Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:43][C:44]1[S:45][CH:46]=[C:47]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:48]=1)=[O:34]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added thereto, and the mixture was stirred at room temperature for 30 min. Next, a solution of ethyl (2-amino-4-thiazolyl)acetate (76 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 23 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:29]([O:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][N:46]([CH2:49][C:50](O)=[O:51])[C:45](=[O:53])[N:44]=1)=[O:41])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:47]=[CH:48][C:43]([NH:42][C:40]([O:39][CH2:29][C:30]2[CH:38]=[CH:37][C:36]3[O:35][CH2:34][O:33][C:32]=3[CH:31]=2)=[O:41])=[N:44][C:45]1=[O:53])[CH3:2]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.71 (s, 1H), 9.22 (brs, 0.6H), 9.08 (brs, 0.4H), 8.40 (s, 1H), 8.07–7.96 (m, 2H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.02 (d, 0.6H), 7.00 (d, 0.4H), 6.99 (s, 1H), 6.91 (s, 2H), 6.02 (s, 2H), 5.08 (s, 2H), 4.81 (s, 1.2H), 4.64 (s, 0.8H), 4.37 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.08 (q, 1.2H), 3.62 (t, 1.2H), 3.47 (t, 1.2H), 3.43 (t, 0.8H), 3.28 (t, 0.8H), 1.24 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.Cl>C(O)CC(C)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH2:3][CH2:2][CH:1]([CH3:21])[CH3:6])=[O:19])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2ccc3n2CCCC3C(=O)O)cc1
Agent: Cl
Solvent: CC(C)CCO
Product: Cc1ccc(C(=O)c2ccc3n2CCCC3C(=O)OCCC(C)C)cc1
Reaction time: 24 h

Procedure:
A solution of 283 mg. of 3-p-toluoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid in 20 ml. of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue purified by chromatography on alumina, to yield isoamyl 3-p-toluoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate.
Reaction SMILES: S(=O)(=O)(O)O.O[C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[C@H:14]([CH3:26])[CH2:13][C:12]1=[CH:11][C:10](=[O:27])[CH2:9][CH2:8]2.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH3:26][C@@H:14]1[CH2:13][C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:27])[CH:11]=2)=[C:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H]1CC2=CC(=O)CCC2=C2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21

Procedure:
To 15 ml of concentrated sulfuric acid (98%) cooled to ˜5° C. was added dropwise ˜20 Mm of a mixture containing 10-hydroxy-7α-methyl-estra-4-ene-3,17-dione (III) and 5,10-dihydroxy-7α-methyl-estra-3,17-dione (IV) from example 2 dissolved in 15 ml of methylene chloride. About 20 minutes after the addition was complete, TLC ({fraction (1/1)} ethyl acetate/hexane, Rf 0.4) showed that the reaction was complete. The deep red reaction mixture was poured over ice, washed in with methylene chloride, partially neutralized with potassium carbonate, and the phases separated. The organic phase was washed with dilute aqueous potassium carbonate, brine, and dried over sodium sulfate, and concentrated under vacuum to a solid product. This material was column chromatographed on 150 g of silica gel with gradient elution from ⅓ to {fraction (1/1)} ethyl acetate/hexane. Fractions 6-9 were combined to give a solid which was recrystallized from ethyl acetate to provide the title product. Mp 208-209° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>>[ClH:1].[CH3:13][N:12]([CH3:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2
Reactant: CN(C)c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc2[nH]ccc2c1
Product: CN(C)c1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1
Product: Cl
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-6-dimethylaminoquinazoline was reacted with 5-aminoindole to give 6-dimethylamino-4-(5-indolylamino)quinazoline hydrochloride in 96% yield, m.p. 221°-226° C.;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([C:20](OCC)=[O:21])[C:11](=[CH:18][CH:19]=1)[CH2:12][C:13](OCC)=[O:14].O>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:20][OH:21])[C:11]([CH2:12][CH2:13][OH:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCc1ccc(Cl)cc1CO
Yield: 87 %

