Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:122])[C:82]2[CH:81]=[C:80]([C:83]3[NH:87][C:86]([C@@H:88]4[CH2:96][C:91]5([O:95][CH2:94][CH2:93][O:92]5)[CH2:90][N:89]4[C:97](=[O:107])[C@@H:98]([NH:102][C:103](=[O:106])[O:104][CH3:105])[CH:99]([CH3:101])[CH3:100])=[N:85][CH:84]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:108]1[CH:109]=[CH:110][C:111]3[N:115]=[C:114]([C@@H:116]4[CH2:120][CH2:119][CH2:118][NH:117]4)[NH:113][C:112]=3[CH:121]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:117]1[CH2:118][CH2:119][CH2:120][C@H:116]1[C:114]1[NH:113][C:112]2[CH:121]=[C:108]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[NH:87][C:86]([C@@H:88]7[CH2:96][C:91]8([O:95][CH2:94][CH2:93][O:92]8)[CH2:90][N:89]7[C:97](=[O:107])[C@@H:98]([NH:102][C:103]([O:104][CH3:105])=[O:106])[CH:99]([CH3:100])[CH3:101])=[N:85][CH:84]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:122])[C:71]=4[CH:72]=3)[CH:109]=[CH:110][C:111]=2[N:115]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4c(c3)C(F)(F)c3cc(-c5ccc6nc([C@@H]7CCCN7)[nH]c6c5)ccc3-4)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4c(c3)C(F)(F)c3cc(-c5ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c6c5)ccc3-4)[nH]1)OCCO2)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-8-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 929.83 [M+H]+. (90 mg, 63%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH3:12])[C:5]2=[O:13].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>COCCO>[CH3:12][N:6]1[C:5](=[O:13])[C:4]2[C:9](=[N:10][CH:11]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[N:3]=2)[N:8]=[CH:7]1
Reactant: Cn1cnc2ncc(Br)nc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: COCCO
Product: Cn1cnc2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1=O
Temperature: 100 °C
Yield: 98.3 %

Procedure:
To a solution of 6-bromo-3-methyl-pteridin-4-one (17.75 g, 73.64 mmol) in 2-methoxyethanol (163.5 mL) was added tert-butyl piperazine-1-carboxylate (24.70 g, 132.6 mmol) and the resulting suspension heated for 2 hours at 100° C. The reaction mixture was allowed to cool in an ice-water bath and the precipitate that formed collected and washed with cold methanol to give the desired product as a yellow solid (25.08 g, 98% Yield).
Reaction SMILES: [CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7](OC)[O:8]C)/[CH3:2].CC(C)=O>O>[CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7]=[O:8])/[CH3:2]
Reactant: C=CC(Br)=N/C(=C\C)C(=O)CCC(OC)OC
Solvent: CC(C)=O
Solvent: O
Product: C=CC(Br)=N/C(=C\C)C(=O)CCC=O
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of N-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]acrylimidoyl bromide (7.0 g, 28.9 mmol) in a solution of acetone (30 mL) and water (1.5 mL) at room temperature, is added Amberlyse-15 (20 g). After mechanical shacking for 3 hr at room temperature, the reaction mixture is filtered. The resin beads were washed with acetone (contain 10% of Et3N). The combined organic layers were concentrated and purified by chromatography (Hexane/EtOAc: 70/30) to yield N-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoyl bromide (5.18 g, 88.1%) as light yellow liquid. M/Z=421, 243.9 [M+1]
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][N:19]([CH3:29])[NH:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C3=NNN(C)N3)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242 in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to provide the title compound as a white solid (0.015 g); mass spectrum (m/e): 365.09 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]#[C:11][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[CH:7]=1
Reactant: C#Cc1c(C)cc(C)cc1C
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 2-ethynyl-1,3,5-trimethylbenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% ethyl acetate in hexane to give 3-chloro-5-(mesitylethynyl)picolinonitrile a as white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[O:12][CH:11]=[C:10]([CH2:13][OH:14])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([C:16]1[CH:11]2[O:12][C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]=1[C:21]([O:23][CH3:24])=[O:22])[CH:9]=[C:10]2[CH2:13][OH:14])=[O:18]
Reactant: COC(=O)C#CC(=O)OC
Reactant: OCc1coc(Cc2ccccc2)c1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C(=O)OC)C2(Cc3ccccc3)C=C(CO)C1O2
Yield: 100.9 %

Procedure:
A stirred solution of 5.6 grams (0.03 mole) of [5-(phenylmethyl)-3-furanyl]methanol and 4.3 grams (0.03 mole) of dimethyl acetylenedicarboxylate in 100 ml of toluene was heated under reflux for 3 hours. The solvent was removed under reduced pressure to give approximately 10 grams of 2,3-bis(methoxycarbonyl)-4-phenylmethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-6-methanol. The alcohol was used without further purification.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[CH2:47](N)[CH2:48]N>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][CH2:14][CH2:9][NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:47][CH3:48])[CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCCN
Product: CCc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4-chloro-6-ethylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=7.6 Hz, 1 H), 7.84 (d, J=7.6 Hz, 1 H), 7.62 (m, 2 H), 7.44 (t, J=8.4 Hz, 2 H), 7.32 (dd, J=1.6, 8.4 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 4.53 (brs, 2 H), 3.58 (s, 2 H), 3.44 (t, J=6.0 Hz, 2 H), 2.97 (t, J=6.4 Hz, 2 H), 2.72 (q, J=7.6 Hz, 2 H), 1.27 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC1CCNC1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Product: OC1CCN(CC(O)COc2ccc(-c3nc4cc(Br)cnc4[nH]3)cc2)C1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and pyrrolidin-3-ol.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[CH:16]1([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2I)[CH2:18][CH2:17]1.O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.[Cu](I)I.CO>[CH:16]1([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH2:18][CH2:17]1
Reactant: Ic1cnccc1C1CC1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cnccc1C1CC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 12.9 %

Procedure:
7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-4-d: 100 mg, 0.465 mmol) was reacted with 4-cyclopropyl-3-iodopyridine (I-73c: 125.3 mg, 0.51 mmol), 1,4-dioxane (5 mL), copper iodide (8.8 mg, 0.0465 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.6 mg, 0.0465 mmol) and potassium phosphate (246 mg, 1.16 mmol). The resulting mixture was stirred for 24 hours at 120° C. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was concentrated to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 20 mg of the product (12.9% yield).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24]C)=[CH:22][CH:23]=3)[N:13]=[C:12]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:11]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br.Br.C(OC(=O)C)C.Cl>C(OCC)(=O)C>[ClH:1].[NH:26]([C:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][CH:19]=2)[N:13]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(CNc2nc(Nc3ccccc3)nc(Nc3ccc(F)cc3)n2)cn1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1ccc(CNc2nc(Nc3ccccc3)nc(Nc3ccc(F)cc3)n2)c[nH]1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 565 mg portion of the N-(4-fluorophenyl)-N′-[(6-methoxypyridin-3-yl)methyl]-N″-phenyl-1,3,5-triazine-2,4,6-triamine hydrochloride synthesized in Invention Example 753 was mixed with 5 ml of 25% hydrobromic acid acetic acid solution and 1 ml of 48% hydrobromic acid aqueous solution and stirred at 80° C. for 6 hours. After evaporation of the reaction solution under a reduced pressure, the residue was mixed with ethyl acetate and sodium bicarbonate aqueous solution in that order and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel column chromatography and eluted with chloroform:methanol (99:1) to obtain a crude product. This crude product was dissolved in ethyl acetate and mixed with 4 M hydrochloric acid ethyl acetate solution, and the thus formed crystals were collected by filtration and dried to obtain 195 mg of 5-[({4-anilino-6-[(4-fluorophenyl)amino]-1,3,5-triazin-2-yl}amino)methyl]pyridine-2(1H)-one hydrochloride as colorless crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([CH:13]=[CH2:14])[C:5]([OH:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:17][CH:18]=[CH2:19]>CN(C=O)C.CCOCC>[CH2:19]([O:12][C:5]([CH3:11])([C:4]([F:15])([F:3])[CH:13]=[CH2:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[CH2:17]
Reactant: C=CC(F)(F)C(C)(O)C(=O)OCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(C)(C(=O)OCC)C(F)(F)C=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH (48.5 mg, 1.212 mmol) was added to a cold (−20° C.) solution of ethyl 3,3-difluoro-2-hydroxy-2-methylpent-4-enoate (214 mg, 1.102 mmol) in DMF (2 mL) and the mixture was allowed to warm to rt (˜30 min) and then 3-bromoprop-1-ene (0.113 mL, 1.323 mmol) was added. The mixture was stirred at rt overnight, diluted with ether (20 mL) and washed with water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (2:1 DCM-hexanes) to afford ethyl 2-(allyloxy)-3,3-difluoro-2-methylpent-4-enoate as a clear oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: NC(=O)C1(c2ccc(Br)cn2)CCCC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CCCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 62 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopentanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 62% of theory; LC (method 2): tR=2.02 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15]([C@H:17]2[CH2:22][CH2:21][C:20]([CH3:23])=[CH:19][CH2:18]2)=[O:16])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]([CH3:27])([CH3:28])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:14]([CH:24]([CH3:25])[CH3:26])[C:15]([C@H:17]2[CH2:22][CH2:21][C:20]([CH3:23])=[CH:19][CH2:18]2)=[O:16])[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@@H]1CC=C(C)CC1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
