Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)C[CH:4]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:11]=[C:10]([N:24]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:9]=1)[C:5]([OH:7])=[O:6].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+]>[CH3:38][CH:37]([CH3:39])[CH2:36][CH2:35][N:24]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=1)[C:10]1[CH:9]=[C:8]([CH2:4][C:5]([OH:7])=[O:6])[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[N:11]=1
Reactant: CC(C)CCN(c1ccc(C(F)(F)F)cc1)c1cc(C(CC(C)C)C(=O)O)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CCN(c1ccc(C(F)(F)F)cc1)c1cc(CC(=O)O)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of [2-[(3-methyl-butyl)-(4-trifluoromethyl-phenyl)-amino]-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (prepared using 3-methyl-iodo-butane in place of 3-bromo-2-methylprepene as described in Example 41) 55 mg, 0.1 mmol) in NaOH (1N, 0.5 mL) and THF (3 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature, acidified with 10% citric acid, extracted with CH2Cl2 (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (5-20% ethyl acetate in CH2Cl2) to give the product as a white solid (50 mg, 59%). 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J=8.29 Hz, 2H), 7.68 (dd, J=8.48, 13.37 Hz, 4H), 7.38 (d, J=8.29 Hz, 2H), 7.14 (s, 1H), 6.47 (s, 1H), 4.12 (d, J=15.45 Hz, 2H), 3.55 (s, 2H), 1.58-1.68 (m, 3H), 0.96 (d, J=6.40 Hz, 6H). MS m/e 511.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:28])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:28])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: C[C@@]1(c2cccc(F)c2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@@]1(c2cccc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 15 h
Yield: 95.6 %

Procedure:
To a solution of N-((4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (7.0 g, 17.57 mmol) in MeOH (100 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (3.15 mL, 21.09 mmol). The mixture was brought up to 60° C. for 15 h until the conversion was completed. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-60% EtOAc/hexane) to afford (4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4.94 g, 16.79 mmol, 96% yield) as white crystalline solid. MS m/z=295.1 [M+H]+. Calculated for C12H11F5N2O: 294.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36]([Cl:39])(=[O:38])=[O:37].[ClH:40]>C(Cl)(Cl)Cl>[ClH:39].[ClH:40].[CH3:35][S:36]([NH:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][CH:3]=1)(=[O:38])=[O:37]
Reactant: Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Reaction time: 1 h

Procedure:
To a solution of 1-(6-aminopyridin-2-ylmethyl)-4-benzhydrylpiperazine (3.58 g) and triethylamine (1.01 g) in chloroform (20 ml) was dropwise added methanesulfonylchloride (1.15 g) at 5° to 10° C. under cooling with stirring, which was continued at the same temperature for 1 hour. To the resultant mixture, additional triethylamine (0.51 g) and methanesulfonyl chloride (0.57 g) were added successively. The mixture was stirred for 1.5 hours. The reaction mixture was washed with water, dried and evaporated in vacuo. The resulting oily product was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The fractions containing the desired compound were combined and evaporated in vacuo to give a residue. According to a conventional manner, the residue was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to give 1-(6-methanesulfonylaminopyridin-2-ylmethyl)-4-benzhydrylpiperazine dihydrochloride (0.97 g). mp: 201°-202° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])[CH:8]=2)[CH:3]=[CH:2]1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH:13][CH2:14][C:15]#[C:16][C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:27])[F:28])=[CH:25][CH:24]=3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCNC(=O)Cc1ccc2cc[nH]c2c1
Product: O=C(Cc1ccc2cc[nH]c2c1)NCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 8 a], 2-(1H-indol-6-yl)-N-prop-2-ynyl-acetamide was reacted with 4-(trifluoromethoxy)-iodobenzene in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6]1)=[O:4].[H-].[Na+].Br[CH2:14][C:15]#[N:16]>CC#N>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:14][C:15]#[N:16])=[O:4]
Reactant: N#CCBr
Reactant: COC(=O)C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1CCC(=O)N1CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
To a solution of 5-oxo-pyrrolidine-2-carboxylic acid methyl ester (3 g, 21 mmol) in CH3CN (60 ml), 60% NaH (863 mg, 22 mmol) was added at 0° C. After stirring for 30 minutes, a solution of 2-bromoacetonitrile (2.59 g, 21 mmol) in CH3CN (10 ml) was added dropwise. After warming at room temperature, and stirring for 20 hours, the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (from DCM to DCM/MeOH 95/5 respectively) to afford the title compound as a pale yellow oil (1.1 g, 29% yield).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: C=CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.78 g of 4-pentenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.02 g of the desired Compound No. 6 in the form of pale brown needles melting at 219°-220° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]([C:9]2[C:10]([CH3:19])=[CH:11][C:12](C)=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[C:6]([CH3:8])[N:7]=1.CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.CC1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O>>[OH:1][CH2:2][C:3]1[NH:4][C:5]([C:9]2[CH:17]=[C:13]([CH:12]=[CH:11][C:10]=2[CH3:19])[C:14]([OH:16])=[O:15])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)O
Agent: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5), except methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) was used in place of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (80 mg, 86%), MS (ISP) m/z=370.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C.C(OCC)(=O)C>[Br:7][C:5]1[CH:6]=[C:2]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: Clc1ncccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Clc1nccc(-c2cc(Br)cs2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in diethylether (30 ml) was added n-butyl lithium (2.5M in Hexanes, 4.55 mmol, 1.82 ml). The solution was maintained at this temperature for 1 hour before the addition of 2-chloropyrimidine (0.47 g, 4.13 mmol) in a single portion. The mixture was maintained at −78° C. for a further 1.5 hours before being allowed to warm up to room temperature. Ethyl acetate (20 ml) was added followed by DDQ (0.94 g, 4.13 mmol). The reaction was stirred for a further 30 minutes before being concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2) (7:3—Hexanes:EtOAc) to give the desired product (0.42 g, 37%) as a pale yellow solid which corresponded to the title compound. m/z (LC-MSW, ESP):275 [M+H]+, R/T=4.72 mins.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]1.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:32])[F:33])[CH:23]=2)(=[O:30])=[O:29])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]1
Reactant: CCC(=O)N1CCC(c2cc(N)ccc2OC)C1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Product: CCC(=O)N1CCC(c2cc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)ccc2OC)C1

