Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:34]1>CN(C=O)C.O.CS(C)=O>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[CH2:34]1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCCC(CBr)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine. trifluoroacetate salt (2.56 g, 7.29 mmol) in DMF (60 ml) was added potassium carbonate (4.03 g, 29.1 mmol) and the mixture was left to stir at 60° C. for one hour under an atmosphere of nitrogen. Reaction was then cooled to room temperature and to this was added phenylmethyl 3-(bromomethyl)-1-piperidinecarboxylate (2.275 g, 7.29 mmol). The reaction was bought back up to 50° C. and left to stir overnight. The reaction mixture was diluted with water (˜40 ml) and partitioned with a solvent mix of 1:1 ethyl acetate:DCM (40 ml). The organic layer was separated using hydrophobic frit and was concentrated in vacuo to give pale yellow thick oil. The crude material was dissolved in 1:1 DMSO:MeOH (5 ml) and half of this solution was initially purified on reverse-phase chromatography using a high pH system on a 330 g C18 silica column. The gradient used was the following:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:17]([O:20]C=C)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[ClH:28].CO>>[ClH:28].[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OC=C)cc23)c1
Agent: Cl
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(O)cc23)c1

Procedure:
(3-Ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-vinyloxy-quinazolin-4-yl]-amine (20 mg; from Example 48) was hydrolyzed by treatment with 6M HCl/methanol (30:70; 3 mL) at 50° C. for 5 days. The solution was concentrated in vacuo, and the residue was partitioned between CHCl3 and brine at a pH of about 7. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title product as its free base (15 mg), which was converted to its HCl salt according to the procedure described for Example 28 (M.P. 135°-150° C. (dec); LC-MS: 336 (MH+); anal. RP-HPLC RT: 3.77 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[O:8][C:7]([CH3:16])([CH3:15])[CH:6]=[C:5]2[CH2:17][CH3:18].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC>C1COCC1>[CH2:13]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:17][CH3:18])=[CH:6][C:7]([CH3:16])([CH3:15])[O:8]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25])[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOc1cc2c(cc1Br)C(CC)=CC(C)(C)O2
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(C)=O)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure H, a solution of 6-bromo-4-ethyl-7-ethoxy-2,2-dimethyl-2H-chromene (Compound 16, 595 mg, 2.08 mmol) in THF was treated with tributyl(1-ethoxyvinyl)tin (1.50 g, 4.17 mmol) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH2:11][O:12][CH3:13])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH2:11][O:12][CH3:13])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(Cl)cccn2c1I
Product: COCc1nc2c(Cl)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 54 %

Procedure:
[step 4] Using 8-chloro-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (500 mg, 1.55 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (227 mg, 0.775 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[8-chloro-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (205 mg, 54%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O>CN(C)C=O>[C:1]1([C:7]2[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCCn1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
4.32 g of 2-phenyl-imidazole in solution in 25 ml of dimethylformamide were added over 75 minutes at ambient temperature to 1.73 g of sodium hydride in 5 ml of dimethylformamide and then, 10.97 g of N-(4-bromobutyl)-phthalimide in 33 ml of dimethylformamide were added. The mixture was stirred for 48 hours at ambient temperature and extraction was carried out with ethyl acetate, followed by drying. The solvent has evaporated and the residue was chromatographed on silica (eluant: ethyl acetate-methylethylamine 95-5). The residue was taken up in ether, chilled and the crystals were separated out and dried to obtain 1.11 g of the expected product melting at 82°-84° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[O:29][C:7]1([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]4[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:26][O:25][C:23]1[C:22]2[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:13]([N:10]2[CH2:9][CH2:8][C:7]3([CH2:6][C:5](=[O:33])[C:4]4[C:30](=[CH:31][CH:32]=[C:2]([C:8]5[CH:9]=[N:10][CH:11]=[CH:12][CH:7]=5)[CH:3]=4)[O:29]3)[CH2:12][CH2:11]2)=[O:14])[CH:24]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Br)ccc2O3)nc2c(OC)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cccnc4)ccc2O3)nc2c(OC)cccc12
Temperature: 110 °C

