Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:44]1[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][N:45]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:43])[C:22]1[CH:27]=[C:26]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)[CH:25]=[C:24]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:40][O:41][CH3:42])=[O:34])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.C(NC1C=C(C=C(C2OC=CN=2)C=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)(=O)C1C=CC=CC=1.C(N(CCC)C(C1C=C(C=C(C2OC=CN=2)C=1)C(O)=O)=O)CC.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:43])[C:22]2[CH:27]=[C:26]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)[CH:25]=[C:24]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@@H:36]3[CH2:40][O:41][CH3:42])=[O:34])[CH:23]=2)[C@H:9]([OH:8])[C@H:44]2[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][NH:45]2)[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)C1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Step 12 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (WO 2002/02512), 45 mg, 0.14 mmol) in dichloromethane (2 mL) was added Hunig's base (54 mg, 0.42 mmol) to make a clear solution and HATU (65 mg, 0.17 mmol) was then added. After stirring for 30 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 1 (A), 81 mg, 0.154 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 20% to 30% to 40% EtOAc/Hexane step gradient) to give 110 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.03 (3H, s), 0.06 (3H, s), 0.69 (3H, m), 0.82 (9H, s), 0.87 (3H, m), 0.96 (3H, m), 1.21-1.28 (2H, m), 1.47-1.51 (11H, m), 1.68 (2H, m), 2.01 (1H, m), 2.18 (1H, d, J=15 Hz), 2.68 (1H, dd, J=10, 15 Hz), 2.88 (1H, dd, J=5, 15 Hz), 3.14 (2H, m), 3.26-3.36 (3H, m), 3.44 (2H, m), 3.74 (1H, dd, J=5, 10 Hz), 3.98 (1H, m), 4.08-4.11 (2H, m), 4.64 (1H, dd, J=10, Hz), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.22 (1H, s), 7.68 (1H, s), 7.97 (1H, s), 8.14 (1H, s), 8.64 (2H, m).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9](=[O:26])[C:10](=[CH:22]OCC)[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[O:12])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9](=[O:26])[C:10](=[CH:22][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[O:12])[CH3:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)N
Solvent: CCO
Product: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Tert-butylamine (6.2 mL, 84.7 mmoles) was added to a solution of 13.15 g (43.5 mmoles) of 3-(2,4,5-trifluorophenyl)-3-oxo-2-(ethoxymethylene)-propanoic acid ethyl ester in 19 mL of dry ethanol at -15° C. After 5 minutes, the mixture was stirred at room temperature for one hour, and then concentrated to dryness. The crude residue (10.87 g) was crystallized from 25 mL of hexane to afford 7.22 g of titled compound.
Reaction SMILES: CNCCNC.[Cl:7][C:8]1[CH:22]=[CH:21][C:11](/[CH:12]=[CH:13]/[C:14]2[N:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1.Br[C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]2([OH:36])[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[C:26]([O:39][CH3:40])[CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:12]=[CH:13]/[C:14]2[N:19]=[CH:18][N:17]([C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]4([OH:36])[CH2:31][C:32]([F:35])([F:34])[CH2:33]4)=[C:26]([O:39][CH3:40])[CH:25]=3)[C:16](=[O:20])[CH:15]=2)=[CH:21][CH:22]=1
Reactant: O=c1cc(/C=C/c2ccc(Cl)cc2)nc[nH]1
Reactant: COc1cc(Br)ccc1OCC1(O)CC(F)(F)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc(/C=C/c3ccc(Cl)cc3)cc2=O)ccc1OCC1(O)CC(F)(F)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.93 %

