Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[C:17]([F:18])=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:15]([NH2:28])=[C:14]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:13]=1>>[CH2:1]([C:4]1([S:7]([NH:28][C:15]2[C:14]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:13][C:12]([F:11])=[C:17]([F:18])[C:16]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: COCCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Product: C=CCC1(S(=O)(=O)Nc2c(OCCOC)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Yield: 15.8 %

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride (450 mg, 2.5 mmol) was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxyethoxy)benzene-1,2-diamine (219 mg, 2.5 mmol) to obtain the title product (230 mg, 78%); m/z=581 [M−1].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([OH:14])[CH:5]=1.Cl[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].O>C1COCC1>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([O:14][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:5]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cc(Br)c2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 95.8 %

Procedure:
Sodium hydride (0.38 g, 15.9 mmol) was added portionwise to a solution of 4-bromo-2-naphthol (3.54 g, 15.9 mmol) in THF (50 mL) with stirring at 0° C. under N2. Ater 0.5 h chlorotriisopropylsilane (3.06 g, 15.9 mmol) was added dropwise at 0. The solution was stirred at room temperature for 2 h, poured into water (200 mL), extracted with DCM (dichloromethane) (4×50 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexanes as eluent. The solvent was removed under reduced pressure to give the title compound (5.78 g, 96%) as a colourless oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:9]2[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Nc1nnc(C2CCC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclobutyl-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[CH:2].[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17](Cl)[CH:18]=1.C([N:24](CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:6][C:5]1[C:4]2=[C:13]3[C:14](=[C:20]([NH2:21])[N:24]=[C:3]2[CH:11]=[CH:10][CH:9]=1)[N:15]=[CH:16][CH:17]=[CH:18]3.[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[C:2][C:17]3[CH:18]=[C:13]([Cl:12])[C:14]([C:20]#[N:21])=[N:15][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Cc1cccc2nc(N)c3ncccc3c12
Product: N#Cc1ncc(C#Cc2ccc3[nH]ccc3c2)cc1Cl
Temperature: 60 °C
Yield: 4 %

Procedure:
To a round bottom flask capped with septa was added 5-ethynyl-1H-indole (from the previous step) (1.1 eq), 3,5-dichloropicolinonitrile (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60° C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 5-((1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:22][CH:23]([CH3:28])[CH2:24][C:25](Cl)=[O:26]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:25](=[O:26])[CH2:24][CH:23]([CH3:28])[CH3:22])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of N-t-butoxycarbonyl-1,4-phenylene diamine (0.2 g) in dry tetrahydrofuran (20 ml) were added pyridine (0.15 ml) and 3-methylbutyryl chloride (0.13 g) and the reaction mixture was stirred for 1 hrs. The solution was diluted with ethyl acetate (50 ml), washed with a 3 N solution of hydrochloric acid (30 ml) and brine (30 ml), dried and concentrated in vacuum to give the title compound (0.27 g). T.l.c. cyclohexane/ethyl acetate 1/1, Rf =0.71.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Cl)=[CH:15][CH:14]=1>C(#N)C>[ClH:1].[Cl:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][C:13]([F:12])=[CH:14][CH:15]=3)=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: Cc1c(Cl)[nH]c2ncccc12
Solvent: CC#N
Product: Cc1c2cccn(CC(=O)c3ccc(F)cc3)c-2nc1Cl
Product: Cl
Yield: 114.7 %

Procedure:
A solution of 1,2 g (7,2 mmol) 2-chloro-3-methylpyrrolo[2,3-b]pyridine and 1,5 g (8,7 mmol) p-fluorophenacyl chloride in 50 ml acetonitrile was refluxed for 48 h. The mixture was allowed to cool and the precipitated product filtered off. The solid was treated with ethyl acetate and filtered off again affording 1,4 g (57%) of the desired product.
Reaction SMILES: [CH2:1]([S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4].[CH3:27][C:28](C)=O.I([O-])(=O)(=O)=[O:32].[Na+]>O1CCCC1.O>[CH2:27]([C:20]1[CH:19]=[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:32])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23])[CH3:28]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)=O
Reactant: CCCCSCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCS(=O)CCCCCCCCCCCNc1ccc(C(=O)O)c(CC)c1

