Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:2].Cl.C(OCC)(=O)C>[Pd].C(O)C>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A 200-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 1.28 g dry weight), 115i (3.00 g, 12.9 mmol), 12% hydrochloric acid (6.5 mL, 25 mmol), ethyl acetate (60 mL) and ethanol (40 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (4.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×20 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (150 mL) and 10% aqueous potassium carbonate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to afford a 71% yield (1.71 g) of 115j as a white solid: mp 102-104° C.; 1H NMR (500 MHz, DMSO-d6) δ 6.61 (s, 1H), 6.22 (br, 2H), 4.15 (m, 4H), 2.77 (m, 2H), 2.59 (t, 2H, J=6.5 Hz), 2.42 (t, 2H, J=6.5 Hz), 1.70 (m, 2H), 1.62 (m, 2H), 1.23 (t, 3H, J=7.0 Hz); MS (APCI+) m/z 237.2 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:47]([O:46][CH2:45][CH2:44][N:27]1[C:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:24]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:25]2[S:30][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][C:26]1=2)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3CCCCC3)c2s1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(OCc3ccccc3)cc1OCc1ccccc1)n2CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.12 g, 2.03 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 97 mg, 2.43 mmol) under ice-cooling and the mixture was stirred for 10 min. (2-Bromoethoxymethyl)benzene (0.53 ml, 3.24 mmol) was added and the mixture was stirred at room temperature for 4 hr. Ethyl acetate (25 ml) was added to the reaction mixture, and the organic layer was washed successively with water (20 ml×3) and saturated brine (10 ml), and dried over sodium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-2:1) to give methyl 4-(2-benzyloxyethyl)-5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.21 g, yield 87%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][NH2:10].[CH2:11]([N:13]1[C:18](S(C)=O)=[C:17]([C:22]#[N:23])[C:16](=[O:24])[N:15]2[N:25]=[CH:26][CH:27]=[C:14]12)[CH3:12]>C(O)C>[NH2:23][C:22]1[N:9]([CH3:8])[N:10]=[C:18]2[C:17]=1[C:16](=[O:24])[N:15]1[N:25]=[CH:26][CH:27]=[C:14]1[N:13]2[CH2:11][CH3:12]
Reactant: CNN
Reactant: CCn1c(S(C)=O)c(C#N)c(=O)n2nccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2nn(C)c(N)c2c(=O)n2nccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
Triethylamine (1.44 g) and methylhydrazine (1.44 g) were added to a solution of 3.25 g of 4-ethyl-5-methanesulfinyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile in 60 ml of ethanol. The mixture was stirred at room temperature for 10 minutes and then stirred at 100° C. for 20 minutes. The reaction mixture was ice-cooled and the crystals precipitated were collected by filtration and sequentially washed with ethanol, methanol and diethyl ether to provide 1.2 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=2)[C:28]=1[CH2:39][CH:40]=[CH2:41])(=O)=O.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:38][O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:39][CH:40]=[CH2:41])=[C:27]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:36]=[CH:35]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: C=CCc1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OC)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12
Yield: 74.7 %

Procedure:
4-Methoxyphenylboronic acid (10.15 g, 66.8 mmol), tripotassium phosphate hydrate (77.6 g, 278.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.93 g, 1.67 mmol, 3 mol %) were added to a solution of 6-methoxy-1-(2-propenyl)-2-naphthyl trifluoromethanesulfonate (19.3 g, 55.66 mmol) in dioxane (300 ml), followed by heating under reflux for 8 hours under argon atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9), followed by recrystallization from hexane, to give 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (12.65 g, Yield 75%).
Reaction SMILES: Cl.[CH3:2][C:3]([OH:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([O:6][CH2:5][CH2:4][C:3]([OH:8])([CH3:7])[CH3:2])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CC(C)(O)CCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 3-methyl-1,3-methanebutane diol (2.00 g, 19.2 mmol), (4-trifluoromethyl)benzene sulfonyl chloride (7.046 g, 28.8 mmol) in dry pyridine (20 mL) was stirred at 0° C. for 2 hours, poured into the cold HCl (50 mL, 2 N), and extracted with ethyl acetate. The organic phase was washed with HCl (4×50 mL, 2 N), brine (1×25 mL), dried over MgSO4, and evaporated to dryness. (3.72 g, 97%). 1H NMR (400 MHz, CDCl3): δ 1.21 (s, 6H), 1.87 (t, J=6.9, 2H), 2.03 (d, J=14.0, 2H), 4.26 (t, J=6.9, 2H), 7.81 (d, J=8.6, 2H), 8.03 (d, J=8.1, 2H). Repeat synthesis: To a solution of 3-methyl-1,3-butane diol (1.9 g, 18.2 mmol) in pyridine (15 mL) was added p-(trifluoromethyl)benzenesulfonyl chloride (3.67 g, 15 mmol). The solution was stirred at 0° C. for 2 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1 M HCl (3×50 mL), saturated aqueous NaHCO3 (1×50 mL) and saturated aqueous NaCl (1×50 mL). The organics were dried over Na2SO4 and concentrated to give a white low melting point solid (3.33 g, 71%). 1H NMR (400 MHz CDCl3) δ 8.04 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 4.72 (t, 2H, J=7.0 Hz), 1.87 (t, 2H, J=7.0 Hz), 1.21 (s, 6H). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 46.14; H, 4.90.
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[Cl:6][CH2:7][C:8]([CH2:10][Cl:11])=[O:9].O>CN(C)C=O.[Zn]>[Cl:6][CH2:7][C:8]([C:2]([F:4])([F:3])[F:1])([OH:9])[CH2:10][Cl:11]
Reactant: O=C(CCl)CCl
Reactant: FC(F)(F)I
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCl)(CCl)C(F)(F)F

