Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:24].C(N(CC)CC)C.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=2)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1
Reactant: COC(=O)CCN
Reactant: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)O)cc2)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic acid (414 mg, 1.19 mmol) in methylene chloride (12 mL) is added triethyl amine (0.5 mL, 3.6 mmol), DMAP (5.0 mg), 3-Amino-propionic acid methyl ester hydrochloride (250 mg, 1.8 mmol) and EDCI (688 mg, 3.6 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (400 mg).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22]C)[CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[OH:22])[CH:14]=3)[NH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1-c1cnc2[nH]cc(-c3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccccc1-c1cnc2[nH]cc(-c3ccccc3)c2c1
Yield: 34 %

Procedure:
To a solution of 3-phenyl-5-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (113 mg, 0.38 mmol) in CH2Cl2 (325 μl) is added BBr3 (1.1 ml of 1 N solution in CH2Cl2, 1.13 mmol). The reaction mixture is stirred for 15 hours at room temperature and neutralized at 0° C. with methanol. The solvent is evaporated under reduced pressure and the residue purified by preparative thin-layer chromatography (CH2Cl2/MeOH 94:6) to yield the expected product in the form of a white solid with a yield of 34%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37]C(OC(C)(C)C)=O)[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:45])=[C:21]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:37][CH:35]1[CH2:34][N:30]2[C:31]3[CH:32]=[CH:33][C:25]([C:23]4[C:22]([CH3:45])=[C:21]([O:46][CH2:47][C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:10]([C:11]([O:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[O:12])=[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[N:24]=4)=[CH:26][C:27]=3[CH:28]=[C:29]2[CH2:36]1
Reactant: Cc1c(-c2ccc3c(c2)cc2n3CC(NC(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(N)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 65.6 %

Procedure:
The intermediate from Step 3 (65 mg, 0.09 mmol) was dissolved in trifluoroacetic acid (1 mL). After 1 min of stirring at room temperature, the mixture was partitioned in CH2Cl2 and aqueous 1 M K2CO3. The organic layer was removed, concentrated and chromatographed on silica gel (0-8% MeOH in CH2Cl2) to provide the product as a white powder (36 mg, 64%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: Oc1ccn2nccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccn2nccc2n1

Procedure:
A mixture of the product (1.35 g, 10.0 mmol) from Step A above and 7.5 mL of phosphorus oxychloride was warmed at reflux for 4 h. The mixture was cooled, and the volatiles were removed under reduced pressure. The dark residue was partitioned between ice water and dichloromethane, and the aqueous layer was extracted with additional dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide a light brown solid, which was purified by flash chromatography (silica gel; 0.5% methanol in dichloromethane eluant) to afford the title compound as a white solid. MS 153.8 and 155.8 (M+1).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](Cl)=[O:5].[NH:7]1[CH2:17][CH2:16][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8]1>>[Cl:1][CH2:2][O:3][C:4]([N:7]1[CH2:8][CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH2:17]1)=[O:5]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)OCCl
Product: CCOC(=O)C1CCN(C(=O)OCCl)CC1

