Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (1.87 g, 12 mmol) in 30 mL pyridine was added acetic anhydride (1.84 g, 18 mmol) and catalytic amount of DMAP and the reaction mixture was stirred at rt for 15 h. The pyridine was removed under reduced pressure; the residue was dissolved in EtOAc (100 mL), washed with 1N HCl (20 mL), water (20 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-fluoro-4-acetoxybenzoic acid in 57% yield (1.35 g). To a suspension of 2-fluoro-4-acetoxybenzoic acid (1.33 g, 6.71 mmol) in 10 mL anhydrous dichloromethane was added oxalyl chloride (2.56 g, 20.13 mmol). Two drops of DMF was added and the reaction mixture was stirred at rt for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure to give 1.48 g of 2-fluoro-4-acetoxybenzoyl chloride which was used in next step without purification. To a solution of 2′-hydroxyacetophenone (0.93 g, 6.83 mmol) in 15 mL anhydrous pyridine was added 2-fluoro-4-acetoxybenzoyl chloride (1.48 g, 6.83 mmol) and the reaction mixture was stirred at rt for 15 h under nitrogen atmosphere. Then the reaction mixture was poured into 100 mL 2N HCl, extracted with EtOAc (200 mL). The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 20% EtOAc in hexanes as eluent) to give 4-acetoxy-2-fluorobenzoic acid 2-acetyl phenyl ester (1.14 g, 53%). The ester compound (0.74 g, 2.34 mmol) was dissolved in 10 mL anhydrous THF. Potassium tert-butoxide (0.53 g, 4.68 mmol) was added in portions and stirred at rt under nitrogen for 1 h. A yellow solid was formed. The reaction mixture was quenched with 15 mL saturated aqueous ammonium chloride. EtOAc (100 mL) was added and the organic phase was separated and dried over anhydrous Na2SO4. Removal of solvent gave crude product (0.725 g) which was used in next step without further purification. This crude compound (0.72 g, 2.62 mmol) was dissolved in 10 mL glacial AcOH, conc. HCl (1 mL) was added and the reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was cooled to rt. The solid was isolated by filtration, washed with AcOH and dried under vacuum to give 126 mg (21%) over 2 steps. MS (ES) m/z: 256.89 (M), 255.86 (M−1); Mp. 287-289° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:6]1[CH3:32].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A mixture of {5-fluoro-3-[4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}acetic acid methyl ester (0.079 g) and tetrahydrofuran (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (1.5 mL), and the resulting mixture was stirred at 40° C. for 1 hour. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:3 to 9:1 by volume) to afford the title compound as a white solid (0.056 g).
Reaction SMILES: Cl[CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14]([NH:18][C:19]([NH2:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:15][C:14]([NH:18][C:19]1[O:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:21]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)NC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Yield: 62.8 %

