Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.FC(F)(F)C(O)=O.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>C(O)(=O)C>[O:26]=[C:20]1[CH:19]([N:18]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: O=C1OC(=O)c2cscc21
Reactant: NC1CCC(=O)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Yield: 122.6 %

Procedure:
1.54 g thieno(3,4-c)furan-1,3-dione and 1.42 g of 3-aminopiperidine-2,6-dione trifluoroacetic acid were dissolved in 15 mL of acetic acid. The reaction mixture was refluxed overnight, cooled, and evaporated to remove the solvent. The residue was dissolved in 20 mL anhydrous THF, and 2 g of CDI, and a catalytic quantity of DMAP were added. The reaction mixture was refluxed for 6 h until a large amount of white solid precipitated. The solid was cooled and filtered to yield 1.9 g of the title compound.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([NH:9][C:10](=[O:11])[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of benzoylisocyanate (4.8 g, 32.6 mmol) in CH2Cl2 (180 mL) at 0° C. was added 4-amino-1-N-boc-piperidine (6.0 g, 30 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was treated with Et2O (100 mL). The precipitate was filtered, washed with Et2O to yield a white solid (5.70 g, yield 55%). LC/MS: m/z (ES+) 337 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]1)#[CH:12]>C(N(CC)CC)C.COC(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]#[C:12][C:2]2[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=2)[CH2:18][CH2:17]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCc1ccc(Br)nn1
Reactant: C#C[C@H]1CC[C@H](CCCCC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(CCC)nn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
8.0 g of 3-bromo-6-propylpyridazine (prepared according to Example 3) were dissolved in 50 ml of triethylamine in a sulphonation flask under nitrogen. The solution was cooled to 0° C., treated with 562 mg of bis-(triphenylphosphine)-palladium (II) dichloride and 76 mg of copper (I) iodide and then treated dropwise within 20 minutes with 7.5 g of trans-1-ethynyl-4-pentylcyclohexane. The mixture was subsequently stirred at 0° C. for several hours, then at room temperature overnight and finally at 50° C. for a further 3 hours. For the working-up, the dark coloured mixture was diluted with 100 ml of tert.butyl methyl ether and suction filtered through a paper filter (rinsing with tert.butyl methyl ether). The filtrate was concentrated on a rotary evaporator. The dark coloured crystalline residue was taken up in 150 ml of tert.butyl methyl ether and washed successively with 100 ml of 2% (wt./vol.) ammonium chloride solution and with 100 ml of water. Each of the aqueous phases were back-extracted with a small amount of tert.butyl methyl ether. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. For the purification, the brown coloured crystals obtained were chromatographed on silica gel with hexane/ethyl acetate (vol. 2:1), there being obtained a fraction of the desired product 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine (5.2 g) and a mixed fraction consisting of 3-bromo-6-propylpyridazine and product (4.8 g). The pure fraction was recrystallized once from ethanol at -20° C. and once from hexane at -20° C. and finally dried well in a vacuum drying oven at 40° C. There were thus obtained 3.4 g (28.5%) of 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine in the form of white crystals of melting point (C-I) 118.5° C., boiling point 210°-220° C./0.08 Torr.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[F:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([F:43])=[C:21]([NH:20][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nn(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Yield: 56 %

Procedure:
In the same manner as in Example 55 and using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (56.4 mg, 0.402 mmol), tetrahydrofuran (5 mL), thionyl chloride (70.0 μL, 0.807 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (92.4 mg, 56%) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: C1CCNC1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(2-pyrrolidin-1-yl-ethoxy)-benzo[d]isothiazole, MS: 404 (MH+, 1Br). 4.6
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[CH:13]=O)=[CH:4][CH:3]=1.[NH2:15]OS(O)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]#[N:15])=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]ccc1-c1ccc(Cl)cc1
Reactant: NOS(=O)(=O)O
Solvent: O
Product: N#Cc1[nH]ccc1-c1ccc(Cl)cc1
Yield: 63.7 %

Procedure:
A mixture of 0.63 g (3.1 mmol) of 3-(p-chlorophenyl)-pyrrole-2-carboxaldehyde in 10 mL of water is stirred and ice-cooled while 0.52 g (4.6 mmol) of hydroxylamine-O-sulfonic acid in 10 mL of water is slowly added. After the addition, the cooling bath is removed and the mixture is heated for 25 minutes. On cooling, the resulting solid is collected and shown, by NMR, to be a mixture of product and starting aldehyde. This mixture is reacted in the same manner with an additional 0.49 g (4.2 mmol) of hydroxylamine-O-sulfonic acid in a total of 30 mL of water. The mixture is heated at 60°-70° C. for 2 hours. The mixture is cooled and the resulting solids are collected and purified by chromatography or silica gel using 1:1 ethyl acetate hexane to give 0.40 g of pink solid, m.p. 114°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O:12][C:13](=O)[CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:15](=O)[CH3:16])C>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:14]2[C:13](=[O:12])[NH:1][C:2]3[C:3]([C:15]=2[CH3:16])=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=3)=[CH:24][CH:23]=1
Reactant: Cc1cc(N)cc(O)c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Product: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Temperature: 150 °C

