Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14])=[N+:2]=[N-:3].C[O:16][C:17](=[O:28])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O.[O-]CC.[Na+]>CCO>[Cl:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:5]([O:13][CH3:14])=[C:4]([N:1]2[C:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[C:18]([C:17]([OH:28])=[O:16])[N:3]=[N:2]2)[CH:9]=1
Reactant: COc1cc(OC)c(N=[N+]=[N-])cc1Cl
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)c(-n2nnc(C(=O)O)c2-c2ccc(F)cc2)cc1Cl

Procedure:
1-Azido-5-chloro-2,4-dimethoxy-benzene (0.4 g, 1.9 mmol), 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester (0.42 g, 2.2 mmol) and sodium ethoxide in EtOH (70 mg of sodium in 15 mL EtOH) were refluxed for 3 hours. During the reaction, the solution turned brown from dark green. After that, EtOH was evaporated off and the resulting oil was dried in vacuum. Trituration with ether (15 mL) gave light brown solids, which were removed by filtration and washed with ether. The solids then re-dissolved in CHCl3 and filtered. After evaporation of the solvent, light brown solids were obtained (0.35 g, 50%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]([CH3:11])([CH3:10])[C:8]#[CH:9].C(N(CC)CC)C>[Cu]Cl.C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]([CH3:11])([C:8]#[CH:9])[CH3:10])[CH3:2]
Reactant: C#CC(C)(C)Cl
Reactant: CCNCC
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.3 %

Procedure:
Prepared using methodology described by Zaragoza, F., et al. J. Med. Chem. 2004, 47, 2833. To a stirred mixture of diethylamine (10.3 mL, 99.6 mmol), 3-chloro-3-methylbut-1-yne (10.2 g, 99.6 mmol), triethylamine (16.7 mL, 119 mmol), and THF (100 mL) at 0° C. was added copper(I) chloride (0.986 g, 9.96 mmol). The resulting suspension was allowed to warm to room temperature, and stirring continued for 4 hours. The reaction mixture was partitioned between diethyl ether (250 mL) and a saturated aqueous solution of NaHCO3 (100 mL). The phases were separated, and the aqueous phase was re-extracted with diethyl ether (100 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. The brown oil was distilled (105-110° C.) at atmospheric pressure under N2. The product was obtained as an oil (1.85 g, 9%). 1H NMR (400 MHz, CDCl3) δ 2.66 (q, J=7 Hz, 4H), 2.21 (s, 1H), 1.40 (s, 6H), 1.08 (t, J=7 Hz, 6H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.C1(=O)O[C:27](=[O:28])[CH2:26]C1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27](=[O:28])[CH3:26])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
N1-Cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (830 mg), succinic anhydride (270 mg) and toluene (30ml) were refluxed together for 30 minutes. After adding 50 ml of acetic anhydride and 82 mg of sodium acetate to the reaction solution, the mixture was stirred at 80° C. for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate). The second eluted substance was N1-cyclopropyl-5-{[2-(2,5-dioxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide, of which 440 mg was obtained as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][CH:5]([C:19](=[O:44])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][OH:27])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:46][CH2:47][O:48][P:49](Cl)([O:51][CH2:52][CH3:53])=[O:50]>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:19](=[O:44])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)(=[O:34])=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][O:27][P:49]([O:51][CH2:52][CH3:53])([O:48][CH2:47][CH3:46])=[O:50])[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)NC(C(=O)NCCCCC(CO)N(CC(C)C)S(=O)(=O)c1ccc(N)c(F)c1)C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Product: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(N)c(F)c1

Procedure:
The product of step A was phosphorylated with chlorodiethylphosphate following the procedure described in example 1, step G. Yields 157 mg, 68%.
Reaction SMILES: [CH2:1]([O:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([O:12][C:13]1[S:14][C:15]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCOc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-undecanoxy-thiophene (4.23 g, 16.6 mmol) in dry THF (80 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 10 mL, 25.0 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 25 mL, 25.0 mmol) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and the reaction mixture was diluted with hexane (250 mL), washed with water (100 mL×2), dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (6.94 g, 100.0%), which was directly used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([N:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:4][C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc2c(O)cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155 %

Procedure:
4-hydroxy-2-methyl indole 1 (50 g, 0.339 mole) was dissolved in anhydrous DMF (1 L). To the mixture sodium hydride 60% in mineral oil (27.9 g, 0.697 mole) was added. The mixture was left to stir at rt. for 1 h. To the mixture benzyl bromide (82.7 mL, 0.697 mole) was added drop-wise. The mixture was left to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (4 L) and washed with water (5×500 mL) then brine (1 L). The organic layer was separated and dried with magnesium sulphate and concentrated. The orange oily residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 86 g (72%) of 2 as an yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 94.2 %

