Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:16][C:17]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:18]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[O:15][CH2:18][C:17]([F:31])([F:16])[C:27]([F:30])([F:29])[F:28]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1OCC(F)(F)C(F)(F)F
Yield: 55.9 %

Procedure:
A solution of methyl 5-(methanesulfonyl)salicylate [101371-44-2] (0.50 g), trifluoro-methanesulfonic acid 2,2,3,3,3-pentafluoro-propyl ester (0.67 g) and potassium carbonate (0.60 g) in acetone was stirred at 60° C. for 5 hours. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound as a white solid (0.44 g). MS (m/e): 363.1 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([OH:13])[CH2:7][NH:8]C(C)(C)C)=[CH:4][C:3]=1[Cl:17].Cl.[CH3:19]O>>[ClH:16].[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([O:13][CH3:19])[CH2:7][NH2:8])=[CH:4][C:3]=1[Cl:17]
Reactant: CO
Reactant: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl
Product: COC(CN)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C

Procedure:
In 100 ml of methanol, 10 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is stirred in an ice bath and dry HCl gas is introduced into the solution. After saturation of the solution, the mixture is stirred at room temperature for an hour and evaporated to dryness. The solid is then stirred in ethyl acetate to afford the title product, which is collected by filtration.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl.O>CCOC(C)=O>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114, 1624-35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ 7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s, 1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s, 1H); APCI−MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46 H2O.0.2 EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:11]1(O[Si](C)(C)C)[CH2:13][CH2:12]1)C.C([BH3-])#N.[Na+]>CO>[CH:11]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:13][CH2:12]1
Reactant: OC1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OC1CCN(C2CC2)CC1
Reaction time: 12 h

Procedure:
5 g of 4-hydroxypiperidine were dissolved in methanol. 23.8 mL of 1[(1-ethoxycyclopropyl)oxy]trimethylsilane and 5.8 g of sodium cyano borohydride were added and the mixture was reacted at 60° C. for 12 h. The same amounts of the two reagents were added again and stirring was continued at 60° C. for another 12 h. The mixture was diluted with methanol, filtered over celite and evaporated to dryness. The residue was taken up in ethyl acetate, extracted twice with 2N sodium hydroxide and once with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography to yield 2 g of product 20, MS: 141 (M+)
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH2:18])[CH2:13][CH2:12]2.N12CCCN=C1CCCCC2>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH:18][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:13][CH2:12]2
Reactant: NC1CCc2cc(Br)ccc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C. and under protective atmosphere, a solution of 2-Propanesulfonyl chloride (11.87 mL, 121 mmol) in DCM (121 mL) was added gradually to a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (12.8 g, 60.4 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (4.83 mL, 32.1 mmol) in Dichloromethane (300 mL). The reaction was stirred at rt overnight. The reaction mixture was washed with 1N KHSO4 (1×) and sat NaHCO3 (2×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil. Purification by column chromatography (25% EtOAc in heptane) afforded the title compound as a white solid.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[C:22]3[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]=1[F:26].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C1COCC1>[F:26][C:9]1[CH:10]=[C:11]([O:12][C:13]2[C:22]3[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)[CH:24]=[CH:25][C:8]=1[NH:7][C:28](=[O:29])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Dry pyridine (125 μL, 1.55 mmol) was added to a suspension of 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (307 mg, 1.13 mmol) in dry THF (20 mL) under Ar and the mixture was cooled to 0° C. Phenyl chloroformate (170 μL, 1.35 mmol) was added dropwise over 5 min and the light brown mixture was stirred at 0° C. for an additional 5 min whereafter the mixture was allowed to warm up to RT and was stirred for 150 min. The brownish mixture was concentrated to dryness and the resulting residue was diluted with EtOAc (60 mL) and H2O (30 mL). The organic layer was isolated and filtered (80 mg of impure product) and the filtrate was washed with aqueous saturated NaHCO3 and brine. The organic layer was evaporated to dryness, re-dissolved in CH2Cl2 and chromatographed on a Biotage 25+M column, eluting with 20%→100% EtOAc in CH2Cl2 to give the title compound as a white solid. Yield: 280 mg (81%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C[N:11]1[CH:28]=[CH:27][C:15]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[N:14][C:12]1=[O:13])(O)=O>ClCCl>[Cl:4][C:2]([CH2:1][N:11]1[CH:28]=[CH:27][C:15]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[N:14][C:12]1=[O:13])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Solvent: ClCCl
Product: O=C(Cl)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of 1-(carboxymethyl)-N4 -(benzyloxycarbonyl)cytosine (15.3 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.CN1CCOCC1.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:27]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:24]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
Trifluoro-methanesulfonic anhydride (14.35 mL, 77.3 mmol) was added to a CH2Cl2 (150 mL) solution of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (11.40 g, 70.3 mmol), N-methylmorpholine (8.5 mL, 77.3 mmol) and DMAP (130 mg, 1 mmol) in 5 min at −80° C. The mixture was warmed to 0° C. in 1 h then poured into a cold solution of saturated NH4Cl. The mixture was diluted with CH2Cl2 (400 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the crude compound which was purified by column chromatography (silica, 0 to 60% CH2Cl2 in hexane) to provide the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(O)C>[Br:20][C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(OC(C)(C)C)c1cn2ccccc2n1
Solvent: CCO
Product: COC(=O)C(OC(C)(C)C)c1nc2ccccn2c1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-{imidazo[1,2-a]pyridin-2-yl}acetate (25c) (108 mg, 0.41 mmol) in ethanol (5 mL) at 0° C. was added N-bromosuccinimide (76 mg, 0.43 mmol) portionwise. The mixture was stirred at 0° C. for 15 minutes and concentrated in vacuo. The residue was dissolved in ethyl acetate (5 mL) and washed with a saturated solution of sodium hydrogencarbonate (2×5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (25d) (127 mg, 0.37 mmol, 90%) as a yellow oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].F[C:18]1[CH:29]=[CH:28][C:21]2[C:22](=[O:27])[N:23]([CH3:26])[CH2:24][O:25][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:16][C@H:12]([O:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([O:1][C:18]2[CH:29]=[CH:28][C:21]3[C:22](=[O:27])[N:23]([CH3:26])[CH2:24][O:25][C:20]=3[CH:19]=2)[CH:10]=1)[C:5]([OH:7])=[O:6])[CH2:13][O:14][CH3:15]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Reactant: CN1COc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)O)c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (175 mg, 0.77 mmol), 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (141 mg, 0.77 mmol) and potassium carbonate (321 mg, 2.32 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 16 hours then reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), the aqueous layer acidified with 1M citric acid and extracted into ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a brown oil (0.24 g). m/z 453 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]([C:16](=[O:18])[CH3:17])[CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(=O)N(CCc1ccccc1)Cc1c(C)noc1-c1ccc(Br)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CCc4ccccc4)C(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using N-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-N-phenethyl-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11](N)[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.C(OCC)(=[O:17])C>C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](=[O:17])[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(N)Cc1ccc2occc2c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Cc1ccc2occc2c1
Yield: 91 %

