Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:30])[NH:28][C:27](=[O:29])[CH2:26][CH2:25]1.[Na]>CN(C)C=O>[C:27]1(=[O:29])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:24](=[O:30])[CH2:25][CH2:26][C:27]2=[O:29])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:24](=[O:30])[CH2:25][CH2:26]1
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Reactant: O=C1CCC(=O)N1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1CCOC(OCCN1C(=O)CCC1=O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
One hundred (100) grams of benzil-di(β-bromoethyl)ketal and 60.5 g of sodium succinimide were dissolved in 500 ml of N,N-dimethylformamide (to be referred to as DMF), and the solution was heated at 50° to 60° C. for 6 hours with stirring. After the reaction, the reaction mixture was poured into 1 liter of ice water. The resulting crystals were filtered, thoroughly washed with water, and dried to afford 95 g (88% yield) of benzil-di(β-succinimidoethyl)ketal as white crystals. Recrystallization from ethanol yielded crystals having a melting point of 90° to 92° C. The product is referred to as initiator 1.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14]([OH:16])=[O:15]>>[CH3:23][O:22][C:18]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]=1[O:20][CH3:21]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Product: COc1cc(C(=O)O)cc(-c2ccccc2)c1OC
Yield: 88 %

Procedure:
5,6-Dimethoxybiphenyl-3-carboxylic acid was prepared by coupling phenylboronic acid with 3-iodo-4,5-dimethoxybenzoic acid according to Method P. The crude product was purified via flash column chromatography on silica gel (5% MeOH in CH2Cl2 as an eluent) to give the desired acid in 88% yield. ESMS: m/z 257.3 [M−H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:36][N:35]=3)[C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[CH:29]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[CH2:20][CH2:19]N3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.C(OCC1C(N2CCC3C4CCCCC=4[S:66]C=3C2=O)=CC(F)=CC=1B1OC(C)(C)C(C)(C)O1)(=O)C.ClC1C=C(NC2C=CC(N3CCN(C)CC3)=CN=2)C2N(C=CN=2)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:36][N:35]=3)[C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[CH:29]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[C:9](=[O:21])[C:10]3[S:66][C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[C:18]=3[CH2:19][CH2:20]2)[CH:7]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn4ccnc34)nc2)CC1
Agent: CN1CCN(c2ccc(Nc3cc(Cl)cn4ccnc34)nc2)CC1
Product: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(sc7c6CCCC7)C5=O)c4CO)cn4ccnc34)nc2)CC1
Yield: 35 %

Procedure:
Following the procedures as described for compound 101, 103g (499 mg, 1.0 mmol), and 6-chloro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine 101b (342 mg, 1.0 mmol) were reacted to give 103 as a white solid (220 mg, 35%). LCMS: [M+H]+ 638. 1H NMR (500 MHz, CDCl3) δ 8.22 (s, 2H), 7.96 (d, J=2.5, 1H), 7.83 (s, 1H), 7.63 (d, J=1.0, 1H), 7.57 (d, J=1.0, 1H), 7.30 (dd, J=3.0, 9.0, 1H), 7.24 (dd, J=2.5, 9.0, 1H), 7.03 (dd, J=3.0, 9.0, 1H), 6.92 (d, J=8.5, 1H), 4.57 (d, J=11.5, 1H), 4.35 (t, J=8.5, 1H), 4.21 (s, 1H), 4.09-4.15 (m, 1H), 3.87-3.92 (m, 1H), 3.16 (t, J=5.0, 4H), 2.85-3.02 (m, 4H), 2.60 (t, J=5.0, 4H), 2.51-2.57 (m, 2H), 2.37 (s, 3H), 1.85-1.95 (m, 4H)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]1[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[C:18]1=[O:29].O>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:21]1[CH2:22][C:23]2[C:28]3=[C:27]([CH2:17][C:18](=[O:29])[N:19]3[CH2:20]1)[CH:26]=[CH:25][CH:24]=2)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCC(=O)Cl
Reactant: O=C1Cc2cccc3c2N1CCC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCCCCC(=O)C1Cc2cccc3c2N(C1)C(=O)C3
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Acetyloxyhexanoic acid chloride (16.7 g, 86.6 mmol) in absolute CH2Cl2 (50 ml) is added in drops at 0° C. within 10 minutes to a suspension of anhydrous aluminum chloride (61.5 g, 461.6 mmol) in absolute CH2Cl2 (500 ml), and it is stirred for 15 minutes at this temperature. 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g (57.7 mmol) in absolute CH2Cl2 (100 ml) is added in drops within 15 minutes at 0° C., then it is heated to boiling temperature and stirred for 30 minutes. It is cooled to 0° C., hydrolyzed with ice and dispersed between water (300 ml) and CH2Cl2 (100 ml). The aqueous phase is extracted with CH2Cl2 (2×100 ml), the combined organic phases are washed with 2N hydrochloric acid (2×250 ml), water (2×250 ml), semi-concentrated aqueous Na2CO3 solution (2×250 ml), concentrated aqueous Na2CO3 solution (2×250 ml) and concentrated common salt solution (1×250 ml), dried (sodium sulfate/activated carbon), and the solvent is removed in a rotary evaporator.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Br[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29].O1CCOCC1.CO>CN(C=O)C>[F:33][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:14])[NH:13][C:4]2=[O:3])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccccc2n1