Procedure:
A reaction vessel was charged with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate and 7.0 g (60 mmol) of tert-butylurea. The reaction mixture was stirred and heated at 140°-150° C. for 19 hours under a calcium sulfate drying tube. With the mixture at room temperature, the mixture was slurried in methylene chloride and washed three times with water. The methylene chloride extract was dried over magnesium sulfate and then concentrated under reduced pressure to yield 8.8 g of a mustard-colored solid material. This solid material was dissolved in hot hexane and then filtered hot. The filtrate was cooled in a dry ice bath. The filtrate yielded 7.3 g of a beige solid product (m.p.=56°-59° C.) identified in Table I.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](N(C)C)=O)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1CCl>C(OCC)C>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCOCC
Product: Clc1ccc2c(c1SCc1ccccn1)CCNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using a method similar to the General Procedure 7, react 3-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (8 g, 20.8 mmol) with 2-picolyl chloride hydrochloride (3.41 g, 20.8 mmol). Dilute the reaction mixture with diethyl ether and filter the precipitate. Concentrate the filtrate in vacuo, dissolve the residue in diethyl ether (100 mL) and add 1N aqueous HCl (100 mL). Stir the mixture for 16 h at ambient temperature. Separate, wash the aqueous layer with diethyl ether, adjust the pH of the aqueous layer to 12 with sodium hydroxide and extract with diethyl ether. Dry over Na2SO4 and concentrate in vacuo to give the free base of the title compound. Use the General Procedure 2-2 to give the title compound as a white solid (4.91 g, 78%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:32])[C:29]([OH:31])=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:32][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:31]
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)O
Reactant: C1COCCN1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCOCC1
Yield: 55 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (250 mg, 0.56 mmol) was reacted with morpholine to give the title compound as a white solid (160 mg, 55%); NMR Spectrum 1.58 (d, 3H), 3.70-3.40 (m, 8H), 5.79 (s, 2H), 5.88 (q, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 7.75 (m, 2H), 7.84 (m, 1H), 8.10 (s, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH+ 516.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][C:6]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:5]1.Cl>O.O1CCCC1>[OH:3][CH:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][C:6]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:5]1
Reactant: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a stirred solution of 78 mg (2.1 mmol) of NaBH4 in 2 ml of water at 0° C. is added over 3 minutes a solution of 250 mg (0.515 mmol) of the title product of Example 17 in 3 ml of tetrahydrofuran (THF). After 30 minutes at 0° C., the mixture was permitted to warm to room temperature, and a further 2 ml each of water and of THF were added. After one hour, the reaction mixture was acidified with 3N hydrochloric acid, and the mixture was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the drying agent removed by filtration, and the solvent removed under reduced pressure. Crystallization of the residue from 50% ethyl acetate/hexane gave the title compound (150 mg), m.p. 131.5°-132.5° C.
Reaction SMILES: [S:1]([CH2:5][CH2:6][N:7]=[C:8]=[S:9])([OH:4])(=[O:3])=[O:2].[Na:10].CO.[C:13]([N:16]([CH3:18])[NH2:17])(=[O:15])[CH3:14]>O>[C:13]([N:16]([CH3:18])[NH:17][C:8]([NH:7][CH2:6][CH2:5][S:1]([OH:4])(=[O:3])=[O:2])=[S:9])(=[O:15])[CH3:14].[Na:10]
Reactant: O=S(=O)(O)CCN=C=S
Reactant: CC(=O)N(C)N
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(=O)N(C)NC(=S)NCCS(=O)(=O)O
Yield: 66 %

Procedure:
175.3 g of sodium sulfoethylisothiocyanate was added to a solution obtained by adding 600 ml of methyl alcohol and 300 ml of water to 114.2 g of 1-acetyl-1-methylhydrazine. The system was then heated under reflux for 4 hours. After the reaction, the reaction solution was dried under reduced pressure. The resulting solid matter was then recrystallized from 1 l of methyl alcohol to obtain 169.4 g (yield: 66.0%) of the desired compound. m.p. 255°-256° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][Cl:17])[P:5](Cl)([N:7]([CH2:11][CH2:12][Cl:13])[CH2:8][CH2:9][Cl:10])=[O:6].[OH:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][OH:24].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:17][CH2:16][CH2:15][N:4]([CH2:3][CH2:2][Cl:1])[P:5]([N:7]([CH2:11][CH2:12][Cl:13])[CH2:8][CH2:9][Cl:10])(=[O:6])[O:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][OH:24]
Reactant: OCCSCCO
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
N,N,N′,N′-Tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 636 mg (1.745 mmol), and bis(2-hydroxyethyl)sulfide, 1 mL (9.67 mmol), were dissolved in 8 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 1.8 mL of 1 M solution in tetrahydrofuran (1.8 mmol), was added over a 10 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. It was then diluted with ethyl acetate; and the ethyl acetate layer separated, washed with 1 M hydrochloric acid and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate), and obtained as a colorless oil, 335 mg (42.6% yield), identified by HPLC and 1H and 31P NMR.
Reaction SMILES: C1(C[O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:18][N:14]1[C:15]2[CH:16]=[CH:17][C:9]([OH:8])=[CH:10][C:11]=2[C:12]2[CH2:21][CH:20]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:19][C:13]1=2
Reactant: [H][H]
Reactant: CN(C)CC1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC1Cc2c(n(C)c3ccc(O)cc23)C1

