Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[N:13]([CH3:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CN(C)C(=O)CO2)cc1OC
Temperature: 25 °C
Yield: 96.9 %

Procedure:
2-(3,4-dimethoxyphenyl)morpholin-5-one (0.10 g, 0.42 mM) produced in Example 1, sodium hydride (60%) (0.02 g, 0.46 mM), and methyl iodide (0.07 g, 0.51 mM) were dissolved in dry N,N-dimethylformamide (2 ml) and the mixture was stirred at room temperature for one night. Water was added to the reaction solution, the solution was extracted with methylene chloride, the extract was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product as a yellow oil. The crude product was purified by flash chromatography (SiO2: eluted by 3% methanol/methylene chloride) to obtain the above-described compound (yield 96.9%) as a colorless solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][CH:30]=[C:31]([C:33]([N:35]2[CH2:40][C:39]3([CH2:45][CH2:44][N:43]([CH2:46][CH2:47][C:48]4[CH:61]=[CH:60][C:51]([CH2:52][CH2:53][O:54][CH2:55][CH2:56][C:57](O)=[O:58])=[CH:50][CH:49]=4)[CH2:42][CH2:41]3)[O:38][CH2:37][CH2:36]2)=[O:34])[N:32]=1)([CH3:27])[CH3:26].[CH3:62][O:63][CH:64]([O:73][CH3:74])[CH2:65][NH:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1.C(N(CC)CC)C>CN(C=O)C>[CH:67]1([N:66]([CH2:65][CH:64]([O:73][CH3:74])[O:63][CH3:62])[C:57](=[O:58])[CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]2[CH:60]=[CH:61][C:48]([CH2:47][CH2:46][N:43]3[CH2:42][CH2:41][C:39]4([O:38][CH2:37][CH2:36][N:35]([C:33]([C:31]5[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][CH:30]=5)=[O:34])[CH2:40]4)[CH2:45][CH2:44]3)=[CH:49][CH:50]=2)[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)O)cc4)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(CN(C(=O)CCOCCc1ccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)cc1)C1CCCCC1)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.23 g) was added in one portion to an ice cold solution of 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid [Example 1, step e] (0.3 g) and N-(2,2-dimethoxyethyl)cyclohexanamine [WO 2008075025] (0.087 g) and triethylamine (0.26 mL) in DMF (10 mL). The mixture was stirred at 20° C. for 1 hour before being partitioned between ethyl acetate and brine. The organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.32 g.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8]
Reactant: CCCCCCCCCCO
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)[C@@H]1CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold suspension of pyroglutamic acid (1.3 g) and n-decanol (1.6 g) in dichloromethane (50 ml), dicyclohexylcarbodiimide (2.1 g) and 4-dimethylaminopyridine (0.1 g) were added. After stirring at ice bath temperature for 2 hours, the cooling bath was removed and the mixture was stirred at room temperature overnight. The dichloromethane was evaporated off. The residue was taken in ether and filtered. The filtrate was washed with 1N HC1, water, aqueous bicarbonate and water. It was then dried over Na2SO4 and evaporated. The residue weighed 2.75 g. It was chromatographed over silica gel. The pure decyl ester was eluted with ethylacetate-chloroform (1:4), 2.3 g m.p. 34-35%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:34])[N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:36]([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])=[O:37]>ClCCl.CN(C)C1C=CN=CC=1.CO>[C:36](=[O:37])([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])[O:27][C@@H:24]1[CH2:25][CH2:26][N:22]([CH:21]([C:18]2[S:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[N:20][CH:19]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH2:23]1
Reactant: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)O[C@@H]1CCN(C(c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccccc2Cl)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (3.00 g, 6.02 mmol) was suspended in 200 mL of anhydrous dichloromethane containing N,N-dimethylpyridin-4-amine (2.20 g, 18.0 mmol). (1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl chloroformate (1.91 mL, 9.00 mmol) was slowly added to the suspension and the resulting mixture was heated to reflux for 16 hours. The resulting pale yellow solution was allowed to cool to room temperature, diluted with 20 mL of methanol, and then evaporated to dryness. The crude reaction mixture was separated on 330 g of silica gel utilizing a gradient of 0-5% methanol in dicholoromethane to yield the pure product as a pale yellow solid (2.0087 g, 2.9529 mmol, 49.1%). ESI-MS m/z calc. 679.3. found; 680.5 (M+1)+; Retention time 3.88 minutes.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C@H:4]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:5][O:6][C:7]1[C:8]([C:23]([CH3:25])=[CH2:24])=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:3][CH:2]([CH3:1])[CH3:34])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)([CH3:25])[CH3:24]
Reactant: C=C(C)c1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@@H](COc1cc2c(cc1C(C)C)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Yield: 1146 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-(prop-1-en-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.1 g, 0.215 mmol) and palladium on carbon (0.07 g, 0.066 mmol) in MeOH (3 mL) and ethyl acetate (3 mL) was stirred at RT under a balloon of hydrogen gas for 24 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-isopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.04 g, 2.464 mmol, 1% yield) as a brown oil, which was carried on without further purification. LC/MS (ESI) m/e 468.4, [(M+H)+, calcd for C27H38N3O4, 468.3]; LC/MS retention time (method D): tR=1.00 min.
