Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: c1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazol (0.71 ml, 10 mmol) in dry THF (20 ml) was added dropwise 1.6 M-BuLi in hexane (6.9 ml, 11 mmol) under argon at -78° C. The reaction mixture was stirred at -78° C. for 0.5 hr and Bu3SnCl (3.1 ml, 11 mmol) was added dropwise. After stirring for 1 hr at -78° C. and for 1 hr at room temperature, the mixture was concentrated, triturated with water (50 ml) and extracted with diethylether (100 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure to give (33) as colorless oil.(3.7 g, quant.).
Reaction SMILES: [S:1]([NH:11][NH2:12])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:13][CH:14]([Cl:17])[CH:15]=O>C(O)(=O)CC>[S:1]([NH:11][N:12]=[CH:15][CH:14]([Cl:17])[Cl:13])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: O=CC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCC(=O)O
Product: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Tosylhydrazine (234 g, 1.26 mol) was suspended in propionic acid (2 L) and dichloroacetaldehyde (142 g, 1.26 mol) was added at 15-20° C. The mixture was stirred at room temperature for 2 hours and under ice-cooling for 3 hours. The precipitated crystals were collected by filtration and washed with toluene. The crystals were dried under reduced pressure to give 2,2-dichloroacetaldehyde tosylhydrazone (247 g, yield 70%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)=O.[C:22]1([Li])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[O:1]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCc2ccccc21
Reactant: [Li]c1ccccc1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1CCC(=O)c1ccccc1
Temperature: -78 °C
Yield: 78 %

Procedure:
A reactor was charged with 2 mmol of tert-butyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (ai1) obtained in Synthesis Example 1 and 6.9 mL of tetrahydrofuran as a solvent to prepare a solution. After cooling the solution to −78° C. using dry ice, 2.0 mL (1.1 M, 2.2 mmol) of phenyllithium (PhLi) was slowly added dropwise to the solution. The mixture was reacted at −78° C. for 7 hours with stirring. The mixture including the reaction product was added to an ammonium chloride aqueous solution (5 mL), and the mixture was stirred. The mixture was extracted twice with ethyl acetate, and the reaction product was washed with a sodium chloride solution. After the addition of excess anhydrous magnesium sulfate to the collected organic layer, the solvent was evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=6/1) to obtain tert-butyl 2-(3-oxo-3-phenylpropyl)phenylcarbamate (white solid) represented by the following formula (an1) (yield: 78%). The analysis data for the resulting aniline derivative (an1) is shown below.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@@:3]([CH2:17][S@:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=O)([OH:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:7])[CH3:6].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[F:28][C:2]([F:1])([F:27])[C@@:3]([CH2:17][S:18][C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)([OH:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:6])[CH3:7]
Reactant: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
To a suspension of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (31.9 g, 76.6 mmol) and sodium iodide (34.4 g, 230 mmol) in 450 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (54.1 mL, 383 mmol) in 200 mL of anhydrous acetone via an addition funnel dropwise over 30 minutes. A greenish brown mixture formed instantaneously. After 15 minutes, the reaction mixture was quenched by slow addition of saturated aqueous sodium sulfite solution and neutralized with saturated aqueous sodium carbonate solution. The mixture became colorless and was concentrated in vacuo to remove most of the acetone solvent. The resulting material was diluted with 400 mL of water and extracted with three 400 mL portions of diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol as a yellow oil (31.0 g, 100%).