Procedure:
N1,N2-dimethylethane-1,2-diamine (12 nL, 0.11 mmol) was added to a mixture of (E)-6-(4-chlorostyryl)pyrimidin-4(3H)-one Part B (25 mg, 0.11 mmol), 1-((4-bromo-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutanol (38 mg, 0.12 mmol), potassium phosphate tribasic (68.4 mg, 0.322 mmol), and copper (I) iodide (20.5 mg, 0.11 mmol) in DMF (1 mL) and stirred at 100° C. overnight. The reaction was filtered and concentrated. The residue was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product (E)-6-(4-chlorostyryl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one J-3 (5.69 mg, 0.01 mmol, 10.93% yield) as a brown solid. LC/MS 475 (M+H)+, tR 1.00 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.17 (1H, s), 7.76 (1H, d), 7.53 (2H, d), 7.40 (2H, d), 7.08 (1H, d), 6.86-6.97 (3H, m), 6.48 (1H, s), 4.13 (2H, s), 3.89 (3H, s), 2.77-2.87 (4H, m)
Reaction SMILES: C([N:8]([C@H:10]([C:21]#[CH:22])[C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH3:9])(OC(C)(C)C)=O.[F:23][C:24]1[C:25](I)=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:23][C:24]1[C:25]([C:22]#[C:21][C@@H:10]([NH:8][CH3:9])[C@H:11]([OH:13])[CH3:12])=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN[C@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)[C@@H](C)O
Reaction time: 2 h

Procedure:
Using Method C above, (2R,3R)-3-(N-Boc-N-methylamino)-2-(tert-butyldimethylsilyloxy)-pent-4-yne (370 mg, 1.13 mmol) (Example 117C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.39 mmol) (Starting Material 6) using (Ph3P)4Pd (45 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(3R,4R)-4-hydroxy-3-methylamino-1-pentynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 53 mg, 37%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16](C)(C)[O:17][SiH2]C(C)(C)C)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>CO.O>[OH:17][CH2:16][C:10]1[CH:9]=[C:8]([C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COC(=O)C1(c2ccc(OC)c(C(C)(C)O[SiH2]C(C)(C)C)c2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(C2(C(=O)O)CC2)cc1CO
Temperature: 40 °C
Reaction time: 8 h
Yield: 132.5 %

Procedure:
To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]-cyclopropane carboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was added a solution of LiOH.H2O (1.5 g, 36 mmol) in water (10 mL) at 0° C. The reaction mixture was stirred overnight at 40° C. MeOH was removed by evaporation under vacuum. AcOH (1 mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to provide 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](O)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc[nH]c2c1
Yield: 3.4 %

Procedure:
To a solution of 6-indole carboxylic acid (5 g, 31.05 mmol) in tetrahydrofuran (310 ml) is added lithium aluminum hydride (5.89 mg, 155.2 mmol) at 0° C. The reaction mixture is refluxed for 6 hours. The resulting mixture is then quenched with 5% potassium hydrogen sulfate (100 ml) and extracted with ether (100 mL). The organic layer is then dried with sodium sulfate and concentrated to give a white solid (156 mg) MS (ESI) m/z 148.8 (M+1).
Reaction SMILES: C(OC([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[CH:12]([CH2:20][CH3:21])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH2:20]([CH:12]1[C:11]2[C:10]3[CH2:22][CH2:23][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14][C:13]1([F:19])[F:18])[CH3:21]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(CC)C(F)(F)C3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CCC1c2c(ccc3c2CCNCC3)CC1(F)F
Temperature: 60 °C
Yield: 49 %

