Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[SH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1.[H-].[Na+].[CH2:21]([O:23][CH2:24][CH2:25]Cl)[CH3:22]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:21]([O:23][CH2:24][CH2:25][S:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1)[CH3:22]
Reactant: Sc1nc(-c2cccnc2)cs1
Reactant: CCOCCCl
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOCCSc1nc(-c2cccnc2)cs1
Temperature: 25 °C
Yield: 9281.9 %

Procedure:
Dissolved in 2.5 ml of N,N-dimethylformamide were 0.50 g of 2-mercapto-4-(3-pyridyl)-thiazole oxalate (1.82 mmol), and 0.10 g (4.17 mmol) of sodium hydride were added to the solution, which was stirred at room temperature. One hour later, 0.40 ml (3.65 mmol) of 2-chloroethyl ethyl ether were added to the suspension, which was then stirred for 2 hours at 80° C. The reaction solution was diluted with 50 ml of chloroform, followed by addition of 50 ml of a 5% saline solution and washing. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residues were then purified by silica gel chromatography to obtain 45 g of the title compound as an yellow oily form (93% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1C=O.N1CCCCC1.CC(N(C)C)=O>O>[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:24](/[CH:11]=[CH:10]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:23][CH:20]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccccc1OCCCO
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
4-Nitrophenylacetic acid (131.4 g, 0.73 mole), -(3-hydroxypropyloxy)benzaldehyde (130.8 g, 0.73 mole, prepared as in U.S. Patent 2,824,084), piperidine (14.2 g, 0.17 mole) and dimethylacetamide were placed in a 1 L round-bottom flask fitted with a mechanical stirrer, a condenser and a thermometer connected to a controller and a heating mantle. The resulting mixture was stirred and warmed to 80° C., at which temperature a brisk evolution of gas was induced. Stirring was continued at 80° C. for 18 h. The mixture was then poured into a beaker and stirred and diluted to 3 L with ice and water. The solid that appeared was collected by filtration, washed with water and dried to give a deep yellow product (142 g). Two crystallizations from aqueous ethanol afforded the analytical sample (76.9 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[C:3]2[C:10](=[CH:28][C:14]3[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Cl)c32)c(C)c1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.3 %

Procedure:
To a mixture of 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (85 mg, 0.5 mmol) and 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (125 mg, 0.5 mmol) in ethanol (4 mL) was added 0.1 to 0.2 mL of piperidine. The mixture was stirred at room temperature for 20 hours. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol, and dried to give 89 mg (45%) of 4-chloro-5-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][CH:25]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)[nH]cc21
Reactant: ClCc1ccc(-c2ccccn2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4ccccn4)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of crude 5-chloro-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.032 mmol), 2-(4-(chloromethyl)phenyl)pyridine (9.7 mg, 0.048 mmol) and cesium carbonate (15.6 mg, 0.048 mmol) in anhydrous DMF is stirred at room temperature for 3 h, and then diluted with saturated NaHCO3 aqueous solution, followed by extractions with CH2Cl2. The combined organic phase is dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude product, which is used in the next step without further purification. MS (ESI) m/z 423.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([F:17])[CH:10]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:7]/[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[C:11]([F:17])[CH:10]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
To a solution of (S)-2-methylpropane-2-sulfinamide (4 g, 33.0 mmol) and 4-bromo-2-fluorobenzaldehyde (7.03 g, 34.7 mmol) in DCM (80.0 ml) were added pyridinium p-toluenesulfonate (415 mg, 1.65 mmol) and magnesium sulfate (39.7 g, 330 mmol) and the reaction mixture was stirred at room temperature over night. Then additional magnesium sulfate (19.85 g, 165 mmol) was added and stirring was continued for 24 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated. The remaining light yellow oil was purified by chromatography (silica gel; heptane/EtOAc 95:5-90:10) to obtain the title compound as colorless oil (4.5 g, 44%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][N:27]([CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)[S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[C:33]([NH2:39])[CH:32]=1)(=[O:30])=[O:29].ClCCl.C(O)C>O1CCCC1>[CH3:26][N:27]([CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)[S:28]([C:31]1[CH:36]=[CH:35][C:34]2[N:37]([CH3:38])[C:11]([CH2:10][O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:39][C:33]=2[CH:32]=1)(=[O:30])=[O:29]
Reactant: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1N
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C#N)cc2)n3C)CC1
Reaction time: 8 h