Procedure:
6-Bromo-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one (200 mg), pyridine-3-boronic acid-1′,3′-propanediol cyclic ester (76.6 mg) and Pd(PPh3)4 (45.2 mg) were suspended in a mixture of 1,4-dioxane (1.6 mL) and aqueous 2 M sodium carbonate solution (0.8 mL), and heated under reflux at 110° C. for 12 hours. The reaction solution was partitioned between ethyl acetate and water, extracted with ethyl acetate, washed with saturated brine, and dried with magnesium sulfate. The desiccant was removed through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified through thin-layer chromatography (chloroform/methanol=95/5) to obtain the intended compound. 1H-NMR (300 MHz, CDCl3) δ: 8.83 (1H, d, J=1.7 Hz), 8.59 (1H, dd, J=4.8, 1.7 Hz), 8.10 (1H, d, J=2.4 Hz), 7.82-7.90 (1H, m), 7.77 (1H, m), 7.76 (1H, d, J=8.6, 2.4 Hz), 7.47 (1H, dd, J=8.2, 7.8 Hz), 7.36 (1H, dd, J=7.8, 4.8 Hz), 7.19 (1H, s), 7.15 (1H, d, J=8.6 Hz), 7.08 (1H, d, J=7.8 Hz), 4.55-4.65 (1H, m), 4.10-4.25 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.55-3.70 (1H, m), 3.30-3.45 (1H, m), 2.87 (1H, d, J=16.7 Hz), 2.80 (1H, d, J=16.7 Hz), 2.20-2.30 (1H, m), 2.05-2.20 (1H, m), 1.80-2.00 (2H, m). MS [M]+=509.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9])[CH3:20]
Reactant: CCO
Reactant: COc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCc1ccc(OC)c(C#N)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 5-chloromethyl-2-methoxy-benzonitrile (254 mg, 1.399 mmol) in ethanol (10 mL) was added potassium carbonate (387 mg, 2.798 mmol). The mixture was heated at reflux for 12 h. Upon cooling to room temperature, the solvent was removed. Water (2-5 mL) was added and the product was extracted with diethyl ether (2×20 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 5-ethoxymethyl-2-methoxy-benzonitrile (182 mg, 68%).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:60]1([O-:65])[CH2:61][CH2:62][CH2:63][CH:64]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:65][N:60]4[CH2:61][CH2:62][CH2:63][CH:64]4[CH:54]3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [O-][N+]1=CCCC1
Reactant: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 53.2 %