Procedure:
1-[3-(2-Methoxy-5-amino-phenyl)-pyrrolidin-1-yl]-propan-1-one (0.44 g, 1.77 mmol) and commercially available 3-trifluoromethoxy-benzene sulfonylchloride (0.23 g, 0.89 mmol) were reacted as described above, to yield, after purification via silica gel chromatography using a ISCO Companion instrument, 0.198 g of the desired compound.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](Cl)=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH3:6]>O>[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10]([O:4][CH2:2][CH3:3])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH3:6]
Reactant: CCO
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Agent: [Na]
Solvent: O
Product: CCOC(=O)c1c(OCC)c2ccc(C)nc2n(CC)c1=O

Procedure:
To a solution of 0.11 g. (0.005 g. atoms) of sodium in 20 ml. of ethanol was added 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester. The mixture was heated under reflux for 4 hours. The mixture was cooled and was diluted with water. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 0.5 g. of the title compound, m.p. 77°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:43]=[CH:42][CH:41]=[CH:40][C:24]=1[CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C1(C)C=CC=CC=1.C(O)C.O.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][C:24]4[CH:40]=[CH:41][CH:42]=[CH:43][C:23]=4[F:22])[CH:30]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3F)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4F)c3)c3cc(Br)cnc32)cc1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
5-Bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate-1) (350 mg, 0.83 mmol) and 1-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate-2) (301 mg, 0.99 mmol) were added to a solution of toluene/ethanol/water (5/5/2.5 ml) previously purged with argon (10 min). The reaction mixture was purged with argon for a further 15 mins, followed by the addition of potassium carbonate (230 mg, 1.6 mmol) and Pd(PPh3)4 (48 mg, 0.0415 mmol). The resulting mixture was heated to reflux at 80° C. overnight. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was cooled and diluted with ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 285 mg (43.64% yield) of titled compound. MS: m/z=527.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:20])=[C:8]([CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[O:10])(=[O:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][S:22]([CH3:21])(=[O:24])=[O:23])=[C:8]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(C(=O)c2ccc(F)cc2F)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C(=O)c2ccc(F)cc2F)c1
Temperature: 0 °C