Procedure:
532 mg (3.0 mMol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mMol) of 1,1'-carbonyldiimidazole were dissolved in 40 ml of tetrahydrofuran and refluxed for 15 minutes. Then 700 mg (2.24 mMol) of 3-amino-4-methylaminobenzenesulphonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were added and boiling was continued for a further eight hours. Then the mixture was evaporated down and the resulting oily residue was refluxed in 30 ml of glacial acetic acid for one hour. The glacial acetic acid was distilled off, the residue was mixed with about 30 ml of water and made alkaline with concentrated ammonia, and the solution was extracted three times with about 20 ml of dichloromethane. The organic phases were dried and evaporated down. The resulting product was further reacted without any purification. Yield: 400 mg (39% of theory), C23H27N5O3S (453.6) Rf value: 0.37 (silica gel; dichloromethane/ethanol=4:1)
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].F[C:41](F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][NH:24][CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[C:36]([CH3:41])[CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(NC(=O)c4ccc(C(C)(C)O)cc4)nc4ccnn34)cc2C1
Solvent: ClCCl
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)CNCC4)n2n1
Reaction time: 0.5 h

Procedure:
tert-Butyl 7-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate from Step A was dissolved in CH2Cl2 (2 ml). Trifluoroacetic acid (1 ml) was then added at 0° C. The mixture was stirred for 30 minutes at that temperature before being concentrated in vacuo. Residual trifluoroacetic acid was removed azeotropically with toluene twice. The residue was then dissolved in acetonitrile before being purified by preparatory HPLC (20-35% MeCN/H2O gradient+0.01% TFA) to give the titled compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=11.22 (s, 1H), 9.11 (br. s., 2H), 8.01 (d, J=8.6 Hz, 2H), 7.99-7.89 (m, 3H), 7.62 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 6.40 (s, 1H), 4.43 (br. s., 2H), 3.47 (d, J=7.3 Hz, 2H), 3.16-3.07 (m, 2H), 2.40 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 442.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[O:20]([NH2:22])[CH3:21]>>[CH3:21][O:20]/[N:22]=[CH:17]/[C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]=1
Reactant: COc1cccc(C#Cc2cncc(C=O)c2)c1
Reactant: CON
Agent: Cl
Product: CO/N=C/c1cncc(C#Cc2cccc(OC)c2)c1
Yield: 78 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using 5-(3-methoxyphenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 91), (290 mg, 1.22 mmol) and methoxylamine hydrochloride (520 mg, 9.78 mmol). The E/Z Isomers were separated during the purification to give the title compound (254 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCC1>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1/[CH:18]=[C:26]1\[C:27](=[O:31])[NH:28][C:29]2[C:25]\1=[CH:24][CH:23]=[C:22]([Cl:21])[CH:30]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 131.9 %

Procedure:
In a manner similar to the method described in Example 1b, [2-(4-Chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (8 g, 27 mmol) was reacted with 6-chloro-1,3-dihydro-indol-2-one (4.5 g, 27 mmol) and pyrrolidine (2.1 g, 30 mmol) in methanol (70 mL) to give title compound as a yellow solid (16 g).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([N:8]([CH2:9][CH3:10])[CH2:2][C:3]([NH2:5])=[O:4])[CH3:7]
Reactant: CCNCC
Reactant: NC(=O)CBr
Solvent: ClC(Cl)Cl
Product: CCN(CC)CC(N)=O
Temperature: 25 °C
Yield: 79 %

Procedure:
2 g of 2-bromoacetamide (0.015 mol) were slowly added to diethylamine (40 mL, 0.387 mol) and the reaction mixture was heated to reflux for 20 h. After cooling to room temperature, the reaction mixture was filtered and precipitate discarded. The filtrate was concentrated under vacuum to result in slightly yellow solid. This solid was dissolved in chloroform (10 mL) and washed with aqueous saturated solution of Na2CO3 (3×10 mL). Combined organic phases were dried over Na2S04. The filtrate was concentrated under vacuum to result in 1.49 g (79% yield) of light yellow solid, which was azeotropically dried with benzene prior to use in the following reactions. 1H NMR (500 MHz, CDCl3, J=Hz): δ 6.19 (2H, s, br, NH2), 3.01 (2H, s, CH2), 2.56 (4H, q, J 7.2, NEt2), 1.04 (6H, t, J 7.3, NEt2). 13C NMR (125.8 MHz, CDCl3): δ 175.6 (C═O), 57.4 (CH2), 48.6, 12.3 (NEt2). HRMS (ESIMS) m/z for C6H15N2O [M+H]+ calcd 131.1184, found 131.0907.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:10][CH:9]=3)[CH2:5][O:6]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was concentrated in vacuo and the solid triturated with MeOH. Filtering the mixture and rinsing with MeOH and hexanes/EtOAc (7:3) afforded the title compound (42.2 mg, 73%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: FC(F)(F)Oc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethoxy)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 165. LRMS (ES)+: 436.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:29])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:2].[Na].C(S)CC.Cl>CN(C=O)C.C(Cl)Cl>[CH2:30]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:29])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:31]
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1
Agent: CCCS
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(O)cc2)c1-c1ccccc1
Yield: 99 %