Procedure:
To a solution of 0.300 g of ethyl 3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[l-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-2-propenoate in 20 ml of toluene is added 0.293 g of 3,4-dihydro-2H-pyrrole 1-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.177 g of the desired product. FAB MASS SPEC 620 (M+H, --Ph3c).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16][CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([O:16][CH3:17])[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: COc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-methoxy-phenoxy)-ethyl]-pyrrolidine (300 mg, 0.86 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (194 mg, 0.91 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]3[NH:34][CH2:33][C:32]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:29]3=[N:30][CH:31]=2)[CH2:22][CH2:21]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:18][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH3:19])=[C:2]([N:34]3[C:28]4[C:29](=[N:30][CH:31]=[C:26]([N:23]5[CH2:24][CH2:25][O:20][CH2:21][CH2:22]5)[CH:27]=4)[C:32]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:33]3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2cccc(F)c2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(F)c2)nc2ncccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(3-fluorophenyl)-3-methyl-1,8-naphthyridine (49.5 mg, 0.182 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (50 mg, 0.182 mmol), sodium tert-butoxide (34.9 mg, 0.363 mmol) and XPhos precatalyst (13.35 mg, 0.018 mmol) in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(2-(3-fluorophenyl)-3-methyl-1,8-naphthyridin-4-yl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 9.13 (1H, dd, J=4.3, 2.0 Hz), 8.13 (1H, dd, J=8.2, 2.0 Hz), 7.66 (1H, d, J=2.3 Hz), 7.42-7.54 (4H, m), 7.15-7.23 (1H, m), 5.79 (1H, d, J=2.3 Hz), 4.14-4.21 (2H, m), 3.71-3.82 (4H, m), 3.56-3.65 (2H, m), 2.95-3.06 (4H, m), 2.30-2.43 (5H, m), 1.62-1.89 (4H, m). Mass Spectrum (ESI) m/e=512.2 (M+1).
Reaction SMILES: CC([S-])C.[Na+].[CH3:6][N:7]([CH3:39])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]3[O:22][C:23]4[C:28]([CH:29]([C:30]5([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31]5)[C:19]3=[CH:18][CH:17]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:12][CH:11]=1)=[O:9].Cl.C(OCC)(=O)C>CN(C=O)C>[CH3:6][N:7]([CH3:39])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]3[O:22][C:23]4[C:28]([CH:29]([C:30]5([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]5)[C:19]3=[CH:18][CH:17]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:12][CH:11]=1)=[O:9]
Reactant: CCOC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)N(C)C)cc4)ccc32)CCC1
Agent: CC(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2ccccc2C3C2(C(=O)O)CCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
Sodium propane-2-thiolate (172 mg, 1.75 mmol) was added to a solution of the product from Step 2 (80 mg, 0.175 mmol) in DMF (5 mL) at room temperature. After 15 h at 60° C., the mixture was cooled to room temperature and adjusted pH2-3 with 1 N aqueous HCl. After addition of ethyl acetate (100 mL), the mixture was washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated. Purification by preparative HPLC gave the desired 1-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)cyclobutanecarboxylic acid (45 mg, 60%). MS (ES+) m/z: 429 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:18][CH2:19][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:25]=2[CH2:26]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCOCC3)c(F)c2)c1
Yield: 39.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-morpholin-4-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.2 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[C:10]([C:3]1[CH:4]=[N:5][N:6]([CH:7]([CH3:9])[CH3:8])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)#[N:11]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)n1ncc(C#N)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncc(C#N)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of crude 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (0.72 g, 4.5 mmol maximum) and 4-nitrobenzoylchloride (1.3 g, 6.8 mmol) in dichloromethane (20 mL) was treated successively with triethylamine (1.8 mL, 14 mmol) and 4-N,N-dimethylaminoaniline (DMAP, 55 mg, 10 mol %). The mixture was heated to reflux (oil bath) for one hour and then allowed to cool to room temperature. The mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in pyridine (20 mL). Water was added, followed by concentrated aqueous ammonium hydroxide (5 mL). The reaction vessel was swirled manually and then left overnight at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with saturated aqueous sodium hydrogen carbonate solution and once each with 0.25 M aqueous hydrochloric acid and saturated aqueous sodium chloride solution. Drying over anhydrous magnesium sulfate was followed by filtration and then concentration under reduced pressure to provide N-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-4-nitrobenzamide as a dark yellow solid (1.3 g, 100%). MS (ES+): 299.6, 299.9 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:75])([CH3:74])[CH3:73])=[O:69].[BH4-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:73])([CH3:74])[CH3:75])=[O:69])=[O:32])=[CH:34][CH:35]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(N2C(=O)[C@H](SCC(=O)c3ccc4c(c3)OCO4)[C@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: CC(C)(C)[C@@H](NC(=O)CN)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(N2C(=O)[C@H](SCC(O)c3ccc4c(c3)OCO4)[C@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)(C)C)cc2)cc1
Reaction time: 15 h

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-methylphenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.020 g, 0.040 mmol) and NMM (0.013 ml, 0.116 mmol) in DMF (3 ml) at RT was added TBTU (0.016 g, 0.050 mmol). The reaction mixture was stirred for 30 min after which glycyl-3-methyl-D-valine (0.009 g, 0.048 mmol) was added. The mixture was stirred for 15 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with MeOH (2 ml) and added NaBH4 (0.017 g, 0.449 mmol). After 15 min the reaction was quenched by the addition of an aqueous solution of hydrochloric acid (1M, 1 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[S:34][CH:35]=2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3csc(-c4ccccc4)n3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (110 mg), 4-(chloromethyl)-2-phenyl-1,3-thiazole (53.1 mg), and DMF (2.5 mL) was added K2CO3 (123 mg). After stirring for 2 hours at 60° C., the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate (133 mg).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:37]#[N:38])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:37]#[N:38])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Product: N#Cc1cc(F)ccc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)c1
Yield: 57 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine was coupled with 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 4-fluoro-3′-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (220 mg, 57%) as a yellow powder: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.45 (1H, ddd, J 8, 1 and 1), 7.53 (1H, dd, J 8 and 3), 7.55-7.61 (2H, m), 7.65-7.67 (1H, m), 7.70-7.75 (1H, m), 7.77 (1H, s), 8.14 (1H, s), 9.14 (1H, d, J 7); m/z (ES+) 383 (M++H).