Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH3:35])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:39]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][N:34]5[CH2:3][CH2:2][CH2:39][CH2:35]5)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)cs4)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCCC5)cs4)cc23)CC1
Yield: 24.1 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (0.083 mL) for 2 M methylamine to afford 14.8 mg of the title compound (24.1%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14][O:15][CH3:16]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[C:4]([CH3:13])=[C:5]([CH3:12])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:3]=[O:2]
Reactant: COc1cc(C)c(OC)c(C)c1C
Reactant: COC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C=O)c1C

Procedure:
1,4-Dimethoxy-2,3,5-trimethylbenzene, 9.00 g (50 mmole), was dissolved in CH2Cl2 (60 ml) and stirred with ice-cooling. After addition of 14.4 g (50×2.5 mmole) of dichloromethyl, methyl ether, 13.8 ml (50×2.5 mmole) of titanium tetrachloride dissolved in CH2Cl2 (30 ml) was added dropwise over 15 minutes. After stirring for further 15 minutes with ice-cooling, the ice bath was removed and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into crashed ice (about 200 g) and stirred vigorously for 30 minutes. The CH2Cl2 layer was washed with water (3 times), and dried (MgSO4), from which CH2Cl2 was evaporated off. The residue was recrystallized from isopropyl ether/hexane (1:1), to give 6.18 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was concentrated, and the residue was purified with silica gel (60 g) column chromatography (eluted with isopropyl ether), to give 3.70 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20](=[O:22])[CH3:21])[CH2:11][CH:10]2[CH3:29])=[O:8])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([N:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:20](=[O:22])[CH3:21])[CH2:11][C@@H:10]2[CH3:29])=[O:8])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccccc3)CC2C)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution N-[1-(4-Methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide (0.1 g) in dichloromethane (2.4 ml) at 0° C., was added boron tribromide (0.265 mmol). After 3 hours, ice and ethyl acetate were added and the solution was washed using water and carbonate potassium. The organic layer was separated and dried over sodium sulfate. The solvent was removed to afford an amorphous materiel. The product was purified by chromatography on silica gel using a mixture of dichloromethane and ethanol (95:5) as eluent to give the title compound (50 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[C:8]=3[CH:16]=2)[CH2:3][CH2:2]1.[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][NH:15][C:23]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:24])[C:8]=3[CH:16]=2)[CH2:2][CH2:3]1
Reactant: N#CCN1CCOc2ccc(C3CC3)cc21
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(NCCN1CCOc2ccc(C3CC3)cc21)C1CCCCC1

Procedure:
The procedure is as in Example 2, starting from the compound obtained in Step A and with the replacement of butyryl chloride with cyclohexylcarbonyl chloride.
Reaction SMILES: B.C1COCC1.[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:17]3=[CH:27][C:28]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:34][CH2:33]4)=O)=[CH:29][N:16]3[N:15]=2)=[C:10]([C:42]([F:45])([F:44])[F:43])[CH:9]=1.Cl>O1CCCC1>[CH3:26][C@@H:21]1[N:20]([C:18]2[C:17]3=[CH:27][C:28]([CH2:30][N:32]4[CH2:33][CH2:34][N:35]([S:38]([CH3:41])(=[O:39])=[O:40])[CH2:36][CH2:37]4)=[CH:29][N:16]3[N:15]=[C:14]([C:11]3[C:10]([C:42]([F:45])([F:43])[F:44])=[CH:9][C:8]([NH2:7])=[N:13][CH:12]=3)[N:19]=2)[CH2:25][CH2:24][O:23][CH2:22]1
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)cc2C(F)(F)F)nn2cc(C(=O)N3CCN(S(C)(=O)=O)CC3)cc12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)cc2C(F)(F)F)nn2cc(CN3CCN(S(C)(=O)=O)CC3)cc12
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
At −40° C., 1 M borane-THF (80 mL) was added dropwise to the solution of compound 24c (1.8 g, 3.17 mmol) in 50 mL of tetrahydrofuran. After the reaction proceeded 0.5 hours at this temperature, the reaction system was refluxed for 2 hours, and then cooled to below 0° C. 100 mL of concentrated hydrochloric acid was added dropwise and afterwards refluxed for 1 hour. When most of hydrochloric acid was removed by rotation evaporation, the pH of the solution was adjusted to about 8 by using saturated sodium carbonate solution. After extracted for three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by column chromatography with dichloromethane/methanol (40:1) to afford white solid (56.9%). m.p. 262° C. 1H NMR (300 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.68 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.77 (s, 2H), 4.87 (br s, 1H), 4.47 (br s, 1H), 3.96 (br s, 1H), 3.77-3.41 (m, 8H), 3.11 (s, 6H), 2.87 (s, 3H), 1.32 (s, 3H). LC-MS: 555 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(C(C)c3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=302.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (1-bromoethyl)benzene.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[CH:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:3]1[C:4]2[C:17]3[C:12]([C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]=2[CH2:1][CH2:2]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: [H][H]
Reactant: C1=Cc2c(c3ccccc3c3ccccc23)C1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)c1c(c3ccccc32)CCC1
Reaction time: 48 h