Procedure:
A mixture of 3-amino-5-methylphenol (0.25 g) and 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (0.52 g) was heated at 150° C. under nitrogen for 7 hours. The mixture was cooled to room temperature and the residue triturated with methanol to afford the title compound as an off-white solid, 0.32 g.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O1.[H-].[Na+]>>[C:15]1([C:4]2[C:5]3[CH2:4][C:15]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:2]=3[C:7]([C:8]#[N:9])=[C:6]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccccc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2

Procedure:
A mixture of 2-oxo-6-phenyl-4-(pyrrolidin-1-yl)-2H-pyran-3-carbonitrile (266 mg), indanone-1 (132 mg) and NaH (31 mg) in THIF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 158-160° C.; ESIMS 336 (M+); IR (KBr) 2203 cm−1 (CN); 1H NMR (200 MHz, CDCl3) δ 2.01-2.05 (m, 4H, 2CH2), 3.68-3.72 (m, 4H, 2CH2), 3.78 (s, 2H, CH2), 6.63 (s, 1H, ArH), 7.30-7.51 (m, 8H, ArH), 8.63 (d, J=7.8 Hz, 1H, ArH); HRMS calcd. for C24H20N2 336.1627. Found 336.1599.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Oc1ccccc1OCc1ccccc1
Product: c1ccc(COc2ccccc2OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
In analogy to example 20.a., 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-benzyloxyphenol to give 4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole as a yellow viscous oil. MS (ISP): 523.5 ([M+H]+)
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH:9]=O>CCO.O.[Pd].C(Cl)Cl>[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9][NH:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: COC(C=O)OC
Reactant: CCCCN
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCCCNCC(OC)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 101 %

Procedure:
To a solution of butan-1-amine (limiting reagent) in EtOH (5 volumes) was added 2,2-dimethoxyacetaldehyde (60%) in water (1 molar equivalent) and the mixture was stirred at room temp for 4 clays. A slurry of 5% palladium on carbon (0.01 molar equivalent) in EtOH (1 volume) was added and the mixture was hydrogenated at 3 bar pressure for 20 hours. The mixture was filtered through a glass fibre filter paper, washed with EtOH (2×3 volumes) and the mother liquor was carefully concentrated to leave a cloudy brown oil. This oil was dissolved in DCM (15 volumes), dried (Na2SO4), filtered and carefully concentrated in vacuo to leave an orange oil. Yield: 101% of theoretical.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:27][CH3:28])[N:21]=[C:22]([CH:25]=[CH2:26])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1.C(O)C>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:27][CH3:28])[N:21]=[C:22]([CH2:25][CH3:26])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1
Reactant: C=Cc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Reaction time: 2 h
Yield: 104 %

Procedure:
The product from Example 92A (0.04 g, 0.083 mmol) and 10% Pd/C (0.022 g, 0.021 mmol) were combined in ethyl acetate (3 mL)/ethanol (3 mL), degassed under vacuum, placed under a balloon of hydrogen and stirred for 2 hours. The mixture was filtered through Celite and the Celite pad was washed repeatedly with ethyl acetate. The filtrate was concentrated to afford the title compound (0.042 g, 105%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)=[O:4].C([O-])(O)=O.[Na+]>CCOC(C)=O.Cl>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:19])[CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-(dimethylcarbamoyl)phenylcarbamate (Int. 73) (1.11 g, 4.21 mmol) in AcOEt (20 ml), HCl 4M in AcOEt (18 ml, 76 mmol) was added, and the mixture stirred for 5 hours at RT. The pH was adjusted at 6/7 by adding NaHCO3 sat. sol. and aqueous phase was extracted with AcOEt (×3). Organic phase was dried over Na2SO4 and evaporated under reduced pressure to give mg 615 of the title product (Int. 74).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:29])[C:13]2[O:19][C:18]3[C:20]([Cl:25])=[CH:21][C:22]([NH2:24])=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:26])[C:14]=2[CH:28]=1)=[O:9])[CH3:6].COC(C1C=C(C)C2OC3C(Cl)=CC(N)=CC=3CS(=O)(=O)C=2C=1)=O>C(O)=O>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:29])[C:13]2[O:19][C:18]3[C:20]([Cl:25])=[CH:21][C:22]([NH:24][CH:1]=[O:2])=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:26])[C:14]=2[CH:28]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Reactant: O=C[O-]
Agent: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Product: CCOC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC=O)cc(Cl)c1O2
Temperature: 0 °C

