Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(OCCOC2CCCCO2)c(Oc2cccc(OC)c2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1

Procedure:
3.5 g of methyl 3-nitro-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in methanol (100 ml), treated with 0.5 g of Ra--Ni catalyst and hydrogenated at room temperature for 1 hour. The catalyst was filtered off and the solution was concentrated on a rotary evaporator. There was thus obtained the desired methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of N-(3,5-dichlorobenzyl)-5-fluoro-2-(methylsulfonyl)benzenamine (2.1 mmol), t-butyl piperazine-1-carboxylate (2.2 mmol), N,N-diisopropylethylamine (4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (23%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H), 5.70 (d, 1 H), 4.42 (d, 2H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 514.47; Observed: 515.6 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:16][C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([O:21]CC)=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[C:3]([S:16][C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([OH:21])=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1cccnc1Sc1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(cc1Sc1ncccc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 34 h
Yield: 84 %

Procedure:
To a solution of ethyl 2 - (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthylthio)nicotinate (Compound 12, 300 mg, 0.78mmol) and ethanol (8 mL) was added 2N KOH (2 mL) and the resulting solution stirred at 50° C. for 34 h. The solution was concentrated in vacuo, water added, and the mixture was acidified with 10% aqueous HCl. The product was extracted with methylene chloride (3×) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The solid residue was recrystalized from acetonitrile/methanol (4:1) to give the title compound (233 mg, 84%) as light yellow crystals:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:42])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH3:41])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH3:41])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:42])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: CNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-[3-(6-methyl-2-methylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K48) (188 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (88 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=O)=O.[Mg+2].[Al]>CC(C)=O>[CH2:34]([O:33][C:31]([C:30]1[N:26]=[C:24]([NH:23][C:12]2[C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[N:10][CH:11]=2)[S:25][CH:29]=1)=[O:32])[CH3:35]
Reactant: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)n1
Reaction time: 3 h

Procedure:
A solution of (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and ethyl bromopyruvate (30.4 mg, 0.140 mmol) in acetone (1.4 mL) in a conical vial was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was placed in an aluminum block preheated to 60° C. and was allowed to stir for 3.0 h. The reaction was cooled and concentrated. The residue was purified using a 5 g silica cartridge (MeOH/CH2Cl2, 1:99) to give 2-[1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-ylamino]thiazole-4-carboxylic acid ethyl ester as a pale yellow solid (42.2 mg; 68%). 1H-NMR (CDCl3): δ, 8.51 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 6.13 (s, 1H), 4.91 (d, 2H, J=4.7 Hz), 4.39 (q, 2H, J=7.0 Hz), 4.05 (s, 3H), 3.99 (s, 3H), 1.50 (s, 9H), 1.40 (t, 3H, J=7.3 Hz); MS: calculated for C23H28N4O6S+H 489.0; found: 489.0.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15]>CN(C=O)C>[CH2:12]([O:13][C:14](=[O:16])[CH2:15][N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]1=[O:3])[CH3:11]
Reactant: Oc1ccccn1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccccc1=O
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL of DMF was added 3.4 g (36.0 mmol) of 2-hydroxypyridine. The mixture was stirred 10 minutes then added to a solution of 3.3 mL (30.0 mmol) of bromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72 hours at rt. then concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water and washed with saturated aqueous NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using MeOH/chloroform as eluent and concentrated to dryness to yield 3.52 g (65%) of the desired product as a colorless oil. 1H—NMR is consistent with structure. MS (ion spray) 182.1 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C(O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:5]=2)=[O:3])=[CH:20][CH:21]=1
Reactant: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(/C=C/C(=O)c2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride was bubbled into an ice-cooled solution of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (1.0 g, 4.0 mmol) and p-anisaldehyde (0.55 g, 4.0 mol) in ethanol (15 ml) for 1 hour. The solution was stirred overnight at room temperature, then diluted with water and the yellow precipitate of present title product collected and dried (1.37 g, 93%); m.p. 177°-180° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:7]/[C:6]2[S:5][C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:3][C:2]=2[CH3:1])/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Cc1nc(-c2ccccc2)sc1C=O
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2sc(-c3ccccc3)nc2C)cc1OC
Yield: 92.1 %

