Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:9][C:10]1[C:11]([C:2]#[C:1][C:3]2([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC1(O)CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclopentanol (35.8 mg, 0.33 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and CuI (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 5 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(1-hydroxy-cyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 32 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Br)cc1
Yield: 36.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-bromophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl) piperazin-1-yl]benzonitrile (1.0 g), the title compound (0.7 g) was obtained, melting point: 288° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:7]=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([N:27]=[C:28]=[O:29])=[C:20]([CH:30]([CH3:32])[CH3:31])[CH:19]=1.[H-].[Na+]>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:30]([CH3:32])[CH3:31])[C:21]([NH:27][C:28]([NH:16][S:13]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=2)(=[O:14])=[O:15])=[O:29])=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Reactant: CC(=O)c1cc(C(C)=O)cc(S(N)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)=O)cc(S(=O)(=O)NC(=O)Nc2c(C(C)C)cc(Cl)cc2C(C)C)c1
Yield: 40.3 %

Procedure:
The title compound was prepared as described in method A from 3,5-diacetylbenzenesulfonamide (0.35 grams), 4-chloro-2,6-diisopropylphenylisocyanate (0.37 grams), sodium hydride (0.06 grams of a 60% dispersion in mineral oil), in tetrahydrofuran (4 mL). This afforded 0.28 grams of the title compound, m.p. 201.9-203.4° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.S(O)(O)(=O)=O.[NH2:63][C:64]1[NH:65][CH:66]=[CH:67][N:68]=1.Cl>C(Cl)Cl.CN(C)C=O.O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:63][C:64]2[NH:65][CH:66]=[CH:67][N:68]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncc[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 2-aminoimidazole sulfate (87 mg, 0.659 mmol) in methylene chloride (4 mL) and N,N-dimethylformamide (1.5 mL) was stirred at 25° C. for 48 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow gel. This yellow gel was diluted with methylene chloride (5 mL), and an off-white solid precipitated. The off-white solid was collected by filtration, and then treated with acetone (5 mL). The acetone mixture was heated to a boil, allowed to cool, and then filtered to afford 3-cyclopentyl-N-(1H-imidazol-2-yl)-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (25 mg, 14%) as a white solid: mp 243-244° C.; EI-HRMS m/e calcd for C18H22N4O5S (M+) 406.1311, found 406.1311.
Reaction SMILES: [C:1]1([CH:7]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CCO.[BH4-].[Na+].O>CCOC(C)=O>[F:27][C:26]([F:28])([F:29])[C:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)=[CH:24][CH:23]=1)([OH:34])[C:30]([F:31])([F:33])[F:32]
Reactant: O=Cc1ccc(OCC(Oc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1ccc(OCC(Oc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
40 mg (0.08 mmol) of rac 4-{2-phenyl-2-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzaldehyde in 2 mL of a mixture of THF/EtOH (1:1) were treated with 31 mg (0.8 mmol) of NaBH4 at 0° C. The mixture was stirred at room temperature, water and EtOAc were added, and the phases were separated. The inorganic phase was extracted with EtOAc, and the combined organic ones were washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography on ISOLUTE Flash NH2 with EtOAc yielded 24 mg (59%) of rac 1,1,1,3,3,3-hexafluoro-2-{4-[2-(4-hydroxymethyl-phenoxy)-1-phenyl-ethoxy]-phenyl}-propan-2-ol as a colorless oil, MS: 485 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][N:6]=1.S(Cl)([Cl:12])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:7][CH2:8][Cl:12])=[N:4][S:5][N:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1nsnc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClCOc1nsnc1Cl
Yield: 79.3 %

Procedure:
A solution comprised of 5 g of 60 percent pure 4-chloro-3-methoxy-1,2,5-thiadiazole in 30 mL of carbon tetrachloride was irradiated over a period of 45 minutes at 80° C. with a sunlamp while adding a solution comprised of 5 g of sulfuryl chloride in 20 mL of carbon tetrachloride. The reaction mixture was then washed with 30 mL of asaturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to yield 4.87 grams of 4-chloro-3-chloromethoxy-1,2,5-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:16]1([N:19]([CH3:27])[C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][N:21]=2)[CH2:18][CH2:17]1>>[CH:16]1([N:19]([CH3:27])[C:20]2[N:21]=[CH:22][C:23]([NH:26][C:13]([C:3]3[C:2]([CH3:1])=[N:6][N:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:4]=3)=[O:15])=[CH:24][CH:25]=2)[CH2:18][CH2:17]1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Reactant: CN(c1ccc(N)cn1)C1CC1
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)C2CC2)nc1