Procedure:
Into a glass vial containing the product from step (b) (42 mg, 0.130 mmol) dissolved in CHCl3 (2 ml), TMSI (176 μL, 1.3 mmol) was added. The stirred reaction mixture was heated to 60° C. for 2 hours. The volatiles were evaporated in vacuo and 2M HCl (2 ml) and water (20 ml) were added. The aqueous mixture was washed with diethyl ether (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo give the title compound as a colorless semi-solid (16 mg). 1H NMR (300 MHz, CDCl3) 7.00-6.93 (m, 2H); 3.43-3.21 (m, 3H); 2.96-2.86 (m, 8H); 2.20 (bs, 1H); 1.75-1.62 (m, 2H); 0.92 (t, J=7.5 Hz, 3H); MS: ESI (positive): 252 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[C:18]4[C:17]([NH:19][C@H:20]([C:22]5[N:27]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:26](=[O:34])[C:25]6=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]6[N:23]=5)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=4[N:12](COCC[Si](C)(C)C)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.N>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[C:18]4[C:17]([NH:19][C@H:20]([C:22]5[N:27]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:26](=[O:34])[C:25]6=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]6[N:23]=5)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=4[NH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc6[nH]ccc56)c34)n(-c3ccccc3)c(=O)c12
Yield: 35.4 %

Procedure:
(S)-2-(1-((5-(1H-Indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.11 mmol) was treated with trifluoroacetic acid (1.50 mL, 19.47 mmol) and a solution of ammonia (7N in methanol, 1.50 mL, 10.50 mmol) according to the method described in Example 27 to give 19.5 mg (44% yield) of the title compound. Purity 97%.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[F:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>O.O1CCCC1>[F:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[OH:28])=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 11.2 g. (0.1 mol) of 1-(methoxymethyl)imidazole and 13.9 g. (0.12 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml. of anhydrous tetrahydrofuran 51 ml. (0.12 mol) of a butyllithium solution (20% in n-hexane) was added drop-wise over the course of one hour at -60° C., and under a nitrogen atmosphere. After the addition was completed, stirring was continued for another two hours. The cooling means was then removed and 25.1 g. (0.1 mol) of 4,4'-difluorobenzophenone in 150 ml. of anhydrous tetrahydrofuran were added drop-wise. The reaction mixture was stirred for 6 hours at room temperature and it was then decomposed with 15 ml. of water. The precipitated lithium hydroxide was filtered off and the filtrate was concentrated by distilling off the solvents. 2N Hydrochloric acid was added to the residue, after which the mixture was extracted with diethyl ether. The aqueous phase was made alkaline with 2N sodium hydroxide solution. The precipitate formed was filtered off, washed with water and twice crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 40°-60° C.). α,α-Bis(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 133° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21](O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[Cl-].[NH4+]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:12][C:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1

Procedure:
A 11.41 g (29.07 mmol) portion of crude ethyl 3-[1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutan-3-yl]-3-hydroxypropionate was dissolved in 100 ml of dichloromethane to which, while cooling in an ice bath and stirring, were subsequently added 2.70 ml (34.9 mmol) of methanesulfonyl chloride and 10.13 ml (72.68 mmol) of triethylamine in that order. After 2 hours of stirring, to this was added 9.56 ml (72.7 mmol) of diazabicycloundecene. After 1 hour of stirring, the reaction mixture was further stirred at room temperature for 2 hours. While cooling in an ice bath and stirring, this was mixed with saturated ammonium chloride aqueous solution and then with ethyl acetate to effect separation of layers. The resulting organic layer was washed with 10% citric acid aqueous solution and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under a reduced pressure and then the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 9.46 g (25.26 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[C:4]([O:13][CH3:14])[CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[C:4]([O:13][CH3:14])[CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc(F)cc2c(O)nccc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(F)cc2c(Cl)nccc12
Yield: 95.1 %

Procedure:
A solution of 7-fluoro-5-methoxyisoquinolin-1-ol (383 mg, 1.983 mmol) in POCl3 (2772 μl, 29.7 mmol) was refluxed (90° C.) for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum to give 1-chloro-7-fluoro-5-methoxyisoquinoline (399 mg, 95% yield).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[CH2:8]([N:11]1[C:19]2[N:18]=[CH:17][NH:16][C:15]=2[C:14](=[S:20])[NH:13][C:12]1=[O:21])[CH2:9][CH3:10].CI>CCCCCC.C(O)C>[CH3:3][S:20][C:14]1[C:15]2[NH:16][CH:17]=[N:18][C:19]=2[N:11]([CH2:8][CH2:9][CH3:10])[C:12](=[O:21])[N:13]=1
Reactant: CN(C)C=O
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CI
Product: CCCn1c(=O)nc(SC)c2[nH]cnc21
Reaction time: 0.5 h