Procedure:
A mixture of 5-acetyl-2-amino-2',4'-difluorobenzophenone (3.3 g), methanesulfonyl chloride (5.5 ml) and pyridine (1 ml) in benzene (30 ml) was refluxed for 4 hours. The reaction mixture was poured into ice-water (100 ml ) and extracted with ethyl acetate (100 ml). The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue (5 g) was purified by column chromatography on silica gel (120 g) eluting with a mixture of toluene and ethyl acetate (20:1), and recrystallized from ethanol to afford yellow crystals of 4'-acetyl-2'-(2,4-difluorobenzoyl)methanesulfonanilide (1.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][CH:8]=[C:9]2[C:14](=O)OC(C)(C)OC2=O)=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)#[N:2].CCCCCC.S(Cl)(Cl)=O.[F:41][C:42]1[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[CH:45][C:43]=1[NH2:44]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C(O)(C)C.CN(C=O)C>[C:1]([C:3]1[CH:20]=[C:19]2[C:6](=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1)[N:7]=[CH:8][CH:9]=[C:14]2[NH:44][C:43]1[CH:45]=[C:46]([OH:50])[C:47]([CH3:49])=[CH:48][C:42]=1[F:41])#[N:2]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C#N)c(OCCCN3CCOCC3)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1cc(F)c(Nc2ccnc3cc(OCCCN4CCOCC4)c(C#N)cc23)cc1O
Temperature: 250 °C
Yield: 3 %

Procedure:
A mixture of 5-((4-cyano-3-(3-morpholinopropoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(2.96 g, 7 mmol) in DOWTHERM A, (trade mark of Fluka Chemie AG), (100 ml) was heated at 250° C. for 30 minutes. The mixture was allowed to cool, hexane was added and the solvent was decanted from the resulting gum. The residue was triturated with hexane to give crude 6-cyano-7-(3-morpholinopropoxy)-1,4-dihydroquinolin-4-one(1.0 g) as a brown solid. A portion of this product (380 mg, 1.3 mmol) was added to thionyl chloride (10 ml)and DMF (0.1 ml) and the mixture was heated at reflux for 3 hours. The volatiles were removed by evaporation and the residue was azeotroped with toluene (×3). 2-Fluoro-5-hydroxy-4-methylaniline (184 mg, 1.3 mmol), (prepared as described for the starting material in Example 1), in isopropanol (10 ml) was added to the residue, and the mixture was heated at reflux for 3 hours. The mixture was allowed to cool, the solid product was collected by filtration and recrystallised twice from methylene chloride/methanol/ethyl acetate to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(3-morpholinopropoxy)quinoline (05 mg, 3% overall).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.BrC1C=C(S(OC2C=CC(N3C(=O)CC(=O)NC4C5CCCCC=5C=CC3=4)=CC=2)(=O)=O)C=CC=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])[CH:28]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C1CC(=O)N(c2ccc(OS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3c(c2N1)CCCC3
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccnc3)cc2)c2ccc3ccccc3c2N1
Yield: 91.5 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (95 mg, 0.3 mmol) obtained in Example 1, (3), and nicotinoyl chloride hydrochloride (64 mg, 0.36 mmol), 5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (116 mg, yield 92%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.C(C=P(C)(C)C)#N>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(-c2ccc[nH]c2=O)cc1
Reactant: CN1CCC(O)CC1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccn(C3CCN(C)CC3)c2=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
Methyl 4-(2-oxo-1,2-dihydropyridin-3-yl)benzoate (316 mg) was suspended in toluene (7 mL), and 1-methyl-4-piperidinol (318 mg) and cyanomethylenetrimethylphosphorane (317 mg) were added thereto, followed by stirring at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=0% to 10%) to obtain methyl 4-[1-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl]benzoate (85 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][C:37]([NH:39][C@H:40]([C:45](OC2C=CC([N+]([O-])=O)=CC=2)=[O:46])[CH2:41][C:42]([NH2:44])=[O:43])=[O:38])=[CH:31][CH:30]=1>CN(C)C=O>[NH:39]([C:37]([O:36][CH2:35][C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1)=[O:38])[C@H:40]([C:45]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:46])[CH2:41][C:42](=[O:43])[NH2:44]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
20.93 g of H-Asn-Phe-NH-NH-BOC are dissolved in 45 ml of dimethylformamide with warming, mixed with 22.7 g of Z-Asn-ONP at room temperature, and stirred until the mixture solidifies. After standing overnight, the solid mass is dissolved in 160 ml of dimethylformamide with warming, precipitated by adding dropwise to 1 liter of ether, and the product is filtered off and washed with acetone until free of nitrophenol. Rf = 0.24 in chloroform-methanol (8:2).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:6]([Cl:26])[CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+].C(O)(=O)C>C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:6]([Cl:26])[CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2ccnn2Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A mixture of 0.553 g of 5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 1.70 g of stannous chloride dihydrate in 20 ml of ethanol is heated at 70°-80° C. for 1 hour. The mixture is chilled, made basic with 1M NaHCO3 and then stirred at room temperature for 0.5 hour. The mixture is brought to pH 5 with acetic acid and extracted (several times) with ethyl acetate. The combined extracts are dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 0.40 g of a glass, m.p. 98°-117° C.; Anal. Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N, 15.6; Cl, 11.7.