Procedure:
With a procedure similar to example 16 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N2-cyclopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H20N6O (m/e) 348, obsd 349 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:21]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)#[N:22]
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c2c1NC(=O)CC2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc(C#N)c2c1NC(=O)CC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
8-Methyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one (4.0 g), zinc cyanide (3.34 g) and tetrakis(triphenylphosphine)palladium (0.299 g) were suspended in DMF (40 ml), and the suspension was stirred at 100° C. for 4 hours. The insoluble matter was filtered off, and ethyl acetate was added to the filtrate, followed by washing with water. After drying over anhydrous magnesium sulfate, the dry product was concentrated, and the residue was recrystallized from a DMF-ethanol mixed solvent to thereby obtain 2.1 g (yield: 87%) of 5-cyano-8-methyl-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](Cl)=[O:18])[CH:11]=[CH:10]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:20][CH:21]([C:29]([F:32])([F:31])[F:30])[C:22]([F:28])([F:27])[S:23]([O-:26])(=[O:25])=[O:24].[C:33]1([S+:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:28][C:22]([F:27])([S:23]([O-:26])(=[O:24])=[O:25])[CH:21]([O:20][C:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:8]=2)[CH:13]=1)=[O:18])[C:29]([F:30])([F:32])[F:31].[C:46]1([S+:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: C=C(C)C(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc2cc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.0 g (11 mmol) of the resulting 6-methacryloyloxynaphthalene-2-carboxylic acid chloride were added 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 1.1 g (11 mmol) of triethylamine and 0.2 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 3 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. The residue was washed with diisopropyl ether and purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(6-methacryloyloxy-naphthalene-2-carbonyloxy)-propane-1-sulfonate was obtained as colorless solid (6.5 g, yield 89%). The compound has the following structure.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[NH:7][C:6](=O)[CH:5]=1.[Br-].[Li+].[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)(=[O:17])[CH3:16]>CN(C=O)C>[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15](=[O:17])[CH3:16])[CH:5]=1
Reactant: CC(=O)OCCCCBr
Reactant: COc1nc(N)cc(=O)[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1nc(N)cc(CCCCOC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 8.2 g, 205 mmol) was added to a mixture of 6-amino-2-methoxy-4-pyrimidone (24.0 g, 170 mmol) in DMF at 0° C. After 0.5 hours, lithium bromide (19.2 g, 221 mmol) was added to the mixture and stirred for 0.5 hours at room temperature. The temperature was slowly increased to 70° C., and a solution of 4-bromobutyl acetate (50 g, 256 mmol) in DMF was added dropwise to the reaction mixture. The mixture was stirred at 70° C. for 3 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified by chromatography on silica gel using CHCl3/MeOH (1-5%) as eluent to give first 6.5 g (15%) of 6-amino-2-methoxy-4-(4-acetoxybutyl)pyrimidine as a white solid followed by 23.4 g (yield 54%) of 6-amino-2-methoxy-3-(4-acetoxybutyl)-4-pyrimidone as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cn(-c2ccc(Cl)cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(Cl)cc2C#N)c1CN(C)C
Yield: 17 %