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F

Procedure:
Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)quinazoline with a substituted alkyl 3-(halomethyl)benzoate, such as methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-cyclopentylcarbonylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[CH2:41][CH3:42]>CN(C=O)C.ClCCl>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:40](=[O:43])[CH2:41][CH3:42])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: CCC(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (85 mg, 0.20 mmol, Example 1) was dissolved in DMF (0.5 mL) and dichloromethane (4 mL). Triethylamine (0.028 mL, 0.20 mmol) was added followed by propionyl chloride (0.021 mL, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propan-1-one (8.0 mg, 8.32%).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:14]4[C:13](=[CH:18][N:17]=[CH:16][CH:15]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2ccncc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (less polar isomer) (12 mg, 0.05 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=1)#[N:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]#[N:16])[CH:18]=2)[CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: N#Cc1cccc(Nc2cccc(C(=O)O)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(Nc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 37.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-cyanophenylamino)benzamide was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.030 g; 0.130 mmol), 3-(3-cyanophenylamino)benzoic acid (0.037 g; 0.155 mmol), HATU (0.064 g; 0.169 mmol) and N,N-diisopropylethylamine (0.060 mL; 0.324 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.020 g (37%) of the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([F:33])[C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([F:33])[C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3F)cc2)CC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine (164 mg, 0.48 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine (110 mg, 0.48 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[SH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].CN(C)C=O.Cl>O.C(N(CC)CC)C>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][S:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cccc(S)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (3.00 g), 3-mercaptobenzoic acid (1.47 g) and N,N-dimethylformamide (30 mL) was dropwise added triethylamine (2.13 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (3.70 g, yield 90%) of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoic acid from a fraction eluted with acetone-hexane (1:1, v/v). Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:2][CH3:3].[Cl:13][CH:14]=[CH:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:13]/[CH:14]=[CH:15]/[CH2:16][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:1][CH2:2][CH3:3]
Reactant: ClC=CCCl
Reactant: CCCNCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 3.30 g (20 mmoi) of N-propyl-3hydroxybenzylamine in 20 ml of dimethyl sulfoxide were added 1.82 g (20 mmoi) of 1,3-dichloropropene (E/Z =2/1) and 1.38 g (10 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 1.5 hours at room temperature and for 3 hours at 50° C., poured into 70 ml of ethyl acetate, washed with 50 ml ×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 2.29 g (yield: 48%) of the above identified compound as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[N:30]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[S:27][CH:28]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cccnc2)n1