Procedure:
3.9 g (20 mmole) of 7-hydroxy-2-methylchromen-4-one, 4.4 ml (40 mmole) of 1-bromo-3-chloropropane and 6.1 g (40 mmole) of anhydrous potassium carbonate in 100 ml of acetone were mixed and refluxed under heating for 16 hours. The mixture was allowed to cool and the insoluble solid was separated by filtration. The filtrate was evaporated to dryness, and the residue obtained was suspended in ethyl ether, filtered, washed with ether and dried at vaccum to yield 4.76 g (85%) of the product, melting point 113°-115° C.
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].S(OC)(O[CH3:30])(=O)=O>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)([CH2:16][O:17][CH3:30])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(CC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1(Cc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium hydride (0.40 g, dry weight, 10 mmol; obtained from washing 0.97 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (45 mL), N-tert-butoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine (1.89 g, 5.9 mmol) in THF (15 mL) was added. The resultant mixture was stirred at room temp. for 1 h, and treated with dimethyl sulfate (1.13 mL, 11.9 mmol). The reacting mixture was stirred at room temp. overnight. The product mixture was cooled to 0° C., quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:27]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution N1-(4-methoxybenzoyl)-1,2-benzenediamine hydrochloride (558 mg, 2.08 mmol) in methylene chloride (100 mL) was added 0.5 N aqueous sodium hydroxide (8 mL) and the resulting mixture was cooled in an ice-water bath. 2,4-Dimethoxybenzoyl chloride (0.40 g, 2.0 mmol) was added slowly with vigorous stirring. The mixture was allowed to warm slowly to room temperature and stirred for 18 h. The organic layer was separated and washed with dilute aqueous sodium bicarbonate solution, dilute aqueous hydrochloric acid, and water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 0.52 g (64%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccco3)c2n1
Reactant: C1CNCCN1
Product: c1coc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(furfuryl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 139°-141° C.) and piperazine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH:34]([OH:37])[CH2:35][OH:36])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH:34]([OH:37])[CH2:35][OH:36])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Reaction time: 1 h
Yield: 119.5 %

Procedure:
To tert-butyl(1-(2-(7-(1,2-dihydroxyethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (2 mg, 0.004 mmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was then stirred for 1 hour, then concentrated and purified by flash column chromatography (DCM/MeOH/NH4OH 20:1:0.1), affording the final product as a white solid (0.002 g; quantitative yield). MS ESI (+) m/z 419 (M+1) detected.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]([O:12][CH3:13])[CH:4]=1)=[CH2:2].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=2)=[C:5]([O:12][CH3:13])[CH:4]=1)=[CH2:2]
Reactant: C=Cc1cc(OC)c2cc[nH]c2c1
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a solution of 6-ethenyl-4-(methyloxy)-1H-indole (D8) (665 mg, 3.84 mmol) in dichloromethane (20 mL) was added 3-fluoro-4-methoxyphenylboronic acid (1.31 g, 7.71 mmol), triethylamine (1.1 mL, 7.91 mmol), copper (II) acetate (1.39 g, 7.68 mmol) and powdered 4A molecular sieves (1.0 g). The reaction mixture was stirred at room temperature in the presence of air for 18 hours. Further quantities of 3-fluoro-4-methoxyphenylboronic acid (330 mg), triethylamine (0.28 mL) and copper acetate (340 mg) were added and the mixture stirred at room temperature in the presence of air for a further 48 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was purified by silica gel chromatography eluting with 5-50% dichloromethane in hexane to yield the title compound (D9), (541 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.Cl[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:23]#[N:24])[CH:14]=1)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[Cl:2][C:3]1[S:7][C:6]([NH:8][S:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:23]#[N:24])[CH:14]=2)(=[O:12])=[O:11])=[N:5][CH:4]=1
Reactant: Nc1ncc(Cl)s1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1C#N
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a solution of 5-chloro-1,3-thiazol-2-amine hydrochloride (1.15 g, 6.7 mmol, 3 eq) in pyridine (7.5 ml) was added methyl 4-(chlorosulfonyl)-2-cyanobenzoate (Preparation 20, 580 mg, 2.2 mmol, 1 eq) portionwise and the reaction mixture was stirred at room temperature for 1 hour. The mixture was slowly added to 6M HCl (40 ml) and the resulting precipitate was collected by filtration and triturated with MeOH to yield the title compound as a brown solid (138 mg, 0.38 mmol, 17%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]COC)=[CH:9][CH:8]=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5].[Si](Cl)(C)(C)[CH3:17]>CO>[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([F:15])[C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: COCOc1ccc(F)c(C(=O)O)c1F
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1c(F)ccc(O)c1F
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a solution of 2,4-difluoro-1-(methoxymethoxy)benzene (2.00 g, 11.5 mmol) in THF (30 mL) under nitrogen at −70° C. was added a solution of n-butyllithium in hexanes (1.4 M, 8.20 mL, 11.48 mmol) dropwise over 10 min. The mixture was stirred at −70° C. for 1.5 hr and was then decanted onto freshly pulverized dry ice (˜20 g). Once the effervescence had subsided the mixture was allowed to warm to RT and water (20 mL) was added. The aq solution was extracted twice with ether and was then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting suspension was sonicated for 5 min and was then extracted twice with DCM and the combined DCM extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with a mixture of isohexane and ether (50:3 v/v) to furnish 2,6-difluoro-3-(methoxymethoxy)benzoic acid as a white solid (1.99 g, 77% yield); Rt 2.31 min (Method 1, basic); m/z 219 (M+H)+ (ES+), which was used directly in the next step (below). To a solution of 2,6-difluoro-3-(methoxymethoxy)benzoic acid (2.74 g, 12.6 mmol) in MeOH (50 mL) was added TMS-Cl (7.94 mL, 62.8 mmol) dropwise and the resulting colourless solution heated at reflux for 3 hr. The resulting mixture was cooled to RT and was then evaporated in vacuo and the residue was subjected to SCX capture and release to afford methyl 2,6-difluoro-3-hydroxybenzoate as a white solid (2.38 g, 100%); Rt 2.29 min (Method 1, basic); m/z 187 (M−H)− (ES−).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=2)O1>>[NH2:48][C:45]1[N:46]=[CH:47][C:42]([C:2]2[N:3]=[C:4]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][CH:21]5[CH2:26][CH2:25][CH2:24][CH2:23][O:22]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:43][CH:44]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C(COC1CCCCO1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)COC5CCCCO5)CC4)cc3n2)cn1