Procedure:
A mixture of 2 g cyclopentaphenanthrene, 0.2 g 10% palladium on carbon and 50 mL toluene was stirred under hydrogen (69 kPa) until hydrogen uptake ceased, about 48 h. Catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated. The crude product remaining weighed 1.97 g. It was further purified by recrystallization from heptane at −40° C. to give 1.8 g colorless plates. Spectroscopic and chemical analysis confirmed the identity of the desired compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]=[CH:12][N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:6]=1[OH:16].C(O)(=O)C>C(O)C.O1CCCC1.O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:6]=1[OH:16]
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(CC[N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To sodium borohydride (1.93 g, 51.2 mmol) suspended in ethanol (15 ml) at +10 to +15° C. is added a solution of 2-methoxy-4-(2-nitro-vinyl)-phenol (10.0 g, 51.2 mmol) in tetrahydrofuran (100 ml) over 1 h. Thereafter the reaction mixture is stirred at room temperature for 30 minutes. Acetic acid (4 ml) in water (100 ml) is then added carefully. The resulting mixture is evaporated to at about a quarter of its volume. It is extracted with ethyl acetate (1×100 ml, 1×50 ml) washed with brine (2×50 ml) dried (Na2SO4) and evaporated. 2-methoxy-4-(2-nitro-ethyl)-phenol (9.64 g) is obtained as an oil, which is purified by kugelrohr distillation (+150° C., 0.02 torr) yielding 7.3 g (72%) of purified material.
Reaction SMILES: ClCCC1N=CC=CN=1.OCCC1N=CC=CN=1.S(Cl)(Cl)=O.[NH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[C:35]([NH:37][C:38](=[N:41][CH3:42])SC)#[N:36]>>[C:35]([NH:37][C:38]([NH:41][CH3:42])=[N:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)#[N:36]
Reactant: NCCSCCc1ncccn1
Reactant: CN=C(NC#N)SC
Agent: ClCCc1ncccn1
Agent: OCCc1ncccn1
Solvent: O=S(Cl)Cl
Product: CNC(=NCCSCCc1ncccn1)NC#N

Procedure:
By the procedures of Example 17 using 2-(2-chloroethyl)pyrimidine, prepared by treating 2-(2-hydroxyethyl)-pyrimidine with thionyl chloride, as the starting material, 2-[2-(2-aminoethyl)thioethyl]pyrimidine is prepared, which when treated with N-cyano-N'.S-dimethylisothiourea by the procedure of Example 3(a) gives the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][S:34]([C:30]5[S:29][CH:33]=[CH:32][CH:31]=5)(=[O:36])=[O:35])[CH:5]=4)[CH:11]=[N:12][C:13]=3[CH:18]=2)=[O:20])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(NS(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide dihydrochloride (60 mg, 0.17 mmol) was dissolved in 2 mL pyridine at 0° C. and 2-thiophenesulphonyl chloride (31 mg, 0.17 mmol) was added in one portion to the mixture, and the reaction was stirred room temperature. After 16 h, the reaction mixture was concentrated in vacuo. The residue was purified using the Waters mass-directed HPLC purification system to yield N-pyridin-3-ylmethyl-1-{3-[(thien-2-ylsulfonyl)amino]phenyl}-1H-benzimidazole-5-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.60 (s, 1H), 8.48 (d, J=12.0 Hz, 2H), 8.30 (s, 1H), 7.90 (t, J=8.0 Hz, 2H), 7.69 (d, J=4.0 Hz, 1H), 7.55 (dd, J=1.2 Hz, 4.0 Hz, 1H), 7.48-7.43 (m, 3H), 7.37 (t, J=2.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 4.67 (d, J=5.4 Hz, 2H). MS (ES+): m/z 490 [MH+].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(-c2ccc(C#CC(O)CCc3cccnc3)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cccc(-c2ccc(CCC(O)CCc3cccnc3)cc2)c1
Yield: 35.3 %

Procedure:
A solution of 1-(3'-acetylbiphenyl-4-yl)-5-(3-pyridyl)pent- 1-yn-3-ol (0.7 g) in absolute ethanol (20 ml) was hydrogenated for 24 hours at 1.2 atmospheres using palladium on carbon (10%, 0.1 g) as catalyst. The reaction mixture was filtered through Celite® and the residue washed with ethanol. The combined filtrate and washings were concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (97:3) to give the title compound as a colourless oil (0.25 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][C:20]=2[O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(N)c(Oc2ccccc2)c1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2Oc2ccccc2)c1C(=O)OC
Yield: 71 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-methoxy-2-phenoxy-phenylamine (0.67 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting 0.9 g of the product at 8:2 hexanes-ethyl acetate, in 71% yield; 1H NMR (CDCl3) δ 3.74 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 6.60 (d, J=2.9 Hz, 1H), 6.69 (dd, J=8.7 Hz, J=2.9 Hz, 1H), 6.85-6.89 (m, 2H), 6.97-7.07 (m, 2H), 7.09 (dd, J=8.5 Hz, J=1.0 Hz, 1H), 7.22-7.29 (m, 4H), 7.84 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[S:10][CH:9]([CH2:11]O)[CH2:8][S:7]1.OCC1CSC[S:16]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[S:10][CH:9]([CH2:11][SH:16])[CH2:8][S:7]1
Reactant: OCC1CSC(c2cccs2)S1
Reactant: OCC1CSCS1
Product: SCC1CSC(c2cccs2)S1