Reaction SMILES: CI.[H-].[Na+].[CH2:5]([C@:8]1([CH2:22][OH:23])[CH2:12][N:11]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:10](=[O:21])[CH2:9]1)[CH:6]=[CH2:7].[CH3:24]N(C)C=O>O1CCCC1.CO>[CH2:5]([C@:8]1([CH2:22][O:23][CH3:24])[CH2:12][N:11]([C@@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:10](=[O:21])[CH2:9]1)[CH:6]=[CH2:7]
Reactant: C=CC[C@@]1(CO)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: C=CC[C@@]1(COC)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methyl iodide (1.87 mL, 30.1 mmol) and sodium hydride (55% in liquid paraffin, 1.31 g, 30.1 mol) were sequentially added to a solution of (4R)-4-allyl-4-hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (7.09 g, 27.3 mmol) in tetrahydrofuran (80 mL)-dimethylformamide (20 mL) in a nitrogen atmosphere at 0° C. The mixture was heated to room temperature and stirred for one hour. Methanol (2 mL) was carefully added and stirred until gas was not generated. Then, the reaction was quenched with a saturated ammonium chloride solution (10 mL). The reaction solution was poured into a mixture of ethyl acetate (100 mL) and water (100 mL), followed by extraction with ethyl acetate (800 mL). The organic layer was sequentially washed with water (200 mL) and brine (200 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1→1:1) to give 7.42 g (99%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7])(=[O:4])=[O:3].C(OCC)C>[Pd].O.C(O)C>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cccc(N)c1
Yield: 84.6 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(methylsulphonylaminocarbonyl)-3-nitrobenzene (4 g, 16 mmol), 10% palladium on carbon (0.5 g, 12.5% (w/w)) in water (5 ml) and ethanol (100 ml), the title compound (2.9 g, 83%) was afforded as a tan powder after trituration with diethyl ether. mp 153°-155° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.3 (3H, s), 6.79 (1H, d, J=7.7 Hz), 7.05 (1H, d, J=7.7 Hz), 7.08 (1H, d, J=1.9 Hz), 7.13 (1H, dd, J=7.7 and 7.7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22]CC[C@H:19]([NH:23][C:24](=O)OC(C)(C)C)[CH2:18]4)[CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[C:15]([N:17]5[CH2:22][CH2:24][NH:23][CH2:19][CH2:18]5)[N:16]=4)=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH2:40][C:39]1=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)C1
Reactant: CN1CCNCC1=O
Product: CN1CCN(c2cc3c(-c4cccc(N5CCNCC5)n4)n[nH]c3cn2)CC1=O
Yield: 28 %

Procedure:
Following the procedure of Example 224, tert-butyl (3S)-1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate and 1-methylpiperazin-2-one were reacted and deprotected by the procedure of Example 229. The mixture was purified by lyophilization from water and trituration of the crude product with cold methanol. The solid material was collected by filtration to afford 52 mg (28%) of 223 over two steps. ESI MS m/z 393.2 (M+1). 1H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 9.07 (s, 2H), 8.81 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 3.95 (s, 2H), 3.88 (m, 6H), 3.48-3.44 (m, 2H), 3.31 (s, 4H), 2.91 (s, 3H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH2:34])[CH3:29].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25])[CH3:29]
Reactant: C#C[C@@H](N)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (1 g), 3(S)-ethynyl-β-alanine ethyl ester hydrochloride (0.48 g) and 1-hydroxybenzotriazole (0.37 g) in dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.5 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3-MeOH (99:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester as a pale yellow oil (1.34 g).
Reaction SMILES: [CH3:1][C:2](=[CH2:7])[CH2:3][NH:4][CH2:5][CH3:6].[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F)([O-:10])=[O:9]>>[CH3:7][C:2](=[CH2:1])[CH2:3][N:4]([CH2:5][CH3:6])[C:12]1[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9]
Reactant: C=C(C)CNCC