Procedure:
Using chloroformic acid chloromethyl ester and ethyl isonipecotate as the raw materials, the same operation as the Example 101(1) gave the title compound as a crude product, and the crude product was used for the next reaction without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 74.5 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 1.22 ml (4.96 mmol) of myristoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.17 g of the desired compound (74.5%, colorless powder), mp: 80.0°-81.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CCCCBr
Product: CCCCOc1ccc(C=O)c(C)c1
Yield: 67.6 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 1-bromobutane (77 μL, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 2-methyl-4-butoxybenzaldehyde (52 mg, 68%). Used without further characterization.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:26])[C:6]=2[N:7]=1.[NH:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:40]=2)[CH:35]=[CH:34]1>>[CH3:26][C:8]1[C:6]2[N:7]=[C:2]([C:38]3[CH:37]=[C:36]4[CH:35]=[CH:34][NH:33][C:41]4=[N:40][CH:39]=3)[N:3]=[C:4]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:5]=2[S:10][C:9]=1[C:11]1[CH:12]=[C:13]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(-c2cccc(C(=O)N3CCN(C)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1c(-c2cccc(C(=O)N3CCN(C)CC3)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone (67 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 19.8 mg of 427. MS (Q1) 554.0 (M)+
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:50]([O:54][CH3:55])(=[O:53])[CH:51]=[CH2:52].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:55][O:54][C:50](=[O:53])[CH:51]=[CH:52][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Br)ccc23)n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
Combine 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (0.15 g, 0.36 mmol), tri-o-tolylphosphine (0.38 g, 1.26 mmol), tribuytlamine (0.12 mL, 0.5 mmol), methyl acrylate (0.065 ml, 0.72 mmol), anhydrous toluene (3 mL), and DMF (1.5 mL). Bubble nitrogen gas through the solution for 20 minutes. Add palladium acetate (4.0 mg, 0.018 mmol). Heat the reaction mixture at 80° C. for 48 hours. Chromatograph the residue on silica gel (elute with 2% methanol/methylene chloride, then 4% methanol/methylene chloride). Further purification by preparative HPLC affords the title compound 42 mg (28%) as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:4]3[C:3]4[C:26](=[CH:25][CH:29]=[CH:7][CH:2]=4)[CH2:27][C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1Cc1ccccc1-2
Yield: 81 %

Procedure:
A mixture of 6-(4-fluorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (298 mg), indanone-2 (132 mg) and NaH (41 mg) in THF 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; yield 81%; mp 130-132° C.; ESMS 369 (M++1); IR (KBr) 2216 cm−1 (CN).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][N:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][N:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reaction time: 5 h
Yield: 101.3 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (33 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and then 10% palladium carbon (17 mg) was added thereto, followed by stirring under a hydrogen atmosphere for 5 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give a crude product of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (31 mg) as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[O:38][N:37]=[C:36]([CH3:39])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:17])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-(isopropyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M107) (0.37 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (74 mg, 25%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1.[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O.Cl>O>[Cl:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)=[N:8][CH:9]=1
Reactant: Cc1cc(Cl)cnc1NCCCCN
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Agent: Cl
Solvent: O
Product: Cc1ccc(Cc2cnc(NCCCCNc3ncc(Cl)cc3C)[nH]c2=O)cn1
Yield: 38.9 %

Procedure:
2-(4-Aminobutylamino)-5-chloro-3-methylpyridine (1.81 g) and 2-nitroamino-5-(6-methylpyrid-3ylmethyl)-4-pyrimidone (1.95 g) were fused together on an oil bath at 140°-50° C. for 2 hr. On cooling the mixture was treated with water and dilute hydrochloric acid and some solid material removed at pH 4. On raising the pH to 5 a precipitate was obtained which on recrystallising twice from dimethyl formamide/water gave 2-[4-(5-chloro-3-methylpyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.2 g; 39%) m.p. 202°-3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1.[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:18]([NH:17][C:15]([CH:14]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])=[CH:3][C:4]=2[F:26])[CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CC(C)CCC(=O)Cl
Solvent: ClCCl
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCC(C)C)cc2F)CC1
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A solution of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N-ethyl-2-phenyl-acetamide (44 mg, 0.12 mmol) in DCM (2 mL) was treated with 4-methylvaleroyl chloride (20 mg, 0.15 mmol) followed by TEA (21 μL, 0.15 mmol). After 16 h, the mixture was purified directly by PTLC to give a beige solid (53 mg, 94%). MS (ESI): mass calcd. for C26H35FN4O2, 454.59; m/z found, 455.5 [M+H]+. 1H NMR (CDCl3): 7.38-7.28 (m, 5H), 7.10-7.04 (m, 2H), δ 7.00 (br s, 1H), 6.86 (t, J=9.0, 1H), 3.88 (s, 1H), 3.40-3.31 (m, 3H), 3.07-3.06 (m, 4H), 2.61-2.57 (m, 4H), 2.34-2.31 (m, 3H), 1.62-1.59 (m, 2H), 1.16 (t, J=7.2, 3H), 0.93 (d, J=6.1, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.Cl.O1CCOC[CH2:19]1>O1CCOCC1>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(CC(=O)O)cc2s1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc2nc(N)sc2c1
Temperature: 75 °C
Yield: 80.8 %