Procedure:
1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone prepared via General Procedure B-3 (250 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 1-(4-((2-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].C(N(CC)CC)C.[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C1(C)C=CC=CC=1>[CH2:7]([N:9]1[C:18]([OH:23])=[CH:19][C:20]([CH3:22])=[N:10]1)[CH3:8]
Reactant: COC(=O)CC(C)=O
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1nc(C)cc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3.9 g of ethyl hydrazine oxalate and 3.6 ml of triethylamine in 80 ml of toluene was stirred at room temperature for 15 min. 2.8 ml of methyl acetoacetate was added and the mixture was azeotroped for 1.5 h. The mixture was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (97:3) for the elution to give 3.1 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol as an orange solid.
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[N+:20](C1C=C(C=CC=1)C(Cl)=O)([O-:22])=[O:21]>>[N+:20]([C:19]1[CH:18]=[C:7]([CH:6]=[CH:5][CH:4]=1)[C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:9])([O-:22])=[O:21]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: O=C1CCCCCN1C(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 3-nitrobenzoyl chloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10](=O)[C:11](=[O:15])[C:12]=2[O:13]C)[CH2:5][CH2:4]1)[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C>C(O)C>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:12](=[O:13])[C:11](=[O:15])[C:10]=2[N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2c(OC)c(=O)c2=O)CC1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CCN1CCN(c2c(N3CCN(C)CC3)c(=O)c2=O)CC1

Procedure:
To a stirred, refluxing solution of 2.2 grams of 3-(4-ethyl-1-piperazinyl)-4-methoxy-3-cyclobutene-1,2-dione dissolved in 30 ml. of absolute ethanol under an atmosphere of dry nitrogen, is added a solution of 1.0 gram of 1-methylpiperazine in 30 ml. of absolute ethanol. The resulting mixture is refluxed for 4 hours and then stripped of solvent under reduced pressure until the volume is approximately 15 ml. The concentrate is treated with decolorizing charcoal and filtered through a bed of diatomaceous earth. Crystallization is induced in the filtrate and the resulting crystalline precipitate is filtered, washed with absolute ethanol, and dried in a steam cabinet. The resulting product, 3-(4-ethyl-1-piperazinyl)-4-(4-methyl-1-piperazinyl)-3-cyclobutene-1,2-dione, is obtained as white crystals melting at about 166.5°-169° C. This product is represented by the following structural formula. ##STR9##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=2[NH:10][C:11]=1O)=[O:5])[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:11]1[S:7][C:8]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=2[N:10]=1)[CH3:2]
Reactant: CCOC(=O)C1=C(O)Nc2cc(Br)ccc2S1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(Br)ccc2s1
Temperature: 110 °C

Procedure:
A mixture of the crude material from Example 2C (2.7 g, 8.5 mmol) in acetic acid (60 mL) and heated to 110° C. Then Zn (18 equivalents) was added slowly in portions over 30 min to the mixture under nitrogen. After the completion the mixture was cooled to room temperature and the Zn residue was filtered off. The filter cake was washed with MeOH. And the combined filtrate was stripped to dryness. The residue was dissolved in 70 mL of chloroform and washed with water twice. The chloroform solution was dried with anhydrous MgSO4 and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 10% EtOAc/Hexane). Purified yield for the three steps from example 2B-2D was 1.11 g (43.3%).
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>C(O)C>[C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([O:20][CH3:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C#Cc1c(-c2ccccc2)nn2ccccc12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C#Cc1c(-c2ccccc2)nn2ccccc12
Yield: 48.2 %

Procedure:
3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)propiolic acid (10.33 g) was added to a mixture of sodium hydroxide (3.15 g) and 95% ethanol (103 g), and then dimethyl sulfate (4.97 g) was added to the mixture. The reaction mixture was heated at 60° to 80° C. for 3 hours and 20 minutes. Ethanol was evaporated in vacuo. Water was added to the residue and extracted with chloroform (50 ml×3). Combined extract was washed with a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give crystals of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propiolate (5.25 g).