Procedure:
4-Methyl-2-phenyl-1,3-thiazole-5-carbaldehyde (407 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 667 mg, 92%).
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH3:24])([CH3:23])[CH2:17][NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][C:16]1([CH3:24])[C:15]2[C:20](=[CH:21][C:12]([NH:11][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[F:1])=[CH:13][CH:14]=2)[C:19](=[O:22])[NH:18][CH2:17]1
Reactant: CC1(C)CNC(=O)c2cc(N)ccc21
Reactant: O=C(Cl)c1cccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CNC(=O)c2cc(NC(=O)c3cccnc3F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-fluoro-nicotinoyl chloride (283 mg, 1.79 mmol) and 7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (340 mg, 1.79 mmol) in CH2Cl2 (10 mL) was added NaHCO3 (573 mg, 7.16 mmol). The resulting mixture was stirred for 30 min at RT and filtered. The filtrate was concentrated and purified on silica gel column to yield the title compound as white solid. MS (ES+): 314 (M+H)+. Calc'd for C17H16FN3O2—313.12
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
The mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (320 mg, 0.9 mmol), tert-butylamine (0.5 mL, 4.5 mmol) and HATU (684 mg, 1.8 mmol) in 50 mL of dry THF was stirred for 4 hours at room temperature. The reaction mixture was evaporated to dryness, then the residue was suspended in 50 mL of 0.5 N HCl, product extracted with ethyl acetate (50 mL×3), dried with sodium sulfate, filtered and concentrated to give 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (258 mg, crude), material used in the next step without further purification. LCMS: (M+H)+=297/299; (M+Na)+=319/321.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[I:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:15]#[N:16].O.Cl>O1CCCC1>[I:11][C:12]1[CH:13]=[C:14]([C:15](=[NH:5])[NH2:16])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(C#N)cc1I
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=N)N)cc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 9.9 mL, 9.9 mmol) was added dropwise over 2 minutes to a cooled (10° C.) solution of 3-iodo-4-methylbenzonitrile (preparation 51a, 2.00 g, 8.2 mmol) in tetrahydrofuran (10 mL). After 1.5 hours, the mixture was cooled to 0° C. and water (20 mL) was slowly added. The pH was adjusted to 1 with 3M aqueous hydrochloric acid and then the mixture was stirred for 30 minutes. The aqueous layer was extracted with diethyl ether and ethyl acetate and then made basic with sodium hydroxide pellets which resulted in the separation of an oil. The mixture was extracted with ethyl acetate and the organic layer was dried and evaporated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (0.54 g, 25%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: COC1CC[C@]2(c3ccccc3F)NOC[C@@H]2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC1CC[C@@](N)(c2ccccc2F)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-(3aR*,7aS*)-7a-(2-Fluorophenyl)-5-methoxyoctahydrobenz[c]isoxazole obtained in Preparation Example 59-(5) (5.60 g) was dissolved in acetic acid (128 mL). Then, zinc powder (14.1 g) was added and the mixture was stirred at room temperature for eight hours. The solid was removed by filtration through celite, and then the celite was washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. Then, a saturated sodium bicarbonate solution was added, followed by vigorous stirring. The organic layer was separated and then the aqueous layer was extracted again with ethyl acetate twice. The combined organic layers were dried over anhydrous magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (5.49 g).
Reaction SMILES: I[Si](C)(C)C.C(#N)C.[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15]>O>[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C)(C)CCCCl
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: CC(C)(CCCCl)C(=O)O
Temperature: 80 °C
Yield: 109.3 %

Procedure:
Iodotrimethylsilane (3.00 g, 15 mmols) was added to an acetonitrile solution (5 ml) of ethyl 5-chloro-2,2-dimethylpentanoate (963 mg, 5 mmols) at room temperature, and heated at 80° C. for 24 hours with stirring. The reaction mixture was poured into water with ice, and extracted with ether. The organic layer was washed with water, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to obtain 0.9 g of 5-chloro-2,2-dimethylpentanoic acid as a brown oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COc1ccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2OC)C(C)(C)CCC3(C)C)cc1
Yield: 105.2 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 1.23 g (3 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 490 μl (3.6 mmol) of 4-methoxybenzyl chloride, 1.58 g (100%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCCCCCl
Yield: 95 %