Procedure:
A mixture of commercial zinc powder (1.30 g, 0.02 mole), trifluoromethyl iodide (2.15 g, 11 mmole) and 1,3-dichloroacetone (5.6 g, 44 mmole) in 30 ml dimethylformamide (DMF) is irradiated in the water bath of an ultrasound laboratory cleaner (35 Watts, 32 KHz) for 30 minutes. The mixture is partitioned between 2% w/v aqueous hydrochloric acid and diethyl ether. The ether extract is dried (MgSO4) and the solvent evaporated to afford the title compound.
Reaction SMILES: ClC1C(C2C=CC=CC=2)=NN=C2N(CCI)N=C(C3C=CC=CC=3)C=12.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]=12.Cl.N1CCNCC1=[O:64].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][N:53]([CH3:56])[C:54](=[O:64])[CH2:55]3)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]=12
Reactant: CN1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Reactant: O=C1CNCCN1
Agent: Cl
Agent: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1=O
Reaction time: 48 h

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (example 74 step 1 (Compound 81)) (100 mg, 0.21 mmol) in CH2Cl2 (1 ml) was added to piperazinone hydrochloride (160 mg, 1.05 mmol) and diisopropylethylamine (DIPEA) (220 μl, 12.6 mmol) in CH2Cl2 (0.5 ml) and the reaction stirred at ambient for 2 days. Further piperazinone hydrochloride (160 mg, 1.05 mmol) and diisopropylethylamine (DIPEA) (220 μl, 12.6 mmol) were added and the reaction stirred for a further 24 h. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC to give Compound 84 as a yellow glass solid (17 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[CH3:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[CH:9]=1
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To a solution of 1.00 g (3.4 mmol) of 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester in 40 ml of THF/MeOH (1:1) was added 8.47 ml (8.5 mmol) of lithium hydroxide solution (1 molar in water) and the reaction mixture was stirred at RT. After 20 hours, the solvents were evaporated and the residue poured into crashed ice, the pH was adjusted to 1-2 with HCl 1N and the reaction mixture was extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by re-crystallization from CH2Cl2/heptane to give 0.94 g (99%) of the title compound as colorless solid. MS: 280.0 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][S:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.82 mL, 8.0 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as an off-white solid (1.13 g, quantitative yield). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.16 (m, 2H), 3.45 (s, 2H), 3.15-3.09 (m, 1H), 2.76-2.60 (m, 6H), 2.62-2.57 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:23][NH2:24]>O>[CH3:23][NH:24][CH2:18][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]3[C:14]4=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]4[CH:12]=[CH:11]3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Reactant: CN
Solvent: O
Product: CNCc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Yield: 94 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 3-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and methylamine in 94% yield as a pale-yellow solid: mp 128-130° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 3.48 (br s, 2H), 3.71 (s, 2H), 4.30-4.33 (m, 2H), 6.69 (s, 1H), 7.17 (t, 1H, J=9.0 Hz), 7.38-7.39 (m, 1H), 7.44-7.46 (m, 2H), 7.54 (s, 1H), 7.80 (t, 2H, J=9.0 Hz), 8.39 (t, 1H, J=6.0 Hz). HRMS calcd. for C19H19N3O 305.3828 (M+), found 305.1520. Anal. (C19H19N3O.0.6 H2O) C, H, N.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:43])[CH2:31][CH2:32][CH2:33][N:34]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:35]>>[CH3:43][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:41][CH:42]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)CCCN(C)c1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)CCCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-(3-dimethylamino-propyl)-N-methyl-amino)-aniline Rf value: 0.5 (aluminium oxide, ethyl acetate) C30H34N4O3
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]\[CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)COc1cccc(C#CCO)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(/C=C\CO)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Quinoline (54 μL) and a Lindlar catalyst (54 mg) were added to a stirred solution of [3-(3-hydroxyprop-1-ynyl)phenoxy]acetic acid tert-butyl ester (547 mg, 2.09 mmol) in methanol (4.3 mL) under a nitrogen atmosphere. The mixture was stirred for 1 hour in a balloon filled with hydrogen, filtered, and the filtrate was taken to dryness. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate, dissolved in diethyl ether, and washed with 2 N hydrochloric acid (10 mL) and 10% sodium bicarbonate, dried over sodium sulfate, and concentrated to give cis-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester as a colorless oil (420 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:24]CC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Reactant: C1CCOC1
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of CeliteTM. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1 -butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL ) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL ) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL ) was treated with 1.0M BH3-THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d,J=7.8, 1H), 7.42 (t,J=7.8, 1H), 7.31 (d,J=7.8, 1H), 7.02 (t,J=7.8, 1H), 2.73 (s, 2H), 1.56 (s, 9 H), 1.49 (s, 6H).
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][CH2:74][CH3:75])[CH:68]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[CH:68]=[C:69]([NH:73][CH2:74][CH3:75])[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: CCNc1cc(Cl)ncn1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CCNc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 143 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloro-N-ethylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (t, J=1.70 Hz, 1H), 6.48 (d, J=1.89 Hz, 2H), 5.70 (s, 1H), 3.89-4.03 (m, 2H), 3.74 (s, 2H), 3.55 (d, J=7.55 Hz, 2H), 1.91-2.03 (m, 1H), 1.76-1.87 (m, 2H), 1.65 (dt, J=4.20, 8.59 Hz, 1H), 1.26 (t, J=7.18 Hz, 3H). EIMS (m/z): calcd. for C19H24Cl2N6O (M+1H) 423. found 423.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:11][C:14](=[O:16])[CH3:15])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(C)c1C(=O)O
Reaction time: 1 h