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Product: C=C(C)CN(CC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Treatment of N-2-methylallyl-N-ethylamine with 2,4-dinitrofluorobenzene as described in Example 1 gave N-2-methylallyl-N-ethyl-2,4-dinitrobenzeneamine as a red oil (13.0 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11](Cl)=[O:12].[OH-].[Na+]>ClCCl.O>[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:12]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of ethyl 2-aminoacetate hydrochloride (1.568 g, 11.24 mmol) in dichloromethane (9 mL) and water (2 mL) at 0° C. was added a solution of 2,4-dibromobutanoyl chloride (3.0 g, 10.21 mmol) in dichloromethane (2 mL). A solution of sodium hydroxide in water (11.5 M, 2 mL) was then added slowly. The reaction was stirred 1 hour at 0° C. and then 15 minutes at room temperature. The reaction was then treated with dichloromethane (40 mL) and water (25 mL). The layers were separated, and the organic layer was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried under vacuum to afford the crude title racemic compound (3.165 g in 90% purity, 84% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ ppm 6.81 (br s, 1H), 4.58 (dd, J=8.84, 4.80 Hz, 1H), 4.21-4.31 (m, 2H), 4.07 (d, J=5.56 Hz, 2H), 3.51-3.63 (m, 2H), 2.62-2.75 (m, 1H), 2.44-2.57 (m, 1H), 1.28-1.36 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:41][C:42]1[C:50]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>ClCCl>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:44]([C:43]3[CH:47]=[CH:48][CH:49]=[C:50]([C:51]([F:52])([F:53])[F:54])[C:42]=3[Cl:41])=[O:45])[CH2:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1cnc2n1CCNC2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Cl)cnc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
3-Chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I20) (450 mg, 2.86 mmol) and diethylaminomethyl polystyrene (2855 mg, 9.14 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (763 mg, 3.14 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford 911 mg of material that was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford a crude product which was further purified by MDAP to afford desired product in 373 mg.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1.[ClH:22]>[O-]S([O-])(=O)=O.[Cu+2].O>[Cl:22][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1
Reactant: CN1C(=O)C2CCCN2Cc2cc(N)ccc21
Reactant: Cl
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CN1C(=O)C2CCCN2Cc2cc(Cl)ccc21

Procedure:
A solution of 3,9 g. of sodium nitrite in 30 ml. of water is added over 10 minutes with stirring to a cooled (-10°to 0°C.) mixture of 11.5 g. of 7-amino-1,2,3,5,10,11a- hexahydro-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11- one, 13 g. of CuSO4. 5H2O, 60 ml. of concentrated hydrochloric acid and 40 ml. of water. The mixture is stirred for one hour without cooling, poured into 80 ml. of concentrated ammonium hydroxide and extracted with benzene. The benzene layer is washed with water and concentrated to remove the solvent. The residue is purified by partition chromatography in order to obtain the pure 7-chloro-1,2,3,5,10,11a-hexahydro- 10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one, which melts at 97°-99°C. The hydrochloride salt melts at 244°-246°C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[C:10]([NH:12][CH3:13])[CH:9]=[C:8]([CH3:14])[C:7]=1/[CH:15]=[CH:16]/[S:17]([N:20]1[CH2:41][CH2:40][C:23]2([N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=3)[NH:25][C:24]2=[O:39])[CH2:22][CH2:21]1)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:13])[C:1]([Cl:4])=[O:2])[CH:9]=[C:8]([CH3:14])[C:7]=1/[CH:15]=[CH:16]/[S:17]([N:20]1[CH2:21][CH2:22][C:23]2([N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:38])[F:37])[CH:29]=3)[NH:25][C:24]2=[O:39])[CH2:40][CH2:41]1)(=[O:18])=[O:19]
Reactant: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(N(C)C(=O)Cl)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
Phosgene (20% solution in toluene, 35 μL, 67 μmol) was added to a mixed solution of 8-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (30 mg, 56 μmol) and triethylamine (15 μL, 84 μmol) in dichloromethane (1.5 ml) and dimethylformamide (0.5 ml) at 0° C. The mixture was stirred at room temperature for three hours, and then quenched with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-chloroformamide (28 mg, 85%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16](/[N:18]=[C:19](/[NH:28][CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([NH:37][C:38](=[O:53])[CH2:39][N:40]([CH2:48][CH2:49][CH2:50]C=C)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[C:32]([Cl:54])[CH:31]=3)\[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:17])=[C:14]([CH3:55])[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:24]([O:23][C:21]([NH:20][C:19]1[NH:28][CH2:29][C:30]2[CH:35]=[C:34]([Cl:36])[C:33](=[C:32]([Cl:54])[CH:31]=2)[NH:37][C:38](=[O:53])[CH2:39][N:40]([C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:48][CH2:49][CH2:50][CH:3]=[CH:2][CH2:1][O:4][C:5]2[CH:10]=[CH:9][C:8](=[CH:7][CH:6]=2)[C:11]2[C:15](=[C:14]([CH3:55])[O:13][N:12]=2)[C:16](=[O:17])[N:18]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: C=CCCCN(CC(=O)Nc1c(Cl)cc(CN/C(=N/C(=O)c2c(-c3ccc(OCC=C)cc3)noc2C)NC(=O)OC(C)(C)C)cc1Cl)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Product: Cc1onc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CCCC=CCOc1ccc-2cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The intermediate (50 mg, 0.063 mmol) from Step 3(B) was dissolved in 15 mL of 1,2-dichloroethane, followed by the addition of Grubbs Catalyst 2nd Generation (17 mg, 0.020 mmol) with 1 mL of 1,2-dichloroethane. The resulted reaction mixture was stirred at 40° C. for 2 hrs. Solvent was evaporated in vacuo to give a crude product, which was purified by flash chromatography (15% EtOAc/DCM) to give two compounds, 11 mg of cis-3C (Rf 0.47) and 23 mg of trans-3C (Rf 0.28).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6](=[O:23])[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[C:9]#[N:10])[CH3:2].[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29]Br>O1CCOCC1>[Br:26][CH2:27][CH2:28][CH2:29][N:5]1[C:6](=[O:23])[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:9]#[N:10])=[C:4]1[S:3][CH2:1][CH3:2]
Reactant: BrCCCBr
Reactant: CCSC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCSC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1CCCBr
Reaction time: 48 h
Yield: 67.8 %

Procedure:
One dissolves 15.0 g 2-ethylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile in 500 ml abs. dioxan, adds 1.4 g sodium hydride (80%) in white oil) thereto and boils under reflux for one hour. One allows to cool somewhat, adds 100.0 g 1,3-dibromopropane thereto and further boils for 48 hours. Thereafter, the reaction mixture is filtered, the solvent and the excess dibromopropane are distilled off under water pump vacuum and the residue is triturated with diisopropyl ether. One obtains 14.0 g 1-(3-bromopropyl)-2-ethylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile of mp 97° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)=[CH:17][CH:16]=1)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:2][CH3:3].[N:32]1[C:41]2[C:40](=O)[CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:29]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:23][C:24]2[NH:28][CH:27]=[CH:26][N:25]=2)[CH:40]2[C:41]3[N:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH2:37][CH2:38][CH2:39]2)=[CH:19][CH:20]=1)[S:10]([CH3:13])(=[O:11])=[O:12])[CH2:30][CH3:31]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)S(C)(=O)=O
Reactant: O=C1CCCc2cccnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)C2CCCc3cccnc32)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.7 %

Procedure:
The compound (154 mg) obtained in Example 50-2 was dissolved in anhydrous methanol (6.2 ml) and added with 6,7-dihydro-5H-quinolin-8-one (75.1 mg) which was synthesized by a known method and sodium cyanoborohydride (64.1 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (69 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:3]=1[C:4]([O:6]CCCCCC)=O.[CH3:20][NH2:21].C[O-].[Na+]>>[NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:3]=1[C:4]([NH:21][CH3:20])=[O:6]
Reactant: CN
Reactant: CCCCCCOC(=O)c1cc(C#N)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 81.1 %

Procedure:
The above-described method (Example 3) was repeated to stir hexyl 2-amino-5-cyano-3-methylbenzoate (1.40 g, 4.89 mmol) with methylamine (10.8 g, 139 mmol, 40% in methanol) and sodium methoxide (441 mg, 0.12 mmol, 30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and stirred with diisopropyl ether. 2-Amino-5-cyano-N,3-dimethylbenzamide (0.75 g, 75.8% of theory, 93.6 area % LC) was obtained as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1)=[O:5])[CH3:2].Cl[C:22]1[N:27]=[N:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=4)[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:43][C:40]1[CH:41]=[C:42]2[C:37]([CH2:36][CH2:35][N:34]2[CH:31]2[CH2:32][CH2:33][N:28]([C:25]3[N:26]=[N:27][C:22]([C:10]4[CH:9]=[N:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=4)=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)=[CH:38][CH:39]=1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: CCOC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
Ethyl 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)acetate was prepared according to the procedure as described in Example 1, Method A, STEP 4, reacting 1-(ethoxycarbonylmethyl)pyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.