Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](N(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure II, 1-{6-chloro-4-[trans-4-(dimethylamino)cyclohexyl amino)-1,5-naphthyridin-3-yl)ethanone (61 mg, 0.16 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (76 mg, 90%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.36 (d, J=8.9 Hz, 1H), 8.10 (s, 2H), 5.65-5.55 (m, 1H), 3.52-3.43 (m, 1H), 2.91 (s, 6H), 2.76 (s, 3H), 2.66-2.56 (m, xH), 2.33-2.26 (m, 2H), 1.88-1.71 (m, 4H). ESI MS m/z 473 [M+H]+; HPLC>99% (AUC), tR=9.51 min.
Reaction SMILES: [Cl:1][C:2](=[CH2:15])[CH2:3][C:4]1[C:5]([OH:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:17](=C)COC1C=CC=CC=1C(OC)=O>>[Cl:1][C:2](=[CH2:15])[CH2:3][C:4]1[C:5]([OH:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:17])=[O:8]
Reactant: C=C(Cl)COc1ccccc1C(=O)OC
Reactant: C=C(Cl)Cc1cccc(C(=O)OC)c1O
Product: C=C(Cl)Cc1cccc(C(=O)OCC)c1O
Temperature: 260 °C
Yield: 88 %

Procedure:
Methyl 3-(2-chloro-2-propenyl)-2-hydroxybenzoate. 274.1 g (1.21 mole) of methyl 2-(2-chloro-2-propenyloxy)-benzoate, placed in a 2 liter round-bottomed flask, are carefully degassed with argon. This is then heated as rapidly as possible to 260° C. At this temperature, an exothermic reaction takes place suddenly: the temperature increases to 293° C. by itself and reflux and blackening of the reaction mixture takes place. After cooling to ambient temperature, the product is distilled under reduced pressure. 241.1 g of ethyl 3-(2-chloro-2-propenyl)-2-hydroxybenzoate are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>>[NH:14]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:15]
Reactant: Cc1cc(Cl)nc2c(C)cccc12
Reactant: NN
Product: Cc1cc(NN)nc2c(C)cccc12

Procedure:
A solution of 2-chloro-4,8-dimethylquinoline (1.00 g, 5.2 mmoles) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
(5R)-3-[3-Fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 19) (4.0 g, 13.7 mmol) was dissolved in dichloromethane (30 ml) and cooled to 0° C. Triethylamine (3.08 ml, 23.3 mmol) was added, followed by methylsulfonyl chloride (1.27 ml, 16.4 mmol). It was stirred for one hour and poured into saturated aqueous sodium bicarbonate solution and diluted with dichloromethane (200 ml). The organic phase was dried over magnesium sulfate and solvent was removed under reduced pressure to give the title product (5.1 g) as a solid, which was used without further purification.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1.OP(O)(O)=O.[ClH:14]>O>[ClH:14].[CH2:3]1[C@@H:4]2[CH2:8][CH2:7][CH2:6][C@@H:5]2[CH:1]=[N:2]1
Reactant: C1CC2CNCC2C1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: O
Product: C1=NC[C@@H]2CCC[C@H]12

Procedure:
To a 3-L 3-neck flask jacketed at 20° C. and stirred at 300 rpm was added 500 mL of dH2O and 20 mL of a 25 wt % octahydrocyclopenta[c]pyrrole solution in water. The pH was adjusted to approximately 7.6 with concentrated H3PO4 to give a colorless, homogeneous solution, to which 2.0 mL of A. niger catalase suspension (Novozyme; “Catalyzyme 101”) and 5.0 g of monoamine oxidase powder of the polypeptide of SEQ ID NO: 16 (prepared by the method of Example 3) were added to give a pale yellow solution. The head space of the vessel was swept with dry air at approximately 0.2 L/min. The pH of the reaction was maintained at 7.5 via feedback controlled addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions. The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction and the reaction mixture became a white slurry. After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added, the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.). The receiver pot contained a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water. 1.1-1.2 equivalent of concentrated HCl was added to the receiver pot break the dimer and give a homogeneous solution of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole hydrochloride in water. This solution was used directly to make (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonitrile in Example 27.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C[O:7][C:8]1[C:9]2[CH:10]=[C:11]3[S:20][CH:19]=[CH:18][N+:12]3=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1>Br>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:7][C:8]1[C:9]2[CH:10]=[C:11]3[S:20][CH:19]=[CH:18][N+:12]3=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc2c[n+]3ccsc3cc12
Agent: Br
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Oc1cccc2c[n+]3ccsc3cc12
Temperature: 115 °C