Procedure:
90.6 g (0.6 mol) of 6-methylanthranilic acid is added to a solution of 24.8 g (0.62 mol) of NaOH in 500 ml of water and 63.4 g (0.62 mol) of acetic anhydride are then added dropwise. After stirring for one hour, the mixture is acidified to pH 3 with conc. HCl with cooling, and the precipitate which deposits is filtered off with suction, washed with water and dried under reduced pressure at 50° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.S(O)(O)=O.[CH2:16](N)[CH2:17][NH2:18]>C(O)CO.O>[CH3:11][C:10]1[C:2]([NH:1][CH2:16][CH2:17][NH2:18])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[CH:4]2
Reactant: Cc1ccc2[nH]ncc2c1N
Reactant: NCCN
Agent: O=S(O)O
Solvent: OCCO
Solvent: O
Product: Cc1ccc2[nH]ncc2c1NCCN

Procedure:
m.p. 153°-155° C., recrystallized from water (yield 31% of theory) by reacting 4-amino-5-methylindazole with an excess of ethylenediamine sulphite in ethylene glycol-water (1:1 v/v) for 24 hours at 110° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH3:5])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(C(C)(C)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
To a solution of 2-methyl-2-p-tolyl-propan-1-ol (405 mg, 2.46 mmol) in DMF (5 mL) was added imidazole (335 mg, 4.92 mmol) followed by tert-butyldimethylsilyl chloride (465 mg, 3.08 mmol). The reaction was stirred for 24 h and water was added. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with water (4×). The organic solution was dried (MgSO4), filtered and concentrated. Medium pressure chromatography (hexanes) provided tert-butyl-dimethyl-(2-methyl-2-p-tolyl-propoxy)-silane (619 mg). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2H), 7.10 (d, 2H), 3.49 (s, 2H), 2.31 (s, 3H), 1.27 (s, 6H), 0.85 (s, 9H), −0.06 (s, 6H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1(=[O:19])[O:14][C:12](=O)[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.S([O-])(O)(=O)=O.[K+]>C(OC)(=O)C1C=CC=CC=1>[CH:16]1[CH:17]=[CH:18][C:10]([C:9]([OH:14])=[O:19])=[C:11]([C:12]2[C:6]3[CH:4]=[CH:3][C:1]([OH:2])=[CH:8][C:7]=3[O:5][C:4]3[C:6]=2[CH:7]=[CH:8][C:1]([CH:3]=3)=[O:2])[CH:15]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: COC(=O)c1ccccc1
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 6 h

Procedure:
A mixture comprising 55 g of resorcinol, 30 g of phthalic anhydride, 2 g of potassium hydrogen sulfate and 500 ml of methyl benzoate is brought to 200° C. for 6 hours. After cooling, the red crystals of crude fluorescein are washed with acetone and dried.