Procedure:
The same method was followed as in Example 1 except that 2-(thiophen-2-yl)-4-hydroxymethyl-1,3-dithiolane produced in Example 5 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-(thiophen-2-yl)-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-9).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)Cl>C(Cl)(Cl)Cl>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: O=C(Cl)N1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)N4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.075 g, 0.25 mmol, Preparation #9) and TEA (0.041 mL, 0.29 mmol) in CHCl3 (1.2 mL) to give a brown suspension. Piperidine-1-carbonyl chloride (0.040 g, 0.27 mmol) was added and the reaction was stirred at ambient temperature for about 3 h. The reaction mixture was heated to about 45° C. for about 16 h. The mixture was cooled to ambient temperature, DCM (25 mL) was added, and the solution was washed with water and brine (about 5 mL each). The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)piperidine-1-carbohydrazide (0.11 g, 100%): LC/MS (Table 2, Method a) Rt=2.09 min; MS m/z: 415 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[CH:10][CH:9]=1>>[C:11]1([CH2:14][CH2:15][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=2)[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)CC(C)=O
Product: O=C(CCCc1ccccc1)CC(=O)CCCc1ccccc1

Procedure:
Using 2,4-pentandione (93.8 g, 0.94 mol) and β-phenethyl bromide (405 g), the reaction was carried out in the same manner as described in Example 17, (1), and the crude product (350 g) was purified by column chromatography on silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with benzene as eluent to give the title compound as a pale yellow oil which was an ca 1:5 mixture of Keto/Enol as seen by the methylene singlet at δ3.43 ppm and the methine singlet at δ5.42 ppm in the 1HNMR spectrum; yield: 66.9 g.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC4CC4)C4CCCC4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (13 mg, 0.023 mol) was stirred at room temperature in a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. The solvent was removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stilling for one hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (9 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:15]1[CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([C:25]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=4)[N:1]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc2nc(-c3ccc4c(c3)OCCO4)[nH]c(=O)c2cc1OC
Yield: 69 %

Procedure:
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (180 mg, 69%) was isolated as a light yellow solid. Selected data: MS (m/z): 341.03; MP 316.4-318.2° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]([N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH2:14][CH3:15])=[O:12])=[CH:8][O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([N:13]([CH2:14][CH3:15])[C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][CH:8]=2)=[O:12])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)c1cocc1C(=O)N(CC)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(C(=O)c1cocc1C(=O)O)c1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of 31.9 gm of 3-[(3,4-dimethoxy-phenyl)-2-ethylaminocarbonyl]-furan-4-carboxylic acid ethyl ester in 150 ml of methanol was admixed with 150 ml of 1 N sodium hydroxide, and the mixture was stirred for 45 minutes at 50° C. The reaction mixture was then neutralized with hydrochloric acid, the solvent was distilled off, and the desired reaction product was extracted from the residue with methylene chloride and crystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22]([OH:24])=O)[C@H:10]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[C:60]2[C:73](=[CH:74][C:75]=1[Cl:76])[CH2:72][C:62]1([C:70]3[C:65](=[N:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]1=[O:71])[CH2:61]2>CN(C=O)C>[Cl:76][C:75]1[CH:74]=[C:73]2[C:60](=[CH:59][C:58]=1[NH:57][C:22](=[O:24])[CH2:21][N:11]1[C:12](=[O:20])[C:13]3([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@H:10]1[C:25]1[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:61][C:62]1([C:70]3[C:65](=[N:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]1=[O:71])[CH2:72]2
Reactant: Nc1cc2c(cc1Cl)CC1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2cc3c(cc2Cl)CC2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.11 g (0.24 mmol) (R)-2-(1-(tert-butoxycarbonyl)-3-(3,5-difluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)acetic acid in 4 ml DMF were combined with 0.11 g (0.3 mmol) HATU and 0.07 ml (0.5 mmol) TEA and stirred for 5 min at RT. Then 70 mg (0.24 mmol) 5-amino-6-chloro-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[NH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([NH:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Nc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1CCC(Nc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The product from step (iii) above (1.2 g) was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (10 ml) added. After 72 hours at room temperature the reaction mixture was evaporated and residue triturated under ether to give the sub-titled product as a solid (1.6 g).