Reaction SMILES: Br[C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1.[CH2:8]([Mg]Br)[CH:9]([CH3:11])[CH3:10]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C[Mg]Br
Reactant: OC1CCC=C1Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1=CCCC1O
Temperature: 25 °C

Procedure:
The alcohol (Intermediate D3, 16 mmol) in THF (30 mL) at 0° C. was treated with isobutyl magnesium bromide (40 mmol). The catalyst, 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3 h. (see: Organ et al. J. Org. Chem. 1997, 62,41523, incorporated herein by reference). The reaction mixture was cooled to rt and quenched with sat. NH4Cl solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over Na2SO4, filtered and concentrated under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx to yield 2-isobutyl-cyclopent-2-enol (Intermediate D4). Use of 2-isobutyl-cyclopent-2-enol (Intermediate D4) in Method A produced 4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 20).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([O:23]C)=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
(2S,4R)-1-tert-Butyl 2-methyl 4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (2.78 g, 8.29 mmol) was dissolved in a 1:1 mixture of MeOH and THF (30 ml) and 2N NaOH (12.5 ml, 26 mmol) was added. After stirring at room temperature for 2 h, the organic solvents were evaporated under reduced pressure and the aqueous phase was extracted twice with dichloromethane. The aqueous phase was then cooled at 0° C. and then acidified with concentrated chlorhydric acid. This phase was extracted twice with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 2.01 g (76% yield) of the final compound were obtained, pure enough to perform the next synthetic step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15](/[CH:17]=[N:7]/[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1)[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C(N)=O)cc1I
Product: Cc1ccc(C(=O)/N=C/N(C)C)cc1I
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A suspension of 3-iodo-4-methylbenzamide (preparation 48a, 2.00 g, 7.7 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (4.0 mL, 30.1 mmol) was heated in a sealed tube at 90° C. with stirring. After 2 hours, the mixture was cooled and concentrated in vacuo. The residue was triturated with diethyl ether and hexanes, and the solid that formed was filtered and dried to give the title compound (1.90 g, 78%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=2)[CH3:9])[CH:2]=1.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[C:29]([OH:36])=[N:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34]>ClCCl>[OH:36][C:29]1[C:28]([CH2:27][NH:26][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH3:9])=[N:11][CH:12]=2)=[C:33]([CH3:34])[CH:32]=[C:31]([CH3:35])[N:30]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1cccnc1)c1ccc(C(=O)O)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccnc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
To a solution of 6-(1-(Pridin-3-yloxy)ethyl)nicotinic acid (150 mg, 0.61 mol) was dissolved in dichloromethane (20 mL), H-benzo[d][1,2,3]triazol-1-ol (124 mg, 0.92 mmol), 1-(3-dmethylaminopropyl)-3-ethylcarbodiimide hydrochloride (176 mg, 0.92 mmol) and triethylamine (3 mL, 1.84 mmol) were added. After stirring at room temperature for 10 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (93 mg, 0.61 mmol) was added. The mixture was stirred at room temperature for 18 hours. Once the start material was consumed, water (30 mL) was added. The mixture was extracted with dichloromethane (40 mL). The organic layer was separated and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-(pyridin-3-yloxy)ethyl)nicotinamide (50 mg, 21.5%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[N:19]([CH2:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])=[O:4])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(OC)c(C(=O)CBr)c(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)c(C(=O)CN=[N+]=[N-])c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(bromoacetyl)-3,5-dimethoxybenzoate was dissolved in DMF, sodium azide (96 mg) was added to it, and stirred at room temperature for 1 hour. The reaction liquid was poured into water, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.C(O)(=O)C.