Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH:11]([CH3:13])[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[NH2:22].C([O-])([O-])=O.[K+].[K+].CO.O>C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:12]2[CH:11]([CH3:13])[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[NH2:22]
Reactant: COc1nc2c(c(Br)c1N)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2c(c(Br)c1N)C(C)CNCC2
Yield: 86.2 %

Procedure:
A solution of NBS (1.16 g, 6.50 mmol) in DCM (40 ml) was added dropwise to a stirred and cooled (0-5° C.) solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (1.97 g, 6.50 mmol) in DCM (40 ml) over a period of 20 min. After 30 minutes of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified by column chromatography to provide 920 mg (37%) of 4-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.36 (0.5H), 4.18 (2H), 4.00 (0.5H), 3.95 (3H), 3.79 (1H), 3.74 (1H), 3.70 (1H), 3.38 (1H), 3.23 (1H), 3.07 (1H), 1.19 (3H) ppm. 4-Bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (57.0 mg, 0.15 mmol) of was deprotected using K2CO3 (62 mg, 0.45 mmol), MeOH (2.3 ml) and H2O (0.5 ml) at 55-60° C. for 30 minutes. After carefully removing MeOH under reduced pressure, the mixture was diluted with aq. NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 37.0 mg (86%) of 4-bromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.96 (s, 3H), 3.54 (m, 1H), 3.26 (dd, 2H), 3.18 (dd, 1H), 3.02 (d, 1H), 2.94 (dd, 1H), 2.78 (dd, 1H), 1.32 (d, 3H) ppm.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+:11]>O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:11]
Reactant: O=C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccccc1

Procedure:
In a separate run, a mixture of 61 g (0.5 mole) benzoic acid and 34.6 g (0.52 mole) potassium hydroxide in 146 g of distilled water was stirred at 80°-85° C. under a stream of air until 115 g of water had evaporated. The resulting mixture was cooled to yield solid potassium benzoate which contained 34 weight percent water based on the total material weight. A portion of the solid was removed for slurry viscosity measurement, and the rest of the solid was filtered to remove excess water. The filtered solid contained about 23 weight percent water based on the total material weight. Separate slurries of the wet KBz solid, and of the filtered KBz solid in terphenyl were prepared at 150° C. The slurry viscosities at 200° C. were 225 centipoise for the wet solid and 14.8 centipoise for the filtered solid.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:27]=1)=[O:7].[H-].[Na+].[CH3:51]I>O1CCCC1.[Cl-].[Na+].O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:33]([CH3:51])[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:27]=1)=[O:7]
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(NC(=O)C(F)(F)F)c3)C2)CCO1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N(C)C(=O)C(F)(F)F)c3)C2)CCO1
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[4-methyl-3-(trifluoroacetylamino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (131 mg) in tetrahydrofuran (2 ml) was added sodium hydride (10 mg) and the resulting mixture was stirred for 20 minutes. Methyl iodide (28 mg) was added to the mixture and the whole was stirred at room temperature overnight. Brine was added to the mixture and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by HPLC to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-(N-methyl-N-trifluoroacetylamino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine (31 mg) as an oil. The obtained compound was converted to its dihydrochloride in a conventional manner.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 81 %

Procedure:
Dissolving 5.0 g (29 mmol) of 2-amino-5-bromopyridine, 3.6 g (30 mmol) of phenylboronic acid and 0.67 g of tetrakis (triphenylphosphine) palladium into 90 milliliter of 1,2-dimethoxyethane, adding 45 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, the resultant solution was further dissolved into ethyl acetate, filtering the solution, washing with water, dried with the use of sodium sulfate. Removing the solvent by distillation, 4.0 g of crude 5-phenyl-2-amino-pyridine was obtained.
Reaction SMILES: C1(N(C(N)=O)N)C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[N:21]=[CH:22]C2C=CC=CC=2)[CH:16]=[CH:17][C:18]=1[F:19].ClC1C=C(NN=CC2C=CC=CC=2)C=CC=1F.CN(C)C(Cl)=O.ClC1C=C(N(C(N(C)C)=O)N)C=CC=1F.C=O>>[Cl:12][C:13]1[CH:14]=[C:15]([N:20]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[N:21]=[CH2:22])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CN(C)C(=O)N(N=Cc1ccccc1)c1ccc(F)c(Cl)c1
Agent: C=O
Agent: CN(C)C(=O)Cl
Agent: CN(C)C(=O)N(N)c1ccc(F)c(Cl)c1
Product: C=NN(C(=O)N(C)C)c1ccc(F)c(Cl)c1

