3)=[O:30])[CH:2]=1
Reactant: O=C(CI)Nc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 4 °C

Procedure:
5-Iodoacetamido fluorescein (5-IAF, 11 mg, 21 μmol) solution in N,N-dimethylformamide (DMF, 50 μL) was slowly added to oxyhemoglobin (60 mg/mL, 5 mL) in 50 mM potassium phosphate pH 7.0 with stirring at 4° C. After three hours of reaction at 4° C., the excess of 5-IAF was removed by extensive dialysis against 50 mM potassium phosphate pH 7.2 until no 5-IAF could be detected in the dialysate. The UV-visible absortion spectrum of the product showed a characteristic fluorescein absorption band at 496 nm.