Procedure:
As described for example 84b, 5-chloro-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and crystallization from ethyl acetate afforded the title compound as a white solid (yield: 17%). MS: m/e=275.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:28])[C:5]([C:24]([O:26]C)=[O:25])=[N:6][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[CH:8]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:4](=[O:28])[C:5]([C:24]([OH:26])=[O:25])=[N:6][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To a solution of methyl 5-methoxy-4-oxo-1-(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydropyridazine-3-carboxylate (2.58 g, 6.31 mmol) in MeOH (26 mL) was added 1 M NaOH aqueous solution (13 mL) at 0° C. The mixture was stirred at room temperature for 90 min. To the mixture was added 1 M HCl aqueous solution (13 mL) at 0° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (2.33 g, 94% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 8.06 (1H, d, J=10.2 Hz), 8.17 (1H, d, J=6.8 Hz), 8.82 (1H, s), 14.66 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[S:9][C:5]=2[C:4](=[O:27])[CH2:3]1.[H-].[Na+].[CH3:31]I>CN(C=O)C>[CH3:1][C:2]1([CH3:28])[CH2:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:31])[CH:18]=3)[S:9][C:5]=2[C:4](=[O:27])[CH2:3]1
Reactant: CI
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3Cc3c[nH]c4ccccc34)nc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CC2COCCN2c2nc3c(s2)C(=O)CC(C)(C)C3)c2ccccc21
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred solution of Example 24 (0.10 g, 0.25 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (0.01 g, 40% dispersion in oil, 0.28 mmol). After stirring at this temperature for 10 minutes, methyl iodide (0.02 mL, 0.28 mmol) was added. The reaction was stirred at r.t. for 1 h and then quenched by the addition of ice. The reaction mixture was then partitioned between EtOAc (15 mL) and water (10 mL) and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 1:1 EtOAc/hexanes) gave the title compound (0.08 g, 79%) as a white solid. δH (CDCl3) 7.79 (1H, d, J 7.7 Hz), 7.09-7.24 (3H, m), 6.90 (1H, s), 4.05 (2H, m), 3.82 (1H, d, J 12.0 Hz), 3.79 (1H, bs), 3.68 (3H, s), 3.57 (2H, m), 3.41 (2H, m), 2.95 (1H, m), 2.67 (2H, s), 2.34 (2H, s), 1.11 (6H, s). LCMS (ES+) 410.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3(OCC[O:15]3)[C:5]3[N:6]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1.S(=O)(=O)(O)O.N>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:4](=[O:15])[C:5]3[N:6]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Clc1cccc2c1C1(OCCO1)C1=NCCCN12
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=C1C2=NCCCN2c2cccc(Cl)c21
Temperature: 0 °C
Yield: 57.6 %

Procedure:
9'-Chloro-2',3',4',10'-tetrahydrospiro[1,3-dioxolane-2,10'-pyrimido(1,2-a)indole] (6.58 g) was added to cooled 98% sulphuric acid (35 ml) with stirring until complete solution was achieved (approx. 2 hours). The solution was poured on to ice (400 ml) and basified to pH9 with conc. ammonia solution. The resulting suspension of the product was stirred with chloroform (100 ml), and after separation, the aqueous phase was exhaustively extracted with further chloroform. Evaporation of the combined, dried (MgSO4) extracts left a brownish orange solid (4.83 g) which was crystallised from benzene to give 9-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one as dark orange prisms (3.16 g) darkening above 165° and melting at 170° with decomposition.
Reaction SMILES: C1OC1CO.C(N(CC)CC)C.[CH2:13]([O:20][CH2:21][CH:22]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]C1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C1C=CC=CC=1>[CH2:13]([O:20][CH2:21][CH:22]1[CH2:27][O:26][C:25]([CH3:28])([CH3:29])[O:24]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OCC(COCc2ccccc2)CO1
Agent: OCC1CO1
Solvent: CCN(CC)CC
Solvent: OCc1ccccc1
Product: CC1(C)OCC(COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Boron trifluoride-diethyl ether complex (0,9 ml,0.007 ml) was dropped in benzyl alcohol (92 ml) of glycidol (22.01 g, 0.3 mol) on ice bath. After dropping the mixture was stirred for 8 hours at 25° C. After the reaction was over, triethylamine was added thereto and benzyl alcohol was removed in vacuo. The desidue was dissolved in acetone and thereto p-toluenesulfonic acid was added. The mixture was reacted for 8 hours at 25° C. After the completion of the reaction triethylamine was added thereto and acetone was removed in vacuo. The crude product was distilled to give a mixture (43.8 g, yield 81%) of 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane and 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane. The ratio of the dioxolane and the dioxane was 8 to 1 by analysis with gas chromatography.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:27]([N:29]([C@@H:41]([CH3:49])[CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH2:47]([O:46][CH:42]([O:43][CH2:44][CH3:45])[C@@H:41]([N:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)[C:27](=[O:28])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH3:49])[CH3:48]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 51 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:23]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C=O)C>[C:23]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[N:11]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)=[O:37])=[CH:39][CH:40]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(NC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (90.9 mg), 4-benzamidobenzoic acid (87 mg) and 1-hydroxybenzotriazole (60.9 mg) in DMF (1.5 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg). The reaction mixture was stirred at room temperature for 2 hr, and poured into 0.5N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (98.0 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])OC(=O)[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:16][NH2:17]>C1COCC1>[NH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=1[C:8]([NH:17][CH3:16])=[O:13]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1N

Procedure:
7-Nitro-1H-3,1-benzoxazine-2,4-dione (1.14 g, 0.00549 mol) was dissolved in THF (50 mL, 0.6 mol). 2 M of Methylamine in THF (10 mL) was added, and a yellow solid formed immediately. The reaction mixture was concentrated under reduced pressure to afford a light orange solid.