Procedure:
A solution of 5.2 g. of 4-[11-(n-butylthio)undecylamino]benzoic acid in 35 ml. of acetone and 20 ml. of tetrahydrofuran is treated with a solution of 3.7 g. of sodium metaperiodate in 3.5 ml. of water and 20 ml. of tetrahydrofuran and the mixture is stirred under reflux for 2 hours and then filtered. The filtrate is extracted with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. Crystallization from acetone-chloroform affords the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](=[N:30][OH:31])[CH3:29])=[N:9]1.[OH-].[K+].Cl.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38]Cl.CS(C)=O>O>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][O:31][N:30]=[C:28]([C:10]1[CH:11]=[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)[CH3:29]
Reactant: CN(C)CCCl
Reactant: CC(=NO)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=NOCCN(C)C)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
A mixture of 1-[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]ethanone oxime (196 mg, 0.415 mmol), KOH (142 mg, 2.3 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (185 mg, 1.3 mmol), and anhydrous DMSO (5 mL) was stirred at 60° C. in a sealed vial for 3 h. The reaction mixture was diluted with water, extracted with ether. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-30% MeOH/DCM) to give the title compound as a white solid (50 mg, 22%). 1HNMR (CDCl3): δ8.04 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.71 (m, 1H), 7.57-7.43 (m, 5H), 7.21 (d, 1H), 7.00 (s, 1H), 6.76 (d, 1H), 4.38 (t, 2H), 3.07 9s, 3H), 2.78 (m, 2H), 2.40 (brs, 6H), 2.31 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Na+].[Na+].[OH:16][CH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.O>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: N#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2cccc(CO)c2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 3-bromobenzonitrile (1.20 g, 6.58 mmol) in toluene (40 mL) was added a solution of tetrakistriphenylphosphinepalladium (0.38 g, 0.33 mmol), 2N aqueous sodium carbonate solution (21 mL) and [3-(hydroxymethyl)phenyl]boronic acid (1.00 g, 6.58 mmol) in EtOH (19 mL), and the mixture was heated under reflux for 10 hr under nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/9→1/1) to give the title compound as a yellow oil (1.28 g, 93%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][C:4]([O:6][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)CCO
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CCO)OCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
3-Hydroxypropanoic acid solution (12 g, 40 mmol, 30% in H2O solution, TCI, TOKYOKASEI) and KOH (2.24 g, 40 mmol, Shantou Xilong chemical factory) was stirred at rt for 30 min, the mixture was concentrated in vacuo to give a white solid. The solid was suspended in 50 mL of DMF was added BnBr (4.75 mL, 40 mmol, Aldrich) via a syringe at rt. After stirring at 80° C. for 5 h, the reaction mixture concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) to give the title compound as colorless oil (3.35 g, 46%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5](=[O:12])[NH:4][CH:3]=1.[NH3:13].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO.O>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH2:13])=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(F)c[nH]c1=O
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
In 3.0 mL of methanol was dissolved 0.12 g of methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, gaseous ammonia was introduced into the solution at an ice-cooled temperature for a period of 10 minutes, after which the mixture thus obtained was allowed to stand at room temperature for 2 days. The solvent was removed under reduced pressure, the residue thus obtained was added to a mixture of 30 mL of ethyl acetate and 30 ml of water, pH was adjusted to 7.5 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. After adding 30 mL of ethyl acetate to the remaining aqueous layer, pH was adjusted to 1.0 with 1 mol/L hydrochloric acid, and the whole mixture was extracted with two 15 mL portions of ethyl acetate. The organic layers thus obtained were united, washed successively with 15 mL of water and 15 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The solid product thus obtained was washed with diisopropyl ether to obtain 0.015 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a yellow-colored solid product.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH:24][C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH:1]1([N:4]([CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:22]/[CH:23]=[CH:24]/[C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:2][CH2:3]1
Reactant: CC(=O)c1cccc(CNC2CC2)c1
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C2CC2)c1
Yield: 60.6 %

Procedure:
3′-(N-cyclopropylaminomethyl)acetophenone (0.35 g; 1.85 mmol) and potassium carbonate (0.36 g; 2.64 mmol) were added to N,N-dimethylformamide (15 ml). While the mixture was stirred in an ice bath, 1-bromo-6,6-dimethyl-2-hepten-4-yn (0.35 g; 1.76 mmol) in N,N-dimethylformamide (5 ml) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 18 hours at room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.33 g of the target compound (yield: 60.6%).
Reaction SMILES: [OH:1][N:2]=C(OCC)C.C(N(CC)CC)C.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24].Cl(O)(=O)(=O)=O>CN(C=O)C.O>[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([O:1][NH2:2])(=[O:25])=[O:24]
Reactant: CCOC(C)=NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a suspension of ethyl N-hydroxyacetimidate (4.72 g, 45.7 mmol) in DMF (453 ml) was added triethylamine (9.53 ml, 68.6 mmol) followed by portionwise addition of mesitylenesulfonyl chloride (1, 10 g, 45.7 mmol). The reaction mixture was stirred for 2 hours at room temperature then poured into ice water (150 mL). The resulting precipitate was collected by vacuum filtration. The collected solids were treated with neat perchloric acid (32.8 ml, 229 mmol) and stirred until homogeneous. Distilled water (30 mL) was used to titurate white crystals of O-mesitylenesulfonylhydroxylamine (2, 8.31 g, 38.6 mmol, 84% yield). MS APCI: [M+H]+ m/z 216.3.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichlorometbane and 1.5 mL of triethylamine at room temperature was added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-(1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2: dichloromethane/methanol=4/I v/v.
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1.[OH2:15].[OH2:15].[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Solvent: c1ccncc1
Product: O
Product: O=C(O)c1cn(C2CC2)c2nc3cc(N4CCNCC4)c(F)cc3cc2c1=O