Procedure:
Sodium formate (0.075 g, 1.1 mmol) was added to a suspension of 2-amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid ethyl ester (0.420 g, 1.1 mmol) [prepared by hydrolysis of compound of Example 1 and followed by esterification with ethanol/H2SO4] in formic acid (25 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (100 mL). The solid precipitated was filtered, washed with water and dried. The crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.21 g (47%); mp 202-204° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.31 (t, 3H, OCH2CH3), 2.64 (s, 3H, CH3), 4.31 (q, 2H, OCH2CH3), 5.25 (s, 2H, CH2, trans minor isomer), 5.33 (s, 2H, CH2, cis major isomer), 7.34 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.31 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.43 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 408 (M−1); analysis: C18H16ClNO6S requires C, 52.75,H, 3.93, N, 3.42, Cl, 8.65, S, 7.82; found: C, 52.47,H, 3.86, N, 3.36, Cl, 8.81, S, 7.67%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][CH:78]([NH2:81])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:81][CH:78]4[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CN1CCC(N)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 1-methylpiperidin-4-amine (10 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 1-methylpiperidin-4-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(1-methylpiperidin-4-yl)acetamide. (49 mg, 0.097 mmol, 69%)
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>O1CCOCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:18]1[NH:17][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Oc1ncnc2ncccc12
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)CC(Nc1ncnc3ncccc13)C2
Yield: 23 %

Procedure:
Using 4-hydroxypyrido[2,3-d]pyrimidine (150 mg, 1.0 mmol) (see J. Am. Chem. Soc., 77, 2256 (1955)), phosphorus oxychloride (1.0 ml), 2-aminoindan (270 mg, 2.0 mmol), triethylamine (1.4 ml, 10 mmol), and dry dioxane (5 ml), a similar procedure to Product ion Example 203 was carried out. The product obtained was purified by silica gel chromatography (ethyl acetate:methanol=19:1) to obtain the title compound (60 mg, 0.23 mmol) having the following physical properties:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:30])[C:7]([CH3:29])([CH3:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])C>O.C(O)C>[O:27]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([OH:22])=[O:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:29])([CH3:28])[C:6]([OH:30])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 13 %

Procedure:
A solution of KOH (25 g) in water (50 mL) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (10.69 g, 155 mmol) in ethanol (400 mL), then heated at reflux for 4 h. After cooling, the solution was evaporated to a volume of ca. 50 mL and diluted with water (800 mL). The organic impurities were removed by extracting with dichloromethane (2×200 mL). The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid (50 mL) and extracted with methyl tert.-butyl ether (MTBE, 3×200 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the crude product (9.51 g) as an oil. Crystallization from hexanes/MTBE (50 mL:25 mL) afforded 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (6.92 g, 79%) as waxy, white crystals. M.p.: 83-84° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 12.03 (s, 2 H), 2.37 (t, 4 H, J=7.3 Hz), 1.52-1.34 (m, 8 H), 1.28-1.10 (m, 8 H), 1.06 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 210.5, 178.8, 41.7, 41.2, 29.1, 25.0, 24.4, 23.1. HRMS (LSIMS, gly): Calcd. for C19H35O5 (MH+): 343.2484, found: 343.2485.
Reaction SMILES: [OH-].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:15]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH2:22]Cl)([CH3:18])([CH3:17])[CH3:16].[CH:32](=[O:36])[CH:33]([CH3:35])[CH3:34].C(Cl)C1C=CC=CC=1.C(=O)C(C)C.Cl>C1C=CC=CC=1.O.C1C=CC=CC=1.O>[CH3:34][C:33]([CH3:35])([CH2:22][C:21]1[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=1)[CH:32]=[O:36]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: CC(C)C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCc1ccccc1
Solvent: O
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 103.8 %

Procedure:
A three-neck, three-liter flask equipped with a mechanical stirrer, thermometer and an addition funnel was charged with 80 grams of sodium hydroxide and 80 milliliters of water under a nitrogen atmosphere. The mixture was stirred until dissolved and a mixture of 450 milliliters of benzene and 12.5 milliliters of 40 percent methanolic benzyl trimethyl ammonium hydroxide was added forming a benzene-water mixture. A mixture of 383 grams of 3,5-di-t-butyl-4-hydroxy benzyl chloride and 144 grams of isobutyraldehyde was prepared and placed in the addition funnel. The benzyl chloride/isobutyraldehyde mixture was added to the mixture of benzene and water while the flask contents were vigorously stirred at a temperature of 50° C. to 60° C. over a two-hour period. After addition was complete, the mixture was stirred for an additional one-half hour at room temperature. The mixture was hydrolyzed with dilute hydrochloric acid until the benzene layer turned clear yellow-orange color. The benzene layer was separated and the benzene evaporated to obtain 453 grams of 2,2-di-methyl-3-(3,5-di-t-butyl-4-hydroxyphenyl)propanal. The melting point of the product was between 72° C. and 74° C. after recrystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[O:22]=[C:23]1[CH:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][NH:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:29](=[O:30])[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([OH:22])[CH:28]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cc[nH]c(=O)c1
Product: Cc1cc(-c2cc(NC(=O)c3ccnc(O)c3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-Chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 1,2-dihydro-2-oxo-4-pyridinecarboxylic acid (CAN 22282-72-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 436.0689 (M−H)−.