(S)-Methyl 5-(3,3-dimethylbut-1-ynyl)-3-(N-isopropyl-4-methylcyclohex-3-enecarboxamido)thiophene-2-carboxylate (123 mg, 0.31 mmol) was dissolved in THF (2 mL). Water (0.5 mL), methanol (0.5 mL) and lithium hydroxide (129 mg, 3.1 mmol) were added. The mixture was sealed and heated to 45 deg C. for 30 min. After an additional 1 h at ambient temperature, the mixture was treated with 10% HCl (until the pH was less than 3) and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate (anhyd) and the residue was purified by reverse phase HPLC to give the title compound, 41 mg (35% yield): MS (m/z): 388.0 [M+H]+; HPLC retention time 4.59 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1)=[N:5][CH:6]=[N:7]2.F[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)=[C:18]([CH3:23])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1O
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
A mixture of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol (0.47 g, 1.5 mmol), 2-fluoro-4-trifluoromethylpyridine (0.371 g, 2.25 mmol), and potassium carbonate (0.31 g, 2.25 mmol) in DMSO (7 mL) was heated at 90° C. overnight. The reaction was complete, as determined by LC-MS. After cooling to room temperature, water was added and the mixture was stirred for 10 min. The solid precipitate was collected by filtration, washed with water, and dried under vacuum at 50° C. to provide 0.533 g (77%) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as an off-white solid, M.P. 108-110° C. 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.31 (d, J=5.1 Hz, 1H), 7.34 (m, 1H), 7.13-7.21 (m, 4H), 6.96-7.03 (m, 2H), 6.71-6.84 (br, 1H), 3.94 (m, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.17 (s, 3H). LC/MS: 461.13 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH2:26][CH3:27])=[N:20][CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25]>CN(C=O)C>[CH2:26]([C:19]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[C:23]([CH2:24][CH3:25])[CH:22]=[CH:21][N:20]=1)[CH3:27]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1ccnc(CC)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccnc(CC)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (839 mg, 5.9 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (2.45 g, 17.7 mmol) and 3-(bromomethyl)-2,4-diethylpyridine (7.1 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-10% DCM/MeOH to afford 2-{[(2,4-diethylpyridin-3-yl)methyl]sulfanyl-6-methylpyrimidin-4-ol (966 mg, 56% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.14-1.22 (m, 6H), 2.22 (s, 3H), 2.68 (q, J=7.5 Hz, 2H), 2.82 (q, J=7.5 Hz, 2H), 4.48 (s, 2H), 6.05 (bs, 1H), 7.08 (d, J=5.1 Hz, 1H), 8.32 (d, J=5.1 Hz, 1H).
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:2]([CH3:13])=[CH:3][C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6]2=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C)cc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
2-(2-oxopropyl)benzoic acid (100 mg, 0.56 mmol), 4-methoxyaniline (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.84 mmol) and pyridine (0.5 mL) were dissolved in chloroform (5 mL) and stirred at room temperature overnight. Chloroform was added, the organic phase was washed by aqueous citric acid solution, sodium hydrogen carbonate aqueous solution and saturated brine in that order, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (hexane/ethyl acetate=10/0-3/7) to obtain the target compound (66 mg, 44%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH2:9])=[N:6][CH:5]=[CH:4][N:3]=1.CO[C:12](OC)(OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]2[N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NNc1nccnc1Cl
Reactant: COC(OC)(OC)c1ccccc1
Product: Clc1nccn2c(-c3ccccc3)nnc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
Title compound 471 (0.8 g, 5.53 mmol) and Trimethyl orthobenzoate (5 mL, 29.1 mmol) were combined and the reaction mixture was stirred at 120° C. for 3 h. The mixture was cooled to room temperature and the solid was filtered and washed with hexanes to afford title compound 472 (1.35 g, 100%) as a beige solid. MS (m/z): 231.1 (M+H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c2ccccc2c1Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
2-Methyl-3-(4-nitrobenzyl)-1H-indole (4.0 g, 15 mmol) was weighed, and dissolved in 30 mL DMF. Cesium carbonate (9.77 g, 30 mmol) was added, and stirred at room temperature for 15 min. Ethyl bromoacetate (2.755 g, 16.5 mmol) was added, and reacted at room temperature for 3 h. Upon completion of the reaction, it was filtered. The filtrate was added into water, and extracted with ethyl acetate. The extract was washed with water, and a saturated solution of sodium chloride, rotate evaporated to dryness, chromatographed on a silica gel column (petroleum ether) to obtain a yellow solid 2.7 g, at a yield of 51.1%.