Procedure:
In a 500 ml Parr hydrogenation bottle was suspended 0.5 g of 10% Pd/C in 50 ml of ethyl alcohol. To this was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-N,N,4-trimethylcyclopent[b]indole-2-methanamine (2.3 g, 0.007 mole) in 200 ml of ethyl alcohol. After shaking at 50° C. under 50 psi hydrogen for two hours, the mixture was cooled and filtered, and the filtrate concentrated to a tan solid, 1.5 g, m.p. 110° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:20]=[CH:21][C:14]=12.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:19]1[C:15]2=[N:16][CH:17]=[N:18][C:13]([O:1][C@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4])=[C:14]2[CH:21]=[N:20]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@H](O)COC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](COC(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 130 °C

Procedure:
(R)-methyl 2-hydroxy-3-isopropoxypropanoate D1a (500 mg, 3.08 mmol), 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine B1 (817 mg, 3.08 mmol) and potassium carbonate (0.186 mL, 3.08 mmol) were suspended in acetonitrile (15 mL). The reaction was heated to 130° C. for 4 hours in the microwave reactor and cooled to ambient temperature. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in EtOAc (25 mL), and washed sequentially with saturated NH4Cl (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane afforded (2R)-methyl 2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate D1b (965 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH:24]=[CH2:25]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH:24]=[CH2:23])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: Clc1ccc(NC2CCNCC2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CCC(Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred mixture of 15 parts of N-(4-chlorophenyl)-4-piperidinamine, 12 parts of N,N-diethylethanamine in 130 parts of benzene is added dropwise a solution of 10.3 parts of 3-bromo-1-propene in 70 parts of benzene. Upon completion, the whole is stirred first for 20 h. 30 at room temperature and further for 40 minutes at reflux. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1,1'-oxybisethane and treated with activated charcoal. The latter is filtered off and the 1,1'-oxybisethane is evaporated again, yielding 2.9 parts of N-(4-chlorophenyl)-1-(2-propenyl)-4-piperidinamine; mp. 90° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)OCC[O:3]1.[OH-].[Na+]>CO>[OH:13][CH2:12][C:9]1[CH:8]=[C:7]([C:2](=[O:3])[CH3:1])[O:11][N:10]=1
Reactant: CC1(c2cc(CO)no2)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1cc(CO)no1
Temperature: 70 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
To a solution of the carbinol 319 (2.39 g, 12.9 mmol) in MeOH (30 mL) 10% HCl (30 mL) was added. The reaction mixture was stirred at 70° C. for 18 hours, cooled and neutralized to pH 6 using 1M NaOH solution. MeOH was evaporated and the resulting aqueous phase was extracted with EtOAc. The organic layer was washed with brine, dried under MgSO4 and concentrated under reduced pressure to produce the title compound as a beige solid (1.67 g, 92% yield), which was used for next step without further purification. 1H NMR (DMSO-d6) δ (ppm): 7.25 (s, 1H), 5.62 (t, J=6.1 Hz, 1H), 4.56 (d, J=5.9 Hz, 2H), 2.56 (s, 3H). MS (m/z): 141.12 (calc) 142.1 (MH+) (found)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)=O)[C@@H:10]([NH:30]C(NC2C=CC=C(C(=O)C)C=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>B.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)[C@@H:10]([NH2:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc(NC(=O)N[C@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](N)C1
Reaction time: 19 h
Yield: 22.5 %

Procedure:
In a dry flask (3R,4R)-3-[3-(3-acetyl-phenyl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (1.19 g, 2.84 mmol) was dissolved in borane (100 mL of a 1M solution in tetrahydrofuran, 100 mmol). The reaction was stirred 19 hours. The reaction mixture was concentrated in vacuo and redissolved in 800 mL of ethyl acetate. The solution was poured into hydrochloric acid (140 mL of a 1M aqueous solution) and stirred vigorously for 16 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash chromatography using 20-0% hexane/ethyl acetate to give a light yellow solid (0.259 g, 22%). 1H NMR (300 MHz, CD3OD), δ: 7.18 (m, 2H), 7.04 (m, 2H), 4.37 (m, 2H), 4.19 (m, 2H), 3.47 (m, 1H), 3.20 (m, 1H), 2.89 (m, 1H), 2.68 (m, 2H), 2.52 (m, 4H), 1.88 (m, 2H), 1.75 (m, 2H), 1.55 (m, 2H), 1.45 (m, 2H), 1.44 (s, 9H). MS (ESI), m+/z: (M+H)+=406.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:20]=[C:19]([O:21]C)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:23])[N:12]=1.[ClH:28]>O1CCOCC1>[ClH:1].[ClH:28].[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([Cl:23])[CH:16]=[CH:15][CH:14]=2
Reactant: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2cccc(Cl)c12
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(NCCCNCc2ccc(Cl)c(Cl)c2)[nH]c2cccc(Cl)c12
Yield: 34 %