Procedure:
A mixture of 16.6 g (0.1 mole) of acetovanillone, 34.3 g (0.2 mole) of 1-bromo-4-chlorobutane and 41.4 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil which readily crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 24.4 g (95%) of title compound as an off-white solid. An analytical sample, mp 68.5°-70.5° C., was prepared from isopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25](B(O)O)[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[CH:25][C:24]=3[CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(C)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3C)cccc2c1N
Yield: 73.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 5-methoxy-2-methyl-phenylboronic acid (125 mg, 1.000 mmol) were reacted to afford the title compound (125 mg, 73% yield). 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.88 (m, 1H), 7.76-7.64 (m, 2H), 7.21 (m, 1H), 6.92-6.81 (m, 2H), 3.79 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.97 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=351 (M+H). HPLC 1.77 min.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([OH:31])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:31][CH2:34][C@H:36]5[CH2:37][O:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Reactant: ClCC1CO1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC[C@H]1CO1
Yield: 8.9 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (320 mg, 0.712 mol) and (R) (−) epichlorohydrin (288 μL, 3.56 mmol) were reacted using the same procedure as described before from Example 111A to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (160 mg, 44%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:24]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]=[C:33]=[O:34])=[O:31])=[CH:28][CH:27]=1)#[N:25]>C(#N)C>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33](=[O:34])[NH:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)=[O:31])=[CH:35][CH:36]=1)#[N:25]
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Yield: 52.6 %

Procedure:
Methyl 4-aminophenoxyacetate, hydrochloride salt (1.09 g), was dissolved, with warming, in acetonitrile (50 ml) containing diisopropylethylamine (0.86 ml). To this solution at ambient temperature was added gradually with stirring a solution of 4-cyanobenzoyl isocyanate (1 g, preparation described in Weikert, R. J. et al (1991), J. Med. Chem. 34, 1630) in acetonitrile (5 ml). The precipitated solid was crystallised from boiling acetonitrile to give methyl 4-[3-(4-cyanobenzoyl)ureido]phenoxyacetate (930 mg) as an off-white solid: m.p. 214°-217° C.; NMR Spectrum (DMSO-d6) 3.70 (3H, s), 4.77 (2H, s), 6.94 (2H, d), 7.48 (2H, d), 8.02 (2H, d), 8.12 (2H, d), 10.49 (1H, s), 11.19 (1H, s); Mass Spectrum m/Z 354 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:8]=1)(=O)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].O1CCC[CH2:31]1>C1(C)C=CC=CC=1.CCOCC>[C:21]([C:5]1[C:4]([C:1]([CH3:31])=[CH2:2])=[CH:8][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:6]=1)#[N:22]
Reactant: C1CCOC1
Reactant: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C(C)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-acetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.75 g) in tetrahydrofuran (5 ml) cooled to −40° C. under an atmosphere of nitrogen was added μ-chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminium (5.18 ml of a 0.5M solution in toluene) and the mixture was stirred for 15 minutes then allowed to warm to room temperature. After 2 hours at room temperature 0.1M aqueous sodium sulphate solution was added dropwise until effervescence ceased. The reaction mixture was diluted with ether (50 ml), washed with aqueous sodium sulphate solution, dried and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions provided the title compound as a tan solid m.p. 63-64° C.
Reaction SMILES: [C:1]([CH:4]([C:11](=[O:13])[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].Cl.[NH2:15]O.CC([O-])=O.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[O:13][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)noc1C
Yield: 3.4 %

Procedure:
A mixture of ethyl 3-acetyl-4-oxopentanoate (37.24 g, 0.2 mol), hydroxylamine hydrochloride (14.6 g, 0.21 mol), NaOAc (17.23 g, 0.21 mol) and ethanol (500 mL) was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was heated in acetic acid (12.61 g, 0.21 mol) and toluene (300 mL) for 6 to 6.5 hours with the removal of water. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford a tan oil which crystallized on cooling. The product was collected by filtration and washed with ether to afford 1.26 g of ethyl 3,5-dimethyl-4-isoxazolylacetate, m.p. 180-182° C. Additional product was obtained by concentration of the ether filtrate and distillation of the residue at 69-81.5° C. and 0.05 mm Hg to afford a total of 31.18 g (85%).