Procedure:
Lithium aluminium hydride (12 g) was suspended in dry ether (500 ml). A solution of diethyl 4-chlorohomophthalate (75 g) in ether (200 ml) was added dropwise to the above suspension over 30 minutes. The reaction mixture was heated at reflux for 2 hrs. Excess lithium aluminium hydride was decomposed carefully with water and the resulting mixture filtered through a pad of diatomaceous earth. The filtrate was partitioned between water (200 ml) and ether (800 ml). The organic layer was dried (magnesium sulphate) and evaporated in vacuo to a semi-solid which on trituation with petroleum ether (b.pt. 40°-60°) gave 2-(4-chloro-6-hydroxymethylphenyl)ethanol as a solid (45 g) m.pt. 75°-76°, characterised by its nmr spectrum.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[C:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)(=[O:10])[CH3:9].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C.O>[OH:4][CH2:9][C:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(=O)CO)cc1

Procedure:
Trifluoroacetic acid (3.5 mL; 47.1 mmol) was added to a solution of 4-acetylbenzonitrile (3.40 g; 23.4 mmol) and [bis-(trifluoroacetoxy)iodo]benzene (20.1 g; 46.7 mmol) in acetonitrile/water (5:1; 300 mL). The reaction mixture was heated under reflux for 18 hours. The solvent was removed in vacuo and the residue partitioned between DCM and 10% aqueous potassium carbonate. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (10:1 to 4:1) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.04 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 4.91 (d, J=2 Hz, 2H), 3.37 (t, J=2.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([O:16]C)=[O:15])=[CH:7][C:6]=2[CH:20]=1.CCO.O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:20]=1
Reactant: COC(=O)/C(=C/C=C/c1cc2cc(Cl)ccc2o1)OC
Solvent: O
Solvent: CCO
Product: CO/C(=C\C=C\c1cc2cc(Cl)ccc2o1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a stirred solution of methyl (2Z,4E)-5-(5-chlorobenzofuran-2-yl)-2-methoxy-2,4-pentadienoate (530 mg, 1.81 mmol) in EtOH/water 1/1 (40 ml) potassium hydroxide (0.43 g, 7.66 mmol) was added. The solution was stirred at RT overnight, then it was treated as seen in example 2. Pure title compound (330 mg, 1.18 mmol, yield 65.4%) was obtained as bright yellow crystals.
Reaction SMILES: Br[C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:16].CCCCCC.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C.Cl>O1CCCC1>[CH3:16][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)[CH:13]=[C:14]([CH3:15])[C:2]=1[B:28]([OH:33])[OH:29]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OC2CCSCC2)cc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OC2CCSCC2)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-thiopyran (3.01 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added dropwise n-butyllithium hexane solution (1.6 M, 6.57 mL, 10.5 mmol) at −78° C., and the reaction mixture was stirred for 1.5 hr at the same temperature. Triisopropyl borate (6.92 mL, 30.0 mmol) was added, and the mixture was stirred overnight, during which the mixture was allowed to warm to room temperature. The reaction mixture was ice-cooled, 2 M hydrochloric acid (50 mL) was added, and the mixture was stirred for 2.5 hr. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine and saturated aqueous sodium hydrogencarbonate while simultaneously adjusting to neutral. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with cool hexane to give the title compound (1.89 g, yield 71%) as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:10][CH:11]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>CS(C)=O>[O:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:9](=[O:8])[CH2:10][CH:11]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC(O)CN1CCOCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(CC(=O)CN1CCOCC1)Cc1cccc2ccccc12
Reaction time: 6 h
Yield: 66.6 %