Procedure:
A mixture of 9-methoxy-thiazolo[3,2-b]isoquinolinium perchlorate (7 g, 22.19 mmol) in 100 ml of 48% HBr was heated for 18 hours at 115° C. The mixture was concentrated in vacuo, the residue was dissolved in warm water and filtered. The filtrate was treated with sodium perchlorate, the resulting solid was filtered, and washed with water to afford 1.0 g (15%) of 9-hydroxy-thiazolo[3,2-b]isoquinolinium perchlorate (Formula II: A=thiazolo; R1 =H; R6 =9-OH; X- =ClO4-).
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN1CCCC1.O>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:6]2[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1cccnc1NC1CCNCC1
Reactant: Clc1nc2ccccc2s1
Agent: CN1CCCC1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1cccnc1NC1CCN(c2nc3ccccc3s2)CC1
Temperature: 180 °C
Yield: 33.9 %

Procedure:
A mixture of 3-nitro-N-(piperidin-4-yl)pyridine-2-amine hydrochloride (intermediate 58, 500 mg, 2.24 mmol) and 2-chloro-benzo[d]thiazole (379 mg, 2.24 mmol) in N-methylpyrrolidine (5 mL) was heated at 180° C. in microwave for 2 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by silica chromatography gave N-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-3-nitropyridin-2-amine (270 mg, 0.76 mmol, 33.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH:17]=[N:16][CH:15]=[N:14]1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: C[C@H](N)c1cccc(-n2cncn2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-n2cncn2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-[1,2,4]triazol-1-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC[C:16](OCC)=[O:17].CC[O-].[Na+].COC1C=CC(S)=CC=1>>[CH3:16][O:17][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2][CH:3]=1
Reactant: CCOC(=O)CSc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: COc1ccc(S)cc1
Agent: [Na+]
Product: CCOC(=O)CSc1ccc(OC)cc1

