Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]2[C:7]([CH2:8][C@:9]3([CH2:19]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]3=[O:18])=[CH:6][C:5]=1[CH2:22][C:23](O)=[O:24])([O-:3])=[O:2].B>C1COCC1>[OH:24][CH2:23][CH2:22][C:5]1[CH:6]=[C:7]2[C:20](=[CH:21][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:19][C@:9]1([C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]1=[O:18])[CH2:8]2
Reactant: O=C(O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: B
Solvent: C1CCOC1
Product: O=C1Nc2ncccc2[C@@]12Cc1cc(CCO)c([N+](=O)[O-])cc1C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of [(2S)-6-nitro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetic acid from Step D (753 mg, 2.22 mmol) in THF (15 mL), at −78° C., was added borane (1 M in THE; 9.1 mL, 9.1 mmol) dropwise. After 5 min, the mixture was warmed to 0° C. and stirring was continued at this temperature for 3 h. The reaction was quenched carefully with 1 N HCl and stirring was continued at ambient temperature. The mixture was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[O:20][CH:21]=[CH:22][N:23]=1>>[O:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16]
Reactant: Nc1ncco1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: O=C(Nc1ncco1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p.=232-235° C., MS: m/e=292 (M+) was prepared in accordance with the general method of example 31 from 9H-xanthene-9-carbonyl chloride and 2-amino-oxazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CNCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 126.6 %

Procedure:
A solution of 257B (411 mg, 1.04 mmol) in CH2Cl2 (5 mL) was treated with TFA (0.5 mL) at room temperature. The reaction mixture was stirred for 5.0 hours, then concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3. The organics were dried (Na2SO4), filtered and concentrated in vacuo to give 365 mg of 257C as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[NH:20][C:19]3[C:21]([C:25](OC)=[O:26])=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:26][CH2:25][C:21]1[C:19]2[NH:20][C:16]([CH2:15][N:13]([CH3:14])[S:10]([C:6]3[C:5]([CH3:29])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:12])=[O:11])=[N:17][C:18]=2[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc2nc(CN(C)S(=O)(=O)c3c(C)cc(OC)cc3C)[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CO)c3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of methyl 2-((4-methoxy-N,2,6-trimethylphenylsulfonamido)methyl)-1H-benzo[d]imidazole-7-carboxylate (2.40 mmol, 1.0 eq.) was added dropwise to a suspension of LAH (5.28 mmol, 2.2 eq.) in abs. THF (5 ml) under N2 at 0° C. When the addition had ended, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was then quenched with THF/water (9:1; 3 ml), while cooling, and filtered over Celite. The filtrate was concentrated to dryness and the crude product was purified by column chromatography over silica gel to obtain the desired product. Yield: 75%
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:19]=[C:18](O)[C:17]3=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:23][N:16]3[N:15]=2)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([P+](O[N:41]1N=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1CN>C(#N)C.O>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:19]=[C:18]([NH:41][CH2:42][C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][N:48]=3)[C:17]3=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:23][N:16]3[N:15]=2)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1nc(-c2nc(O)c3c(-c4ccccc4)ccn3n2)cs1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)NS(=O)(=O)c1nc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
N-(tert-Butyl)-4-(4-hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (0.0600 g, 0.140 mmol) was dissolved in acetonitrile (5 mL) and cooled to 0° C. BOP reagent (0.0620 g, 0.140 mmol) was added slowly, followed by DBU (0.0210 mL, 0.140 mmol). The reaction mixture was allowed to reach ambient temperature for 1 h then cooled to 0° C. Pyridin-2-ylmethanamine was added, (0.0150 g, 0.140 mmol). The reaction mixture was allowed to reach ambient temperature and stir for 14 h and diluted with water. The aqueous mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 1.2% methanol in CH2Cl2) to afford N-(tert-butyl)-4-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (0.0400 g, 55.0%). The impure compound was taken to the next step as such. LCMS Condition B-13: retention time 2.13 min, [M+1]=520.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20](Cl)[C:21]4[CH:22]=[C:23]([C:27]([CH3:30])([CH3:29])[OH:28])[CH:24]=[CH:25][CH:26]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:32][CH2:33][CH:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:32][CH2:33][CH:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:28])([CH3:30])[CH3:29])[CH:22]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)CS
Reactant: CC(C)(O)c1cccc(C(Cl)c2cccc(C=Cc3ccc4ccc(Cl)cc4n3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(C)CSC(c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)c1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
To the crude chloride of Step 4 dissolved in 10 mL of DNE, ethyl 3-mercapto-2-methylpropanoate (Step 6; 350 μl, approx. 2.4 mmol) and Cs2CO3 (1.61 g, 4.9 mmol) were added and the mixture was stirred at r.t. for 3.5 h. 25% Aq NH4OAc was then added and the reaction mixture was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 7.5:92.5 and 10:90 to yield 347 mg of the title compound as an oil (52% yield for Steps 6 and 7).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:31][C:30]([F:33])([F:32])[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:21]2)[N:13]=3)=[C:2]([F:1])[CH:3]=1)[OH:6]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a mixture of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (2.00 g, 5.34 mmol) and trimethyl(trifluoromethyl)silane (0.911 g, 6.41 mmol) in 20 mL THF under nitrogen at 0° C. was added TBAF 1.0 M in THF (0.534 mL, 0.534 mmol). The reaction mixture became immediately dark brown and homogeneous. The water bath was removed and the reaction mixture was allowed to stir for 3 h. 1N aq. HCl (20 mL) was added and the reaction mixture allowed to stir overnight. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford racemic 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol as a pale yellow foam. The racemic mixture were separated by Multigram II SFC (Column: Chiralpak ADH (21×250 mm, 5 um); A=supercritical CO2; B=Isopropanol; 30% B, 65 mL/min total flow, 40° C., 100 bar outlet pressure) to give (R)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol and (S)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol. MS (ESI) m/z: calculated: 444.1; Observed: 445.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=CC=1>CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][CH:27]=[N:26][CH:25]=2)=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Clc1ccc(-c2cnco2)cn1

