Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: O=C(Cl)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 3-trifluoromethylbenzoic acid with thionyl chloride affords 3-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 3-trifluoromethyl-N,N-diethylbenzamide. Following a procedure similar to that described in Example 22A, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylaminesulfonate affords 3-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 7-trifluoromethyl saccharin.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Temperature: 20 °C
Reaction time: 3.75 h

Procedure:
Preparation of (3R,3aR,6S,6aS)-Benzyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (34). Ethanol (6 mL) was added dropwise to a mixture of 10% palladium on charcoal (50 mg) and anti-(33) (547 mg, 1.26 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred at 20° C. for 3.75 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (40 mL) then the solvents removed in vacuo from the filtrate to obtain (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[N:4]=[C:3]1[C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[CH:23][CH:22]=1.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[C:26]1([N:25]2[C:21]([C:3]3[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH:8]4[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]4)[N:4]=3)=[CH:22][CH:23]=[N:24]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1ccn(C2CCCNC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 3-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]piperidine-1-carboxylate (15.9 g) in dichloromethane (76 mL) was added 4M hydrogen chloride in 1,4-dioxane solution (9.4 mL) at 0° C., and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure to give the title compound (12.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH2:20])(=[O:10])=[O:9].Cl.[N:26]1([C:31](N)=[NH:32])C=CC=N1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH:20][C:31]([NH2:32])=[NH:26])(=[O:10])=[O:9]
Reactant: N=C(N)n1cccn1
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A solution of 3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyamine (0.43 g, 0.0012 mol), as prepared in the preceding step, in anhydrous N,N-dimethylformamide (15 mL) was treated with 1H -pyrazole-1-carboxamidine hydrochloride (0.34 g, 0.0034 mol). The reaction mixture was stirred overnight at ambient temperature. An additional 100 mg of 1H -pyrazole-1-carboxamidine hydrochloride was added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under high vacuum. The residue was treated with acetonitrile, and the resulting crystalline material was collected by filtration and discarded. The filtrate was evaporated to dryness and partitioned between ether and water. The aqueous layer was washed with ether (4×25 mL). The aqueous layer was separated and basified with 2N sodium hydroxide, and the resultant aqueous layer was extracted with ethyl acetate (4×50 mL). The combined ethyl acetate extracts were washed with brine, dried, and evaporated to give 0.46 g of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ7.94 (d, J=7.6 Hz, 1H), 7.54-7.62 (m, 2H), 7.34-7.40 (m, 1H), 6.57 (br s, 1H), 6.48 (m, 2H), 5.75 (br m, 2H), 3.96 (t, J=6.2 Hz, 4H), 2.21 (s, 3H), and 2.05 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20ClN3O5S: 4.14.1 (M+H). Found: 4.14.2
Reaction SMILES: NC1N(C2C=CC=CC=2[O:13]C)N=CC=1C(N)=O.[NH2:18][C:19]1[N:23]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:22]=[CH:21][C:20]=1[C:29]#[N:30]>>[NH2:18][C:19]1[N:23]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:22]=[CH:21][C:20]=1[C:29]([NH2:30])=[O:13]
Reactant: N#Cc1cnn(CC(F)(F)F)c1N
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Product: NC(=O)c1cnn(CC(F)(F)F)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbonitrile provided the tile compound. 400 MHz 1H NMR (DMSO) δ 7.75 (s, 1H), 7.30 (brs, 1H), 6.78 (brs, 1H) 6.58 (m, 2H), 4.88 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:5])C.[CH3:16][C:17]1[N:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:20][C:21]=1[CH:22]=O>>[CH3:16][C:17]1[N:18]=[C:19]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[S:20][C:21]=1[CH2:22][NH:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:3])=[O:5])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Yield: 25 %