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate starting with ethyl bromoacetate (11.7 g), a 2M ethanolic solution of sodium ethylate (35 cc) and 4-methoxythiophenol (10 g). Ethyl (4-methoxyphenylthio)acetate (13.6 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[C:34]([O-:37])(=[O:36])[CH3:35].[K+]>CN(C)C=O>[CH2:25]([C@:23]1([OH:24])[C:13]2[CH:12]=[C:11]3[N:16]([C:15](=[O:19])[C:14]=2[CH2:20][O:21][C:22]1=[O:27])[CH2:17][C:18]1[C:6]([CH2:5][CH2:4][Si:3]([CH2:2][O:37][C:34](=[O:36])[CH3:35])([CH3:33])[CH3:32])=[C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]2=[N:9][C:10]3=1)[CH3:26]
Reactant: CC(=O)[O-]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)COC(C)=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of Compound 3 (200 mg) and potassium acetate (200 mg) in dry N,N-dimethylformamide (4 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and the N,N-dimethylformamide was removed under vacuum with mild heating. The obtained crude material was directly purified on a silica gel column using 1-2% ethanol in dichloromethane to obtain the required product in 72% yield (150 mg).
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N.[C:25]1(=[C:31]([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[C:32]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]1(=[C:31]([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[C:32]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH2:3])=[O:41])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.121 g, 0.63 mmol), 1-hydroxybenzotriazole hydrate (0.087 g, 0.644 mmol), 4-dimethylaminopyridine (0.012 g, 0.098 mmol), pyridine (5 mL), and ammonia (0.5 M in 1,4-dioxane) (1.4 mL, 0.7 mmol) was added a solution of (2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic acid (8) (174 mg, 0.52 mmol) in pyridine (5 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 d. The reaction mixture was concentrated and the crude product was partitioned between H2O and CH2Cl2. The organic phase was separated and washed with 1 N HCl (aq.) followed by brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 90:10) to give the desired product. The solid was dried under vacuum at 70° C. to give 29 mg (17%) of compound 12 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.54 (m, 6H), 2.15 (m, 4H), 6.53 (d, J=15.8 Hz, 1H), 6.67 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 7.06 (m, 3H), 7.36 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.50 (br s, 1H), 9.33 (s, 1). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C25H31NO2Si: 405.2124 (M+.). Found: 405.2126.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1([CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Cl)cc2C=O)COC1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (4.5 g, 29 mmol), toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester in Example 13c (6.4 g, 25 mmol) and K2CO3 (8 g, 58 mmol) in anhydrous N,N-dimethylformamide (40 mL) was heated at 100° C. for 1 h. Then the mixture was filtered and the filtrate was concentrated. The residue was dissolve in EtOAc (50 mL). The solution was washed with water, dried and concentrated to give title compound as a yellow oil (5.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([N:18]([CH3:20])C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].C[O-].[Mg+2].C[O-].Br[CH2:34]CNC(=O)OCCCC>CO.CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:34][CH2:20][NH:18][C:16](=[O:17])[C:12]3=2)[C:7]1=[O:23]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CCCCOC(=O)NCCBr
Agent: C[O-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1NCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (1.00 g, 2.63 mmol; Example 1, Step 9) and magnesium methoxide in methanol (13.1 mL, 6-10% methanol solution available from Aldrich) in DMSO (26 mL) was heated at 60° C. for one hour. Methanol was exhaustively removed under vacuum over 45 minutes. The resulting DMSO solution was treated with tort-butyl (2-bromoethyl)carbamate (2.94 g, 13.13 mmol) and stirred at 60° C. under an atmosphere of nitrogen for one hour. The reaction mixture was diluted with ethyl acetate and washed successively with 10% sodium thiosulfate and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:5][CH:4]=1.O1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1.C(O)C>O>[O:21]=[C:18]1[CH:19]=[CH:20][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[S:13][C:12](=[O:14])[NH:11][N:10]=3)=[CH:7][CH:8]=2)[CH:16]=[CH:17]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(-c2n[nH]c(=O)s2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1ccn(-c2ccc(-c3n[nH]c(=O)s3)cc2)cc1

Procedure:
A mixture of 5-(4-aminophenyl)-1,3,4-thiadiazol-2(3H)-one hydrochloride (1.25 g), 4H-pyran-4-one (0.58 g), ethanol (10 ml) and water (50 ml) was stirred under reflux under nitrogen for 31/2 hours. The cooled reaction mixture was filtered and the collected orange solid was washed with aqueous potassium hydrogen carbonate and water and was dried. The crude product (1.35 g) was treated with boiling dimethylformamide (200 ml) and the resultant suspension was cooled and filtered. The collected solid was washed with ethanol and ether, dried and suspended in water (100 ml). Sufficient aqueous sodium hydroxide (2N) was added to the suspension to form a solution which was filtered. The filtrate was acidified to pH 6 with hydrochloric acid which caused the precipitation of the title compound as a yellow solid, 0.96 g, m.p. 343°-4° C. (decomp).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[Cl:9][C:10]1[C:14](Cl)=[N:13][S:12][N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:14]([N:6]2[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]2)=[N:13][S:12][N:11]=1
Reactant: CC1CNCC(C)N1
Reactant: Clc1nsnc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2nsnc2Cl)CC(C)N1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
2,6-Dimethyl-piperazine (8.1 g, 71 mmol) was heated to 100° C. in DMF (8.0 ml). 3,4-Dichloro-1,2,5-thiadiazole (3.3 ml, 35 mmol) was added and the mixture stirred at 100° C. for 3-4 h. The reaction mixture was poured into H2O and extracted with EtOAc (4×). The combined EtOAc extractions were washed with sat'd NaHCO3 (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give 7.9 g (97%) of 1-(4-chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine which was used without further purification. 1H NMR (CDCl3) 3.90-3.86 (m, 2H), 3.05 (m, 2H), 2.52 (m, 2H), 1.12 (d, 6H) ppm. LC-MS (MH+)=233.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:18][CH2:19][CH2:20][N:21]1[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:22]1=[O:29].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:4][C:5]([NH:18][CH2:19][CH2:20][N:21]2[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[NH:23][C:22]2=[O:29])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(-c2cc3ccncc3s2)n1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3ccncc3s2)n1
Temperature: 170 °C