Procedure:
2.3 g (14.7 mmole) of a sulfur trioxide/pyridine complex and 2.1 ml of triethylamine were added at room temperature to a solution of 1.96 g (4.91 mmole) of t-butyl 4-hydroxy-5-morpholino-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 12) dissolved in 20 ml of anhydrous dimethyl sulfoxide. The mixture was stirred for 6 hours, allowed to stand overnight and then mixed with water, after which it was extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 10: 90 by volume mixture of methanol and methylene chloride), to afford 1.30 g (66.7%) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>S(Cl)(Cl)=O>[CH3:12][CH:7]1[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9](=[O:11])[CH2:8]1
Reactant: CC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CC1CC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
As presented in the following reaction formula, a mixture of 3-phenylbutanoic acid (30 g, 0.18 mol) in thionyl chloride (SOCl2; 100 mL) was refluxed under heating for 2 hours, and then the thionyl chloride was removed. Toluene (200 mL) and aluminum chloride (AlCl3; 24 g, 0.18 mol) were added to the resulting mixture at 0° C., and the reaction mixture was stirred at 0° C. for 0.5 hours, followed by refluxing under heating. After the completion of reaction, the mixture was treated with ice water and then extracted twice with 200 mL of dichloromethane (DCM). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL), and dried and concentrated with magnesium sulfate to give a crude product. The crude product was purified by gel column chromatography (using 100 g of silica gel (product of Merck Co., Ltd.)) using an eluent of pentane (PE):ethyl acetate (20:1 (by volume)) to give 3-methyl-2,3-dihydro-1H-inden-1-one (16 g, yield: 60%) as a brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH3:14])[CH:10]([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[C:25]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)(=[O:29])=[O:28])=[CH:24][C:23]([Cl:41])=[CH:22][N:21]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([NH:26][C:25]2[C:20]([C:16]3[N:15]([CH:10]4[CH:11]([O:13][CH3:14])[CH2:12][NH:8][CH2:9]4)[CH:19]=[N:18][N:17]=3)=[N:21][CH:22]=[C:23]([Cl:41])[CH:24]=2)(=[O:29])=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:40])[F:38]
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CNCC1n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To 3-{3-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (71 mg, 0.11 mmol) was added 1:1 mixture of TFA-CH2Cl2 (2 mL) at room temperature and stirred for 2 h. Solvents were evaporated, 1:1 mixture of CH3CN—H2O (5 mL) and lyophilized to obtain 4-chloro-N-{5-chloro-2-[4-(4-methoxy-pyrrolidin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a white solid in quantitative yield. MS (ES) [M+H]+ expected 537.0. found 537.0.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOC(C)=O.C1COCC1>[Cl:16][C:17]1[C:22]([CH:34]([C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:32]=2)[OH:35])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Temperature: 0 °C