Procedure:
A mixture of 2-(2-aminobenzo[d]thiazol-6-yl)acetic acid (95%, 10.0 g, 45.6 mmol), methanol (50 mL), 4 N HCl/1,4-dioxane (12.0 mL, 48.0 mmol) in 1,4-dioxane (30 mL) was heated at 75° C. for 9 hr and then concentrated under vacuum. The residue was suspended into water (50 mL) and basified to pH 9 with 1N NaOH solution. The title compound (8.19 g, 81% yield) was collected as a pale solid by suction filtration and dried under vacuum at 50° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(C1C=C(C)C(=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)(C)(C)C.Cl>C(OCC)C>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.53 g of 2,7-di-tert-butyl-fluorene (9.10 mmol) was dissolved in 70 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 6.4 ml of a n-butyl lithium/hexane solution (1.56M: 9.98 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 3.01 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (10.0 mmol) in 40 ml of dehydrated diethyl ether was added and stirred with refluxing for 7 days. The reaction mixture was added to 100 ml of a hydrochloric acid aqueous solution (1N) and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown liquid. The liquid was purified by a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remainder was re-crystallized using methanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.65 g (2.85 mmol) as a pale yellow solid (yield: 31%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:9])[CH2:4][CH2:5][C:6](O)=[O:7].[NH2:10][C@@H:11]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[CH2:31]([O:30][CH2:29][C@H:11]([NH:10][C:6](=[O:7])[CH2:5][CH2:4][N:3]([CH3:9])[CH3:2])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)CCC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CN(C)CCC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 10 %

Procedure:
Proceeding as in Example 1, but substituting 3-dimethylaminopropionic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)propanamide, gave Compound 209, (S)-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)-2-(3-(dimethylamino)propanamido)propanamide (6 mg, 10%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.15 (br s, 1H), 8.48-8.47 (d, 1H), 7.65-7.61 (d, 2H), 7.42-7.39 (d, 2H), 7.43-7.39 (m, 2H), 7.32-7.26 (m, 5H), 7.06-6.96 (m, 4H), 4.72-4.67 (m, 1H), 4.52 (s, 2H), 3.65-3.64 (d, 2H), 2.47-2.43 (m, 2H), 2.33-2.30 (m, 2H), 2.12 (s, 6H). MS (EI) for C27H30ClN3O4. found 496.0 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]3[N:17]=[CH:18][C:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]([NH2:39])[CH3:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]([NH:39][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([C:19]2[CH:18]=[N:17][N:16]3[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=4)=[CH:13][N:14]=[C:15]3[CH:20]=2)[CH:22]=1)[CH3:38]
Reactant: CC(N)c1ccccc1F
Reactant: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)O)c4)cnn23)c1
Product: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)NC(C)c5ccccc5F)c4)cnn23)c1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 96, Step 4 starting from 3-[3-(3-{[(methylamino)carbonyl]amino}phenyl)imidazo[1,2-b]pyridazin-7-yl]benzoic acid and 1-(2-fluorophenyl)ethanamine. LCMS (M+H)+: m/z=509.2
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([O:43][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:45]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Oc2ncnc3cc(OCCOC)c(OC)cc23)c1

Procedure:
Using the procedure described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate described in Example 166A (0.138 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureido)-1H-pyrazol-1-yl]acetate as solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[C:27]([O:30][CH2:31][CH2:32]Br)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:31]([O:30][C:27]([CH2:28][NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[CH:14]=[CH:13][C:12]=2[CH2:11]1)=[O:29])[CH3:32]
Reactant: CC(=O)OCCBr
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Yield: 60.7 %

Procedure:
A mixture of pivalic acid 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (110 mg), bromoethyl acetate (400 mg), sodium acetate (200 mg) and ethanol (2 ml) was refluxed overnight. A saturated aqueous solution of sodium bicarbonate was added, and the solution was extracted with ethyl acetate. The solution was washed with brine, dried over magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (83 mg).