Procedure:
A suitable method for preparing the 2-phenylsemicarbazones comprises converting a 2-phenylsemicarbazone of one specific aldehyde into a 2-phenyl-semicarbazone of a different aldehyde by hydrolyzing the initially prepared 2-phenylsemicarbazone into the corresponding 2-phenylsemicarbazide which is then reacted with the desired aldehyde. For example, benzaldehyde 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazone prepared e.g., from benzaldehyde 3-chloro-4-fluorophenylhydrazone and dimethylcarbamoyl chloride is hydrolyzed to 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazide which is reacted with formaldehyde to give formaldehyde 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazone.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:5]1([C:3](=[O:4])[CH2:2][N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cn1cccn1)c1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 1.5 g (9.7 mmol) of 2-chloroacetophenone in 10 mL of MeCN, 0.7 g (10.3 mmol) of pyrazole was added. After all the solids dissolved, 1.4 g (10.1 mmol) of ground K2CO3 was added and the mixture was stirred for 5 h. The reaction was diluted with EtOAc, filtered, and the solid was washed with EtOAc. The filtrate was washed with water and brine, then was dried and concentrated. The residue was chromatographed on a flash column using a gradient of 10-50% EtOAc-hexane to isolate desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[CH2:15][CH3:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCC(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: [Ti+3]
Agent: [Cl-]
Product: CCC(c1ccc(N)cc1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
In the manner given in Example 1B, 1-(p-fluorophenyl)-4-[1-(4-nitrophenyl)propyl]piperazine is reduced with aqueous titanium trichloride to give 1-(4-fluorophenyl)-4-[1-(4-aminophenyl)propyl]piperazine.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:50]=[CH:51][C:52]=1[O:53][CH3:54])[CH2:32][O:33][C:34]([NH:36][C:37]1[N:45]=[CH:44][N:43]=[C:42]2[C:38]=1[N:39]=[CH:40][N:41]2[CH2:46][C:47](O)=[O:48])=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:47](=[O:48])[CH2:46][N:41]2[CH:40]=[N:39][C:38]3[C:42]2=[N:43][CH:44]=[N:45][C:37]=3[NH:36][C:34]([O:33][CH2:32][C:31]2[CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:29]([O:28][CH3:27])[CH:30]=2)=[O:35])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(3,4-dimethoxybenzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.58 (s, 1H), 8.58 (s, 0.6H), 8.56 (s, 0.4H), 8.35 (m, 1H), 8.30 (s, 0.4H), 8.27 (s, 0.6H), 8.26 (m, 1H), 7.73 (m, 2H), 7.07 (s, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 5.38 (s, 1.2H), 5.27 (s, 0.8H), 5.12 (s, 2H), 4.56 (s, 0.8H), 4.28 (m, 2.4H), 4.09 (t, 2H), 3.87 (t, 0.8H), 3.76 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:26](OC(C)(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]2[CH:13]=[N:26][NH:1][C:2]=2[CH:11]=1
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Cl)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 equiv.) in chloroform (13 mL per 1 mmol), potassium acetate (1.05 equiv.) and acetic anhydride (2 equiv.) were added and reaction mixture stirred at room temperature for 12 h. After this time, tert-butyl nitrite (4 equiv.) and 18-crown-6 (0.35 equiv.) were added and the reaction stirred again at 65° C. for 3 h. On completion, the reaction mixture was cooled to room temperature, diluted with chloroform (500 mL) and washed with sat. sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated to afford the title compound (yield 90-95%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CC(CO)CCC1NCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Benzylamino-3-methyl-cyclohexyl)-methanol (0.1 g, 3.00 mmol) in DCM (30 mL) and pyridine (3 mL) is treated with TsCl (0.86 g, 4.50 mmol) and the resulting mixture is stirred at RT overnight. The reaction mixture is partitioned between DCM and water and the organic portion is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (1:2 increasing to 1:4) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2H, d), 7.50 (2H, d), 7.30 (4H, m), 7.20 (1H, m), 3.80 (2H, d), 3.63 (2H, q), 2.41 (4H, m), 2.01 (1H, m), 1.72 (2H, m), 1.58 (1H, m), 1.49 (2H, m), 1.20 (1H, m), 1.02 (1H, m), 0.85 (1H, m), 0.81 (3H, d).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:16][C:17]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:27][C:28]1[C:29]2[O:36][CH:35]=[C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30]=2[N:31]=[CH:32][N:33]=1.O>C(#N)C>[CH:1]1([S:4]([N:40]2[CH2:39][CH2:38][CH:37]([C:34]3[C:30]4[N:31]=[CH:32][N:33]=[C:28]([NH:27][C:18]5[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:17]=5[F:16])[C:29]=4[O:36][CH:35]=3)[CH2:42][CH2:41]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(S(=O)(=O)C5CC5)CC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of cyclopropanesulfonyl chloride (4 mg, 0.028 mmol) in anhydrous acetonitrile (0.2 mL), and triethylamine (10 μL, 0.069 mmol) were added to N-[2-fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (10 mg, 0.023 mmol) under ice-cooling, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=50:1) to give the titled compound (8.5 mg, 75%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([NH2:12])[N:5]=1.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([NH:12][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH3:13])=[O:16])(=[O:25])=[O:24])=[O:28])[N:5]=1
Reactant: COCc1nc(N)nc(SC)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COCc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 0.8 g of 4-methoxymethyl-6-methylthio-2-amino-1,3,5-triazine in 15 ml of anhydrous methylene chloride was added 1.5 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was heated for one hour and then stirred at ambient temperature for 18 hours. Solvent was removed in vacuo and the residue was triturated with 1-chlorobutane (50 ml) and filtered to give 1.7 g of the desired product, m.p. 147°-149° C. mmr: 2.6 ppm δ, 3H; 3.4 ppm δ, 3H; 3.85 ppm δ, 3H; 4.45 δ, 2H; 7.65-8.5 broad, 4H.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([C:17]([OH:19])=O)=[CH:15][S:16][C@H:11]12)=[O:8].CN1CCOCC1.ClC(OCC)=O.[C:51]1([SH:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(OCC)(=O)C.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[C:14]([C:17]([S:57][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:19])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: Sc1ccccc1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)O)=CS[C@H]12
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)Sc3ccccc3)=CS[C@H]12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a cooled (-10° C.), stirred solution of benzhydryl 7-(2-thienylacetamido)-3-carboxy-2-cephem-4-carboxylate (.267 g., 0.5 mmol.) in 25 ml. of methylene chloride under an argon atmosphere was added 0.152 g. (1.5 mmol.) of N-methylmorpholine. The reaction mixture was then cooled to -20° C. and 0.135 g. (1.25 mmol.) of ethyl chloroformate was added. The mixture was stirred at 0° for 30 minutes after which time the mixture was cooled to -10° and 0.165 g. of thiophenol was added. After stirring the reaction mixture at 0° for 1 hour, ethyl acetate was added, and the resulting solution was washed successively with aqueous sodium bicarbonate, water, and brine and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which was chromatographed on a silica gel column using a tolueneethyl acetate gradient to provide 0.208 g. (66.5%) of the title product: ir (CHCl3) 1798 cm-1 (β-lactam C = 0); nmr (CDCl3) 3.80 (s, 2, side chain CH2), 5.06 (d, 1, J = 4.0 Hz, C6 --H), 5.42 (q, 1, J = 4.0 and 8.0 Hz, C7 --H), 5.70 (s, 1, C4 --H) and 7.87 ppm (s, 1, C 2 --H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Solvent: CCOC(C)=O
Product: Nc1cnc2ccccc2c1NCC1(O)CCCCC1