Procedure:
In an argon atmosphere(9.77 g (244 mmol) of 60% sodium hydride was washed with n-hexane 3 times. The solvent was evaporated under reduced pressure and dried. After 900 ml of N,N'-dimethylformamide was added 57.0 g (271 mmol) of 3-n-propyl-6-thioxanthine (Japanese Published Unexamined Patent Application No. 183287/86) was gently added under ice cooling. 15 minutes after, 15.2 ml (244 mmol) of methyl iodide was dropwise added to the reaction mixture. After stirring for 30 minutes, 50 ml of ethanol was added and the mixture was concentrated under reduced pressure. Then 400 ml of water was added and precipitates were collected by filtration to give 13.9 g (yield, 23%) of Compound b as light yellow powder. The filtrate was extracted 5 times with 200 ml of chloroform. After washing with a saturated aqueous sodium chloride solution, the extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% methanol/chloroform) to give further 16.0 g (yield, 26%) of Compound b as a light yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([N:27]2[CH2:51][CH2:50][C:30]3([CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[CH:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:31]3)[CH2:29][CH2:28]2)[N:3]=1.[C:52]1([OH:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[CH:7]=[C:2]([O:58][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:3]=[C:4]([N:27]3[CH2:51][CH2:50][C:30]4([CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)=[O:36])[CH:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:31]4)[CH2:29][CH2:28]3)[N:5]=2)[C:10]([F:12])([F:11])[F:13])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(Cl)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CC2(CCN(c3nc(Oc4ccccc4)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (by-product from Step 3, Example 30a) (250 mg, 0.347 mmol) in 1,4-dioxane (9.0 mL) was added phenol (1.00 g, 10.6 mmol) and Cs2CO3 (3.65 g, 11.2 mmol). The reaction was heated at 80° C. for 12 h, then cooled to RT diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cnc1Cl
Yield: 92 %

Procedure:
3-Methyl-5-nitropyridin-2-ol (134 g, 0.872 mol) (J. Org. Chem. 1949, 14, 328-332) was divided into 3 portions and placed in three 1-L round bottom flasks. POCl3 (200 mL) was added to each flask and the mixtures were heated to reflux for 2 h. The solutions were cooled and the excess POCl3 was removed in vacuo. The residues were poured into ice water (1 L) with stirring and the precipitates were collected by filtration and air dried for 20 min. The combined products were recrystallized from 10% ethyl acetate in hexanes (300 mL) and air dried to give 2-chloro-3-methyl-5-nitropyridine (139 g, 92% yield) as a white solid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[OH-].[NH4+:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Agent: [OH-]
Product: Cc1ccc(Br)cc1S(N)(=O)=O
Yield: 55 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.89 g, 7 mmol) and ammonium hydroxide (20 mL) to give the title compound (0.96 g, 55%) as a white solid. MS (ISN) 248.0[(M−H)−], 250.0[(M+2−H)−].
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-]>C1COCC1.CO.[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-methoxyphenyl)-quinoline (210.7 mg, 615 μmol) in THF 5 mL and MeOH 12 mL was added palladium, 10 wt. % on activated carbon (0.329 mmol) and placed under a medium balloon containing H2. The reaction was complete after 2 h, it was filtered (Celite™) and solvents removed.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:19]1[C:16]2=[N:17][CH:18]=[C:13]([C:12]3[C:7]([NH:6][C@@H:3]4[CH2:4][CH2:5][N:1]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[N:14]=[C:15]2[CH:21]=[CH:20]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-((R)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-butan-1-one was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and butyryl chloride, following the general synthetic procedures described in the above Examples.