[Br:25]Br>O>[Br:25][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)naphthalene (9.68 g, 36.6 mmol) and glacial acetic acid (150 mL) was slowly added a solution of bromine (5.85 g, 36.6 mmol) in glacial acefic acid (20 mL). The mixture was stirred for 1 hour and the resulting suspension was poured into water (200 mL) and the solid product was collected by filtration. The solid was triturated first with water and then with ethyl acetate to yield 11.25 g (90%) of the title compound as a white solid: mp 172–174° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.05 (3H, s), 7.04 (2H, d, J=8.56 Hz), 7.30 (1H, d, J=9.01 Hz), 7.67 (2H, d, J=8.65 Hz), 7.81 (1H, dd, J=1.61 Hz, J=8.84 Hz), 7.87(1H, J=9.04 Hz), 7.94 (1H, d, J=1.47 Hz), 8.27 (1H, d, J=8.92 Hz); MS (El) m/z 343 (M)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[CH3:20][O:21]C1C=CC(OC)=CC=1C=O>>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([O:21][CH3:20])=[CH:7][C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1ccc(OC)c(C=O)c1
Product: COc1ccc(OC)c(C(O)C#Cc2ccccc2)c1
Yield: 93 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,5-dimethoxybenzaldehyde (1.00 g, 6.02 mmol) was reacted to give the title compound (1.50 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.34 (m, 5H), 7.18-7.15 (d, 1H), 6.97-6.94 (d, 1H), 6.87-6.83 (m, 1H), 6.03-6.01 (d, 1H), 5.77-5.74 (d, 1H), 3.78 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[N:34]1([CH2:40][CH2:41]Cl)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: ClCCN1CCOCC1
Product: COc1cc(-c2nc3ccc(OCCN4CCOCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(morpholin-4-yl)ethyl chloride essentially as previously described. mp 175° C., NMR, IR, MS 572.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (115 mg, 0.26 mmol), (S)-2-aminopropan-1-ol (0.21 ul, 0.27 mmol), and HATU (104 mg, 0.27 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.2 mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to provide 76 mg (57%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36]([OH:38])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[N:49]1([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36](=[O:38])[N:52]1[CH2:53][CH2:54][N:49]([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:50][CH2:51]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: CC(C)(C)OC(=O)NCCC(F)(C(=O)O)c1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
PyBrop (562 mg, 1.21 mmol) was added in a single portion to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid (400 mg, 1.21 mmol) and 4-piperazin-1-yl-quinazoline dihydrochloride (346 mg, 1.21 mmol) in DCM (12 mL) cooled in an ice bath. DIEA (0.84 mL, 4.82 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was diluted with DCM and washed with 0.1N HCl. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using 2% MeOH/DCM followed by 5% MeOH/DCM as eluent to give [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (230 mg). LCMS (APCI+) m/z 528, 530 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:8]([NH:33][C@@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:35][OH:36])=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:14]=2)=[N:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:36][CH2:35][C@@H:34]([NH:33][C:8]1[C:7]([F:6])=[CH:12][N:11]=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[CH:14]=2)[CH:9]=1)[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CO)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (1.83 mL, 23.67 mmol) was added to a cold (0° C.) solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol, 54a, (9.50 g, 18.94 mmol) and triethylamine (3.30 mL, 23.67 mmol) in dichloromethane (118 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 10.5 g of the desired product as a pale yellow foam: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 580.41 (M+H) RT=2.00 minutes.
Reaction SMILES: [C:1]1([C:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17](=[O:27])[CH2:16]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[H][H].[Pd]>[C:34]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[CH2:16]3)[N:10]=[CH:9]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: [H][H]
Reactant: O=C1CC(C=Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1CC(CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN1c1ccccc1

Procedure:
The product from Step I is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.