Procedure:
A suspension of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol (15.0 g, 49.8 mmol) in ethyl acetate (225 mL) in a Parr vessel was purged with nitrogen; 5% platinum on carbon (1.5 g) was added. The reaction was placed under hydrogen pressure (35 psi, 2.4×105 Pa) for 3.5 hours and then filtered through a layer of CELITE filter agent. The filter cake was washed with ethyl acetate (100 mL), and the filtrate was concentrated under reduced pressure to provide 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexanol as a yellow solid.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=O)=[CH:12][CH:11]=2)[N:3]=1.P(Cl)(Cl)([Cl:21])=O>C(OCC)(=O)C>[Cl:21][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]#[N:16])=[CH:12][CH:11]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1ccc(Nc2ncc(I)c(O)n2)cc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2ncc(I)c(Cl)n2)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 4-((4-hydroxy-5-iodopyrimidin-2-yl)amino)benzamide (J11, 1.35 g), phosphorus oxychloride (14 mL) was added at room temperature, and the mixture was stirred at 90° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then poured into ice, and then ethyl acetate was added to the mixture. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with a mixed solvent of diisopropyl ether and chloroform, and then dried under reduced pressure to obtain 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 764 mg) as pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>O.[Cu].[Cu]I>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: Oc1ccc(F)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(F)cc1Oc1ccc(F)cc1
Yield: 1.2 %