Procedure:
Experimental procedure analogous to that described for synthesis of compounds III-2a and III-3a but instead using (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.61 g, 2.97 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde to give 0.30 g (25% yield) of pure title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=7.87 Hz, 2H), 7.65 (d, J=8.24 Hz, 2H), 6.97 (d, J=8.42 Hz, 2H), 6.60 (d, J=8.61 Hz, 2H), 4.46 (s, 2H), 2.51 (m, 1H), 2.50 (s, 3H), 1.79 (m, 1H), 1.59 (m, 1H), 1.35 (m, 1H). ES-MS m/z 432 (MH+). [α]25,D=+128° (chloroform, c=3.8). Product was determined to be 96% ee by chiral SFC according to Method 2.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>CN(C=O)C>[Br:39][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCCC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCCCCC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of 6-cyclopentyl-hexan-1-ol (1.20 g, 7.06 mmol) in DMF (20 mL) was added triphenylphosphine (2.08 g, 7.93 mmol). The solution was cooled to 0° C. and NBS (1.36 g, 7.64 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford (6-bromo-hexyl)-cyclopentane (1.55 g, 94%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, t, J=6.9 Hz), 1.85 (2H, m), 1.73 (3H, m), 1.38–1.64 (6H, m), 1.24–1.38 (6H, m), 1.04 (2H, m); 13C NMR (75 MHz, CDCl3) δ 40.38, 36.37, 34.35, 33.12, 32.99, 29.33, 28.87, 28.49, 25.46.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Product: c1cn2nc(N3CCOCC3)c3c(c2n1)CCCC3
Temperature: 0 °C

Procedure:
A mixture of 10 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine and 20.9 g of morpholine was heated at reflux for 72 hours. The mixture was then poured into about 200 ml of ice water and a solid formed immediately. This was separated by filtration and air-dried to give 6-(4-morpholinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 160°-161° C. This compound has the following structural formula ##STR3##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
To a stirred solution of (E)-methyl 3-(2,4-dichlorophenyl)acrylate (5052 mg, 21.86 mmol) in THF (109.00 mL) at RT was added 2M NaOH (32.8 mL, 65.6 mmol) and the mixture allowed to stir for 24 hrs. The THF was removed under reduced pressure and on cooling HCl (37%) was added dropwise to the aqueous solution. A solid precipitated out of solution which was filtered and dried to afford the title product;
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18](/[CH:22]=[CH:23]/[C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[O:25])=[CH:17][C:16]=3[CH3:32])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43]/[CH:44]=[CH:45]/[C:46]2[CH:51]=[CH:50][C:49]([CH2:52]Cl)=[CH:48][C:47]=2[CH3:54])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18](/[CH:22]=[CH:23]/[C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH2:52][C:49]5[CH:50]=[CH:51][C:46](/[CH:45]=[CH:44]/[CH2:43][O:42][C:39]6[CH:38]=[CH:37][C:36]([CH3:35])=[CH:41][CH:40]=6)=[C:47]([CH3:54])[CH:48]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:17][C:16]=3[CH3:32])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC/C=C/c2ccc(CCl)cc2C)cc1
Reactant: Cc1cc(/C=C/C(=O)N2CCNCC2)cc(C)c1Oc1ccc(OCc2ccc(F)cc2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC/C=C/c2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(OCc6ccc(F)cc6)cn5)c(C)c4)CC3)cc2C)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 73.1 %

Procedure:
To a solution of (E)-3-[4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]-1-(piperazin-1-yl)prop-2-en-1-one (0.328 g) and (E)-3-[4-(chloromethyl)-2-methylphenyl]prop-2-en-1-yl 4-methylphenyl ether (0.204 g) in DMF (2 mL) was added DIPEA (0.13 mL) at room temperature under an Ar atmosphere. The mixture was stirred at room temperature for 20.5 hours, and then heated at 50° C. for 1 hour, and then cooled to room temperature, and evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to afford (2E)-3-[4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]-1-(4-{3-methyl-4-[(1E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazin-1-yl)prop-2-en-1-one (0.370 g) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]1([NH2:32])[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[C:25]1([NH:32][C:22]([C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)=[N:14][C:15]=3[CH:21]=2)=[O:24])[CH:30]=[CH:29][C:28]([NH:31][C:22]([C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=4)=[N:14][C:15]=3[CH:21]=2)=[O:24])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Reactant: Nc1ccc(N)cc1
Product: O=C(Nc1ccc(NC(=O)c2ccc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc3c2)cc1)c1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1