Procedure:
A THF (20 mL) solution of 2M n-BuLi in cyclohexanes was cooled to −78° C. and charged with 2,2,6,6-tetramethylpiperidine (1.8 mL, 10.48 mmol). The reaction vessel was removed from the cooling bath and allowed to warm to 0° C. for 15 min, then cooled back to −78° C. and charged with 2-chloropyrazine (1.0 g, 8.73 mmol) dropwise. The reaction was allowed to react for 15 min, and charged with a 10.0 mL THF solution of 3-benzyloxybenzaldehyde (2.0 g, 9.60 mmol) slowly at −78° C. The reaction was allowed to react for 2 h (TLC analysis (30% EtOAc:Hex)) and quenched with HClconc. (2.0 mL), and H2O (30.0 mL). The crude product was extracted from the aqueous/THF layer 4× with CH2Cl2. The organic layers were combined and washed 1× with H2O, 1×brine, dried over Na2SO4 and concentrated in vacuo, to yield the crude product as a brown oil. High performance flash chromatography (HPFC) with a 70 g Jones silica gel column (30% EtOAc:Hex) was applied to yield the desired product as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 5.01 (s, 3H), 6.00 (s, 2H), 6.90-6.96 (m, 3H), 7.23-7.41 (m, 6H), 8.36 (d, 1H, J=2.4 Hz), 8.54 (d, 1H, J=2.5 Hz); MS (ES) 327.16 (M+1), 329.16 (M+3).
Reaction SMILES: C([O:9][C:10](=[CH:15][C:16]1[CH:24]=[C:23]([CH3:25])[C:22]2[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])(=O)C1C=CC=CC=1.CO.[H][H].O.[OH-].[Li+]>O.[Pd]>[OH:9][CH:10]([CH2:15][C:16]1[CH:24]=[C:23]([CH3:25])[C:22]2[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[N:21]=2)[CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(=Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(CC(O)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A Parr bottle was charged with 1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxoprop-2-en-2-yl benzoate (1.0 g, 2.14 mmol), methanol (15 mL), and palladium (10% on charcoal, 100 mg). The Parr shaker was pressurized to 60 psi of hydrogen and shaken for 6 h. The reaction was filtered through celite and concentrated. The resulting residue was dissolved in tetrahydrofuran (8 mL) and methanol (8 mL) and cooled to 0° C. To this was added a solution of lithium hydroxide monohydrate (358 mg, 8.54 mmol) in water (8 mL). The reaction was stirred at 0° C. for 1 h, then at room temperature for 2 h. The reaction was concentrated, dissovled in water, cooled to 0° C., and acidified with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×). The organics were washed with a minimum of brine, dried over magnesium sulfate, and concentrated. Column chromatography (5% to 10% methanol/dichloromethane) gave 340 mg (45%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) 8-0.04 (s, 9H), 0.93 (m, 2H), 2.53 (s, 3H), 2.92 (m, 1H), 3.19 (m, 1H), 3.61 (m, 2H), 4.46 (bs, 1H), 5.68 (s, 2H), 6.93 (s, 1H), 7.31 (bs, 1H), 7.94 (bs, 1H). Mass spec.: 351.36 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[F:8][C:7]1[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Fc1cccnc1Cl
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncccc4F)cc23)n1

Procedure:
The compound of Example 155 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-fluoropyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Si:11](C#N)([CH3:14])([CH3:13])[CH3:12].C[C:18]#[N:19]>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([O:8][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:18]#[N:19])[CH:9]=1
Reactant: CC#N
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C[Si](C)(C)C#N
Agent: CN(C)c1ccncc1
Product: C[Si](C)(C)OC(C#N)c1cc(Br)ccc1F
Reaction time: 3.75 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (3.4160 g, 16.8 mmol) and DMAP (0.0256 g, 0.21 mmol, 0.012 equiv) in CH3CN (35 mL) was added TMSCN (1.8885 g, 19.0 mmol, 1.13 equiv) dropwise via a syringe under nitrogen at room temperature. After 3.75 h, the solvent was removed under reduced pressure. The crude product was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[CH3:11][C:12]([C:14](Cl)=[O:15])=[CH2:13].O>O1CCCC1>[C:14]([O:4][CH2:3][CH2:2][Cl:1])(=[O:15])[C:12]([CH3:13])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)OCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloroethanol of 6.7 ml (0.1 mol) and 8.9 ml (0.2 mol) of pyridine were added to 200 ml of tetrahydrofuran. A solution in which 10.7 ml (0.11 mol) of methacryl chloride was dissolved in 50 ml of tetrahydrofuran was added dropwise in 30 minutes to the resulting solution, stirred at room temperature for one hour, and mixed with water. The resulting mixture was extracted with ethyl acetate. The extraction solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-chloroethyl methacrylate. DABCO of 11.2 g (0.1 mol) and 11.5 g (0.1 mol) of benzyl chloride were added to 100 ml of ethanol and heated under reflux for 48 hours. The reaction mixture was filtered off to obtain a solid, and the solid was washed with acetone to obtain N-ethyl-DABCO monoammonium chloride (Compound D). Compound D of 11.9 g (0.05 mol), 7.4 g (0.05 mol) of 2-chloroethyl methacrylate, and 0.9 g (0.005 mol) of t-butylcatechol were added to 50 ml of ethanol and heated under reflux for 48 hours. The reaction mixture was filtered off to obtain a solid, and the solid was washed with acetone to obtain 10.5 g of ASM-4. The chemical structure of ASM-4 was confirmed according to 1H-NMR and IR.