Procedure:
This amine was dissolved in 20 mL ethyl acetate and then a 1 N solution of hydrogen chloride in diethyl ether was added dropwise. The resulting slurry was filtered, the solid washed with 3 mL ethyl acetate, and the solid dried under vacuum to provide 0.548 gm (91%) of the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[C:21]1[N:26]=[C:25]([CH3:27])[N:24]([CH2:28][CH3:29])[C:23](=[O:30])[C:22]=1[CH3:31].O>O1CCOCC1>[CH3:27][C:25]1[N:24]([CH2:28][CH3:29])[C:23](=[O:30])[C:22]([CH3:31])=[C:21]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH2:8][C:7]3[CH:18]=[CH:19][C:4]([F:3])=[CH:5][CH:6]=3)=[CH:11][CH:12]=2)[N:26]=1
Reactant: OCc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCn1c(C)nc(Cl)c(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(C)nc(OCc2ccc(OCc3ccc(F)cc3)cc2)c(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Sodium hydride (55% in mineral oil) (0.23 g) was suspended in 10 ml of dioxane, and then 1.24 g of 4-(4'-fluorobenzyloxy)benzyl alcohol was added thereto. The resulting mixture was stirred for one hour at room temperature, then incorporated with 1.00 g of 6-chloro-2,5-dimethyl-3-ethyl-4(3H)-pyrimidinone and stirred for 15 hours. The resulting solution was poured into water, and the resulting crystals were filtered off and recrystallized from a benzene-hexane mixture to give 1.83 g of the intended product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([C:14]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:23]2[CH:22]=[N:21][C:20]([N:17]3[CH2:18][CH2:19][C:14]([CH2:12][CH3:13])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:15][CH2:16]3)=[N:25][CH:24]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3ccc(N)c([N+](=O)[O-])c3)cn2)CC1