Yield: 79.7 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.060 g, 0.215 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.044 g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g, 0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example 274 affording 0.080 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.20 (d, 3H), 4.40 (m, 2H), 4.51 (m, 1H), 7.02 (d, 1H), 7.81 (d, 1H), 7.94 (m, 3H), 8.33 (s, 1H), 8.38 (d, 1H), 8.54 (d, 1H), 8.71 (d, 1H), 9.25 (bs, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[O:16][C:17]=1[CH2:18][OH:19])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[O:16][C:17]=1[CH:18]=[O:19])[CH3:12]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (2.0M/DCM, 3.52 mL, 7.04 mmloe) in DCM (50 mL), is injected DMSO (0.998 mL, 14.1 mmole) and stirred for 15 minute at −78° C. A solution of [4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (1.59 g, 5.86 mmole) in DCM (10 mL) is then added. After stirred for 30 minutes, triethyl amine (4.08 mL, 29.3 mmole) is added. The reaction is kept at −78° C. for another 30 minutes, then warmed up to room temperature for 2 hours, washed with brine (3×50 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (silica gel, 10% ethyl acetate in hexane) and concentrated to provide the titled compound as a white solid. Mass [EI+] 270 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:60][O:61][C:62]1[N:67]=[CH:66][C:65](B(O)O)=[CH:64][CH:63]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[CH:7][CH:8]=2)[C:3](=[O:33])[C:2]=1[C:65]1[CH:66]=[N:67][C:62]([O:61][CH3:60])=[CH:63][CH:64]=1
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 77 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 of Example 108 as a starting material instead of 6-(2-morpholino ethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (77%).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.N.[N+]([O-])([O-])=O.[Ag+:31].[Ag].[NH4+]>C1C=CC=CC=1.O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:31]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: [Ag]
Agent: N
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
3.4 g of behenic acid was dissolved in 100 ml of benzene at 60° C., and the solution maintained at 60° C. while 100 ml of water was added to the above solution to form an emulsion with stirring. Ammonia water was added to 80 ml of an aqueous solution containing 1.7 g of silver nitrate to prepare a silver-ammonium complex, and then water was further added to make the total volume 100 ml. The resulting silver-ammonium complex-containing solution (which was chill-set at 10° C.) was added to the above emulsion, resulting in the formation of crystals of silver behenate. The reaction product was warmed to room temperature (25° C.), and allowed to stand for 20 minutes, it then separated into an aqueous phase and a benzene phase. After removal of the aqueous phase, the benzene phase was washed with 400 ml of water by decantation. 400 ml of methanol was then added to the benzene phase, and silver behenate collected by centrifuging. 4 g of spindle-like silver behenate about 1μ in longer diameter and about 0.05μ in shorter diameter was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:40][CH:37]4[CH2:39][CH2:38]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.7 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.00 equiv), piperidine (13 mg, 0.15 mmol, 0.50 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 70 mg (42%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+. 1HNMR (300 MHz, CDCl3, ppm) 8.405 (1H, s), 7.762˜7.715 (2H, m), 7.282˜7.223 (2H, m), 6.656˜6.575 (4H, m), 6.696 (2H, s),5.022˜4.924 (1H, m),4.8˜2.9 (4H, m), 2.424˜2.301 (2H, m),2.271˜2.259 (3H, d),1.295˜1.228 (2H, t),0.903˜0.892 (2H, d).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCC(F)(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 33.6 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 88 mg of sodium hydride (60% in oil), and 0.53 g of 1-iodo-4,4,4-trifluorobutane, and according to the process described in the Production Example 1, there was obtained 0.25 g of 2-(4,4,4-trifluorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (78)).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH2:28].[Cl-].[Li+]>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:27][CH3:28]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)c(CCC(=O)OC(C)(C)C)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC=Cc1ccc(OC)cc1CCC(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 171.6 %

Procedure:
Argon was passed through a solution of tert-butyl 3-(2-trifluoromethylsulfonyloxy-5-methoxyphenyl)propionate (15 g, 39 mmol), allyltributyl tin (15.8 mL, 51 mmol), and lithium chloride (2.1 g, 51 mmol) in DMF (120 mL) for 10 min, and bis(triphenylphosphine)palladium dchloride (1.5 g, 2.2 mmol) was added. The reaction mixture was heated at 95° C. for 1.5 h and evaporated. The residue was partitioned between 10% KF aquoues solution and ether. The combined extracts were dried and evaporated to give the titled compound (18.5 g).