Procedure:
1-Cyclopropyl-7-fluoro-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1 g of 8-chloro-1cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.6 g of piperazine in 10 cm3 of pyridine. 0.6 g of 1-cyclopropyl-7-fluoro-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid dihydrate is obtained in the form of a yellow solid melting at 342°-343° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:24])[C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[N:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([N:8]([CH3:24])[C:9]3[N:14]=[C:13]4[S:15][C:16]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])=[N:17][C:12]4=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(c1cccc(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of N-{5-[(3-aminophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.295 mmol) produced in Example 8(x) in N,N-dimethylformamide (1.0 mL) was added 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (78.4 mg, 0.354 mmol), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration and recrystallized from hexane/tetrahydrofuran to give the title compound (118 mg, 72%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
Following the procedure of N. I. Carruthers et al. (J. Med. Chem. 2005, 48, 1857-1872), to a −78° C. solution of 2-bromobenzotrifluoride (12.9 g, 7.8 mL, 57 mmol) in THF (225 mL) was added dropwise a solution of n-BuLi (2.5 M in hexanes, 26 mL, 65 mmol) over 10 min. After 1 h, the reaction mixture was stirred at 0° C. for 10 min, recooled to −78° C., and a solution of N-benzyl-4-piperidone (10.7 g, 57 mmol) in THF (40 mL) was added dropwise via addition funnel over 10 min. After 2 h at −78° C., sat. NH4Cl solution (200 mL) was added and the mixture was warmed to room temperature. The aqueous phase was extracted with EtOAc (2×200 mL). The organic phase washed with H2O (200 mL) and brine (150 mL), dried (MgSO4), and concentrated. Flash chromatography afforded the alcohol (2.7 g), a yellow oil, slightly contaminated with piperidone starting material, in ˜15% yield.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[C:7]([N:14]1[CH:18]=[CH:17]N=[CH:15]1)([N:9]1C=CN=[CH:10]1)=O.CN(C=[O:23])C>>[CH3:10]/[N:9]=[CH:7]\[N:14]([CH:18]=[CH2:17])[C:15]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:23]
Reactant: CN(C)C=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC(F)(F)F
Product: C=CN(/C=N\C)C(=O)NCC(F)(F)F

Procedure:
TEA (1.3 mL, 0.8 mmol) was added to a solution of 2,2,2-trifluoroethylamine (72 mg, 1 mmol) and 1,1′-carbonyldiimidazole (135 mg, 0.8 mmol) in DMF (4 mL) (clear colorless solution). The solution was used for the synthesis of compound 5 without further isolation of compound 5a.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12](=O)[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC.Cl>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)N(CCN(C)C)c2ccccc2-1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CCN(CCN(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution (0.1 M) of methyl 12-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-6,7-dihydro-5H-thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]benzodiazepine-10-carboxylate (from Example 7, Step 5) in THF was treated with borane-dimethylsulfide complex (2 M solution in THF, 20 eq.). The mixture was stirred at RT for 2 h then treated with HCl in methanol (1.25 M) and heated at 75° C. for 30 mins. The solvents were removed in vacuo and the residue taken into EtOAc and washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.99 (s, 1H), 7.40-7.36 (t, J 8, 1H), 7.29-7.27 (d, J 8, 1H), 7.23-7.21 (d, J 8, 1H), 7.14-7.10 (t, J 8, 1H), 4.17 (m, 2H), 3.82 (s, 3H), 3.43-3.39 (m, 2H), 3.20-3.17 (m, 2H), 2.70-2.67 (m, 1H), 2.32-2.23 (m, 2H), 2.01 (s, 6H), 1.81-1.23 (m, 10H). MS (ES+) m/z: 452 [M+H]+.