Procedure:
To a solution of 4-bromo-2-nitroaniline (10.0 g, 46.07 mmol) in 1,4-dioxane (240 mL) and MeOH (140 mL) was added ethyl 4-ethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (21.59 g, 55.28 mmol) and potassium phosphate (14.69 g, 69.10 mmol) and the mixture degassed by purging N2 for 15 min
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=O.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.N.O>CN(C=O)C>[NH2:30][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
356 mg (1 mmol) of (Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 10 ml of DMF and combined with 194 mg (1 mmol) of CDI. The mixture is stirred for 2 hours at ambient temperature, 2 ml of methanolic ammonia solution are added, then stirring is continued for 16 hours at ambient temperature. Then water is added, the precipitate is removed by suction filtering, washed with water and a little ether and dried at 80° C.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:26]3[CH:25]=[C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:29]=[CH:28][CH:27]=3)[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-methanesulfonylaminophenylboronic acid (74 mg, 0.344 mmol), affords 37 mg (29%) of the Z-isomer (Example 206(a)) of the title compound as a colorless oil (MS (ES) 408 (M−H). HPLC shows 99% purity. Continue to elute and obtain 23 mg (18%) of the E-isomer (Example (b)) of the title compound as a colorless oil (MS (ES) 408 (M−H); HPLC shows 92% purity).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:14](OC)=[O:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2
Reactant: COCN1c2cc(C(=O)OC)ccc2Sc2nccnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCN1c2cc(CO)ccc2Sc2nccnc21
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Into a solution of 350 g of methyl 10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate in methylene chloride (2.5 l) was added dropwise under a nitrogen atmosphere 3.2 l of a 1.01 M solution of diisobutylaluminum hydride in toluene while maintaining the system at a temperature not exceeding 15° C. Then the reaction mixture was poured into ice and stirred for 1 hour. After filtering off the insoluble matter, the filtrate was washed with water. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were washed with diisopropyl ether to thereby give 250 g of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][NH:3]1.[CH3:15]I>>[CH3:15][N:3]1[CH2:4][CH2:5][C@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: CN1CC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-methyl-2-oxopyrrolidin-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxopyrrolidin-3-ylcarbamate (Example 6) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% acetone/hexanes to provide compound (2a) in 45% yield.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:21])([F:20])[C:10]1[C:11]([C:15]([O:17]CC)=[O:16])=[CH:12][NH:13][CH:14]=1.I[CH2:23][CH3:24]>O>[CH2:23]([N:13]1[CH:14]=[C:10]([C:9]([F:8])([F:20])[F:21])[C:11]([C:15]([OH:17])=[O:16])=[CH:12]1)[CH3:24]
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a mixture of 60% sodium hydride (212 mg, 5.31 mmol) and N,N-dimethylformamide (25 mL) was added with stirring at 0° C. ethyl 4-(trifluoromethyl)-1H-pyrrole-3-carboxylate (1.00 g, 4.83 mmol), and the mixture was stirred at room temperature for 30 min. Iodoethane (581 μL, 7.24 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (4 mL) and 8N aqueous sodium hydroxide solution (2 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr and at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give the title compound (710 mg, 71%) as a white solid.
Reaction SMILES: [CH2:1]([C@:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[OH:26])=[CH:11][C:10]=1[Cl:27])[CH2:5][OH:6])[CH:2]=[CH2:3].[OH2:36]>C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C@@:4]([CH2:1][CH2:2][CH3:3])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])=[CH:11][C:10]=1[Cl:27])[CH2:5][OH:6])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=CC[C@@](CO)(CCc1ccc(Sc2cc(C(F)(F)F)ccc2O)cc1Cl)NC(=O)OC(C)(C)C
Reactant: O
Solvent: CCOC(C)=O
Product: CCC[C@@](CO)(CCc1ccc(Sc2cc(C(F)(F)F)ccc2OC(=O)OC(C)(C)C)cc1Cl)NC(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A palladium on activated carbon/ethylene diamine complex (100 mg) was added to a solution of the compound of Example 33 (473 mg) in ethyl acetate (9 mL) to form a first reaction solution. This first reaction solution was stirred at normal temperature for 20 hours under hydrogen purging. The first reaction solution was filtrated through Celite, and the solvent was removed by distillation. The resultant residue was dissolved in acetonitrile (9 mL). Triethylamine (145 μL) and di-tert-butoxydicarbonate (284 mg) were added to this solution to form a second reaction solution. This second reaction solution was stirred at normal temperature for 2 hours and then left to stand overnight. Then, water was added to the second reaction solution, and the second reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the target product (434 mg) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C1COCC1.[CH3:29][NH2:30]>O>[CH3:29][NH:30][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CN
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CNCC(=O)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.1 g, 0.85 mmol) in THF (10 mL) diisopropyl ethyl amine (81 mg, 0.62 mmol) was added at 0° C. followed by methyl amine solution (30% solution, 10 mL). The reaction mixture was allowed to stir for overnight at room temperature. The reaction mixture was poured into a large volume of water (50 mL) and the solution was extracted with ethyl acetate. The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain the title compound (20.0 mg, 22.90% yield) as an off-white solid.