Procedure:
2-[3-(3,4-Dichlorobenzylamino)prop-1-ylamino]-5-chloro-4-methoxyquinoline (78 mg, 0.18 mmol) in dioxane:concentrated aq. HCl 1:2 (7 ml) was heated at 80° C. for 18 h. Volatiles were evaporated in vacuo and the residue was triturated with CHCl3:tBuOMe 2:1 and filtered to give the title compound as a colourless solid, (30 mg, 34%). δH (CD3OD) 2.10-2.27 (m, 2H, CH2CH2CH2), ca. 3.27 (t, merged with MeOH peak, 2H, CH2CH2CH2), 3.67 (t, J=6.7, 2H, CH2CH2CH2), 4.29 (s, 2H, Ar—CH2—N), 6.39 (s, 1H, HCC═O), 7.47-7.56 (m, 2H, Ar—H), 7.60-7.72 (m, 2H, Ar—H), 7.78-7.90 (m, 2H, Ar—H); MS (ES+) 410 (MH+, 59%), 235 (100).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].C(O)(=O)C.Cl>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c(N)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 79 %

Procedure:
A 10.43 g (30.6 mmol) portion of ethyl 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate was mixed with 150 ml of acetic acid and 150 ml of concentrated hydrochloric acid and then heated under reflux for 1 hour. After completion of the reaction, the reaction solution was spontaneously cooled and mixed with 700 ml of water. The thus formed crystals were collected by filtration, washed with water (100 ml×2), ethanol (300 ml×1) and ether (300 ml×1) in that order and then dried to yield 7.52 g (79%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:23][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccc(OC(F)(F)F)cc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc2nc(CBr)sc2c1
Yield: 38.2 %

Procedure:
A mixture of 2-methyl-6-(trifluoromethoxy)benzo[d]thiazole (9 g, 0.0386 mol) and NBS (6.9 g, 0.0386 mol) and benzoyl peroxide (0.25 g) in CCl4 (250 ml) was heated to reflux under lamp light (150 Watt) for 4 hr. Then the mixture was filtered, evaporated and purified using the Combi-Flash instrument to give 4.3 g (28.5%) of di-bromo product, 3.1 g (34%) of starting material and 4.6 g (38.2%) of 2-(bromomethyl)-6-(trifluoromethoxy)benzo[d]thiazole.
Reaction SMILES: C(OC([NH:8][CH:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:10]([NH:12][CH:13]1[C:36](=[O:37])[N:15]2[C:16]([C:29]([O:31]C(C)(C)C)=[O:30])=[C:17]([CH:20]=[CH:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH2:18][S:19][C@H:14]12)=[O:11])=O)(C)(C)C>C(O)=O>[NH2:8][CH:9]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:10]([NH:12][CH:13]1[C:36](=[O:37])[N:15]2[C:16]([C:29]([OH:31])=[O:30])=[C:17]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CC(C)(C)OC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Solvent: O=CO
Product: NC(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CC(=O)O)CS[C@H]12)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 25 mg. of tert-butyl 7-(2'-tert-butoxycarbonylamino-2'-phenylacetamido)-3-(2'-tert-butoxycarbonylvinyl)-3-cephem-4-carboxylate, prepared as described in Example 19, in 5 cc of 98-100 percent formic acid was allowed to stand for 1 hour at room temperature. After evaporating under reduced pressure the formic acid, the acid residue was taken up in trifluoroacetic acid and the NMR spectrum was taken. The trifluoroacetic acid was removed under reduced pressure and the acid residue showed a β-lactam in the IR spectrum and an acceptable UV [λ max.=317 mμ (ε = 13,700)]. The bioautograph showed only one antibiotically active zone against Sarcina lutea, which was more polar than cephalexin. Disc plate assay procedures showed antibiotic activity against a variety of Gram positive and Gram negative microorganisms.