Procedure:
A mixture of 2-chloro-4-fluorobenzoic acid (1.74 g, 10 mmol), 4-fluorophenol (2.24 g, 20 mmol), copper (50 mg, 0.78 mmol), copper(I) iodide (50 mg, 0.28 mmol), potassium carbonate (2.76 g, 20 mmol), and pyridine (0.40 mL, 5.0 mmol) in water (6.0 mL) was heated under reflux for 2 h with stirring. The reaction mixture was diluted with water and filtered through a pad of Celite®. The pH value of the filtrate was adjusted to 9.0 by the addition of 2 M aqueous solution of sodium carbonate. The aqueous mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried (sodium sulfate), and concentrated to afford 29 mg (99%) of the title compound: MS (ESI) m/z 250 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)[C:14]([F:34])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.CC(O)C>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][NH:20]4)[C:14]([F:34])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Agent: Cl
Solvent: CC(C)O
Product: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NCC1CC(F)(F)CCN1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate, 13k, (0.09 g, 0.18 mmol) in 2-propanol (2 mL) was added propan-2-ol hydrochloride (2 mL of 6 M, 12.00 mmol). After stirring the reaction mixture at room temperature for 17 hours, an additional 1 mL of IPA/HCl was added and the reaction mixture was heated at 45° C. for 1 hour. All volatiles were removed at reduced pressure and the residue was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1[C:11]2[CH:10]([OH:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C2=C(C=CCC2)SCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2ccccc2CSc2ccccc21
Temperature: -10 °C
Reaction time: 3 h

Procedure:
48 g (212 mmol) 6.1-dihydro-dibenzo[b,e]thiepin-11-one are dissolved in 480 ml absolute methanol and cooled to ca. −10° C. 19.2 g (507 mmol) sodium borohydride is added portion wise to this solution. The mixture is stirred for three hours at RT without further cooling. After the careful addition of 30 ml water, the suspension is concentrated under vacuum. The residue is taken up in 500 ml dichloromethane and washed twice each with 150 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from 180 ml toluene. Colorless crystals of MP. 108° C.: Yield 41.2 g (85%).