Procedure:
2-(5-Bromo-2-chloropyrimidin-4-yl)thieno[2,3-c]pyridine (0.38 g, 1.16 mmol), 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (0.393 g, 2.3 mmol), diisopropylethyl-amine (0.4 mL, 2.3 mmol) and isopropyl alcohol (2 mL) were all placed in a microwave tube and heated to 170° C. for 20 min. The volatiles were removed in vacuo and the residue dissolved in 9:1 mixture of dichloromethane, preadsorbed onto silica gel and purified by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=0.4 g. MS (M+H)+ 461/463.
Reaction SMILES: S(Cl)(Cl)=O.BrC1SC(C(O)=O)=CC=1.BrC1SC(C(Cl)=O)=CC=1.[Br:23][C:24]1[S:28][C:27]([C:29]([N:31]=[C:32]=[S:33])=[O:30])=[CH:26][CH:25]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[C:51]([CH3:56])[CH:50]=1>C(O)C.C1(C)C=CC=CC=1>[Br:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]([NH:53][C:52]2[CH:54]=[CH:55][C:49]([O:48][C:39]3[C:38]4[C:43](=[CH:44][C:45]([O:46][CH3:47])=[C:36]([O:35][CH3:34])[CH:37]=4)[N:42]=[CH:41][CH:40]=3)=[CH:50][C:51]=2[CH3:56])=[S:33])=[O:30])=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Br)s1
Agent: O=C(Cl)c1ccc(Br)s1
Agent: O=C(O)c1ccc(Br)s1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)s4)c(C)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-bromo-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-bromo-2-thiophene isothiocyanate was prepared using the resultant 5-bromo-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 5-Bromo-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (58 mg, yield 65%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20]CC3C=CC=CC=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)[nH]c2)cc1N
Yield: 110.3 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (160 mg, 0.409 mmol) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as an off-white solid (136 mg).
Reaction SMILES: [K].O(CC(NC1C(=O)N2C(C(O)=O)C(C)(C)S[C@H]12)=O)C1C=CC=CC=1.OO[S:28]([O-:30])=O.[K+].[CH3:32][C:33]1([CH3:54])S[C@@H:36]2[C@H:38]([NH:41][C:42]([CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:43])[C:39](=[O:40])[N:35]2[C@H:34]1[C:51]([O-:53])=[O:52].[K+]>O>[CH3:32][C:33]1([CH3:54])[S:28](=[O:30])[C@@H:36]2[C@H:38]([NH:41][C:42]([CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:43])[C:39](=[O:40])[N:35]2[C@H:34]1[C:51]([OH:53])=[O:52]
Reactant: O=S([O-])OO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: [K+]
Agent: [K]
Solvent: O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To 50 ml. of water were added 19.4 grams (50 millimoles) of the potassium salt of 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylic acid. A solution of 20 grams (65 millimoles active oxygen) of Oxone® in 100 ml. water was added dropwise to the penicillin solution over a 45 minute period. The mixture was stirred for about 10 minutes at room temperature. The resulting precipitate was collected by filtration and washed with 25 ml. of water. The precipitate was dried in vacuo at 40° C. overnight to afford 17.95 grams (98%) of the corresponding penicillin sulfoxide. Analysis of the product by high performance liquid chromatography (HPLC) indicated the presence of 23.0% of the α-isomer and 74.1% of the β-isomer.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[CH2:6][C:3]1([CH2:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:5][CH2:4]1
Reactant: COC(=O)CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
To a solution of methyl [1-(hydroxymethyl)cyclopropyl]acetate (1 eq.) from the previous step in DCM (0.1 M) at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to 0° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound appendage 3 as an oil.