Procedure:
Compound 280 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinylphenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C42H38N8O4: 719.30; found: 719.12.
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([Cl:40])=[C:18]([NH:24][C:25]3[N:30]=[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)[C:28]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]4[N:26]=3)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:12][C@H:11]1[O:41][Si:42]([CH:49]([CH3:51])[CH3:50])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)CC)C>ClCCl>[Cl:40][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)[C:28]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]3[N:26]=2)=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][C@@H:10]([NH:9][C:1](=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6])[C@H:11]([O:41][Si:42]([CH:46]([CH3:48])[CH3:47])([CH:49]([CH3:51])[CH3:50])[CH:43]([CH3:44])[CH3:45])[CH2:12]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 174D, 19 mg, 0.031 mmol) and triethylamine (8.53 μl, 0.061 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. More 2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added and stirring continued over the weekend, still about 30% SM left. More triethylamine (100 μL) and 2-methoxyethyl carbonochloridate (20 μL) was added and stirred for another day. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0-40% ethyl acetate/dichloromethane) to give 2-methoxyethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (12 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]=[C:13]([CH3:14])[CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(=O)CBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(CCO)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 10 g of 2-(4-hydroxyphenyl)ethanol, 21.6 g of bromoacetone, 30 g of potassium carbonate and 100 ml of dimethylformamide, the title compound was obtained having an Rf=0.31 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Br[C:2]1[S:24][C:5]2[N:6]([CH2:22][CH3:23])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[S:24][C:5]=3[N:6]([CH2:22][CH3:23])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)sc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)sc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a suspension of 2-bromo-N-(4-chlorobenzyl)-7-ethyl4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide (Example No. 11) (0.500 g) in diethylamine (12 mL) is added copper iodide (0.067 g) and Pd(PPh3)2Cl2 (0.041 g) followed by addition of 3-butyn-1-ol (0.11 mL). The reaction is stirred at rt for 3 d. The diethylamine is removed in vacuo and the resulting residue is partitioned between H2O (50 mL) and CH2Cl2 (50 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organic layers are washed with a saturated NH4Cl solution (50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo. The resulting yellow solid is recrystallized from methanol to yield 0.312 g (64%) of the title compound as a pale yellow, crystalline solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[O:32][CH2:33][CH3:34])(=[O:3])[CH3:2].Cl[C:36]1[CH:45]=[C:44]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43]2)[C:37]=1[C:46]([O:48][CH3:49])=[O:47].Cl>BrCCBr.C1COCC1.Cl[Si](C)(C)C.[Zn]>[CH2:33]([O:32][C:25]1[CH:26]=[CH:27][C:28]([CH2:30][C:36]2[CH:45]=[C:44]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43]3)[C:37]=2[C:46]([O:48][CH3:49])=[O:47])=[CH:29][C:24]=1[C@H:6]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7]1)[CH3:34]
Reactant: CCOc1ccc(CBr)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: COC(=O)c1c(Cl)cc2cccccc1-2
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc3cccccc-3c2C(=O)OC)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Two drops of 1,2-dibromoethane was added to a suspension of zinc powder (0.17 g) in THF (5.0 ml) in an argon atmosphere and the mixture was refluxed with heating for five minutes. After cooling to room temperature, two drops of chlorotrimethylsilane was added to the reaction mixture. The mixture was stirred for 15 minutes. Next, (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol (1.4 g) was added to the reaction mixture and the mixture was refluxed with heating for one hour. After cooling to room temperature, tetrakistriphenylphosphine palladium (0) (0.27 g) and methyl 2-chloroazulene-1-carboxylate (0.28 g) were added to the reaction mixture. The mixture was refluxed with heating for six hours. After cooling to room temperature, the reaction mixture was poured into 10% aqueous solution of hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 2-(4-ethoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.58 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C)C=CC=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mechanically stirred solution of 1H-Indole-5-carboxylic acid (5-1, 20.01 g, 124 mmol) in THF (500 mL) was added at ambient temperature slowly a solution of 1M-LAH in toluene (186 mL, 186 mmol, 1.5 equiv). The reaction mixture was heated at reflux for 1 h, quenched with ice, partitioned between ethylacetate and saturated aqueous NaHCO3. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude product solidified upon standing under the reduced pressure. The crude solid was suspended in hexanes (200 mL) and ethyl acetate (10 mL), stirred overnight, collected by filtration and air-dried to afford the desired product as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 7.62 (s, 1H), 7.36 (d, 1H, J=8.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.20 (s, 1H), 6.54 (s, 1H), 4.75 (s, 2H), 1.68 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)=[C:20]([F:25])[CH:19]=1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.11 mL (0.97 mmol) of 4-chloro-2-fluoroaniline in 6 mL of 2-ethoxyethanol is heated at reflux temperature for 4 days. A catalytic amount of pyridine hydrochloride is added and the reaction mixture is heated at reflux temperature overnight then cooled to room temperature. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo to provide 120 mg (40%) of a beige solid, mp 259–261° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:18][CH:19]=1)[C:6](=[O:10])[CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)C(C)C

Procedure:
The title compound was prepared by the method of Preparation 1b using 4-methyl-3-oxopentanoic acid ethyl ester and 1-(4-bromomethylphenyl)-1H-pyrazole.