Procedure:
A solution of 14 g (00.33 mol) of N-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide of example 34 and 0.16 mol of the sodium salt of 1 propanethiol in 375 mL of DMF was heated at 155°-160° C. for 2 hours. The reaction was chilled and the excess thioproxide was neutralized with ethanolic HCl. The DMF solution was stripped under vacuum at 30°, dissolved in methylene dichloride, and washed with aqueous sodium carbonate, then water, and finally brine. The methylene chloride was dried over sodium sulfate and the solvent removed in vacuo to yield 13.4 g of gummy product. Seven grams of the gummy product was chromatographed on a silica gel column eluted with methanol/isopropylamine/chloroform (2:3:95) to yield 5.1 g of purified product. The residue was taken up in isopropyl acetate, washed twice with water, washed once with brine, and dried over sodium sulfate. The isopropyl acetate was evaporated in vacuo, but removal of the last traces of isopropyl acetate required extensive drying under high vacuum to yield 2.5 g of product as a glass.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: c1ccccc1
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Yield: 48.1 %

Procedure:
In a closed tubular reactor, 1.3 g of 5-fluorouracil, 5 ml of benzene and 14 g of 2,3-dihydrofuran were heated together at 200° C. for 6 hours. After cooling, the reaction mixture was concentrated to dryness under reduced pressure and the residue was separated and purified by column chromatography on 25 g silica gel. From the chloroform eluate, the fractions rich in the contemplated compound were collected. The solvent was distilled off and the residue was recrystallized from petroleum ether. By the above procedure was obtained 1.3 g of 1,3-bis-(tetrahydro-2-furyl)-5-fluorouracil.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:32](=[O:47])[CH2:33][C@@H:34]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:37]1[CH:38]=[CH:39][C:35]([C@H:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:2][C:3]3[S:4][C:5]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[CH:6][C:7]=3[CH3:8])=[CH:42][CH:41]=2)[CH2:33][C:32]([N:27]2[C@@H:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:30][O:29][C:28]2=[O:31])=[O:47])=[N:36]1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 62.7 (0.23 mmol), 7.5 (76 mg, 0.19 mmol), and Cs2CO3 (226 mg, 0.69 mmol) in DMF (2.3 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (15-45% EtOAc/hexane) to afford 62.8 (94 mg, 75%) as a white solid.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][C@@H:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([O-:35])=[O:34])=[C:17]([CH2:20][N+:21]([CH3:32])([CH3:31])[CH2:22][C:23]4[NH:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][C@@H:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([O-:35])=[O:34])=[C:17]([CH2:20][N+:21]([CH3:32])([CH3:31])[CH2:22][C:23]4[NH:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a suspension of 7β-[2-(2-formamidothiazol-4-yl)- 2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.70 g) in methanol (35 ml) was added conc. hydrochloric acid (0.53 ml). After being stirred at ambient temperature, the reaction mixture was diluted with water (50 ml) and methanol was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 1.0 and subjected to column chromatography on Diaion HP-20 (50 ml). The column was washed with water and the elution was carried out with 40% aqueous isopropanol. The fractions containing the object compound was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl} ammonio]methyl-3-cephem-4-carboxyl ate (syn isomer) (0.53 g).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4](=[O:17])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8].[CH:18]1([CH2:24][CH2:25]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[NH2:3][C:4](=[O:17])[CH2:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:25][CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: BrCCC1CCCCC1
Reactant: NC(=O)CC(C(=O)O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)CC(C(=O)O)c1ccc(OCCC2CCCCC2)cc1
Temperature: 25 °C
Yield: 14 %

Procedure:
Aqueous sodium hydroxide solution (2.0 M; 50 μL, 100 μmol) was added in one portion to a stirred solution of 4-amino-2-(4-hydroxyphenyl)-4-oxobutanoic acid (10 mg, 47 μmol) in ethanol (1 mL) at room temperature. After stirring for 10 min cyclohexylethylbromide (9.0 mg, 47 μmol) was added and the resulting mixture heated at reflux for 12 h. On cooling to room temperature the volatiles were evaporated and the residue purified by mass directed auto-preparative reverse phase HPLC to give the title compound as a white solid (2.1 mg, 14%). LC/MS: 3.34 min; z/e 320, calcd (M+1) 320. 1H NMR (400 MHz: MeOD): 7.20 (2H), 6.85 (2H), 4.00 (3H), 2.95 (1H), 2.55 (1H), 1.70 (6H), 1.50 (1H), 1.25 (4H), 0.92 (2H). The absolute regiochemistry of the product was unambiguously assigned using an HMBC correlation experiment.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1>C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[CH:27][O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Product: CON=C1C[C@@H](c2ncon2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
To a suspension of (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8, 170 mg, 0.48 mmol) in TMOF (20 ml), a catalytic amount of p-toluenesulfonic acid was added and the reaction mixture was heated to reflux for 16 h. TMOF was then evaporated in vacuo and the residue dissolved in DCM (15 mls). This was washed with NaHCO3(aq) (2×15 ml), dried over MgSO4 and evaporated in vacuo. Silica gel chromatography eluting with 15% EtOAc in hexanes gave the desired product, (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime (59 mg).