Procedure:
To a stirred suspension of 6-chloronicotinaldehyde (1.5 g, 10.59 mmol, Organic Letters 2005, 7(14) 2965-2967) and potassium carbonate (1.46 g, 10.5 mmol) in MeOH (50 mL) was added toluenesulphonylmethyl isocyanide (2.06 g, 10.59 mmol, Aldrich). The reaction mixture was heated to reflux for about 4 h. The reaction mixture diluted with water (50 mL) and the product was extracted with EtOAc (2×150 mL). The combined organic layers were washed successively with water (2×50 mL) and brine (1×50 mL), dried over sodium sulphate and evaporated to dryness. The crude material was purified by silica gel column chromatography eluted with 15% EtOAC in hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 5-(6-chloropyridin-3-yl)oxazole as an off white solid 1.2 g (42.8. %), 1H NMR (400 MHz, CDCl3): δ 8.7 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), MS m/z: 181 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1cccc(Cl)n1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)n2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (6-chloro-2-pyridinyl)acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. The resulting suspension was poured into water (10 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, and the residue was washed with water (10 mL), dried at the pump for ca. 1 hour. The solid residue was dissolved in acetone and adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-{1-[(6-chloro-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (99.8 mg, 53.7% yield) as a beige solid. LC-MS (ES) m/z=419 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (t, J=8.34 Hz, 2H), 3.74 (s, 3H), 4.08 (s, 2H), 4.27 (t, J=8.46 Hz, 2H), 5.92-6.22 (m, 2H), 7.20-7.28 (m, 2H), 7.33 (s, 1H), 7.38-7.46 (m, 2H), 7.87 (t, J=7.83 Hz, 1H), 8.10 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1.[F:11][C:12]1[C:25]2[O:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:26](O)=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH:8][C:26]([CH:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[C:25]=3[O:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:27])=[N:5][CH:4]=1
Reactant: O=C(O)C1c2ccccc2Oc2c(F)cccc21
Reactant: Nc1ncc(C(F)(F)F)o1
Product: O=C(Nc1ncc(C(F)(F)F)o1)C1c2ccccc2Oc2c(F)cccc21

Procedure:
The title compound, white solid, m.p. 228° C. and MS: m/e=379.2 (M+H+) is prepared in accordance with the general method of example 3c from 5-trifluoromethyl-oxazol-2-ylamine and (RS)-4-fluoro-9-xanthene-carboxylic acid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=1
Reactant: BrCCBr
Reactant: CCCCCOc1cccc(O)c1
Product: CCCCCOc1cccc(OCCBr)c1
Yield: 90.9 %

Procedure:
Prepared according to the method described in Example E above from 3-(n-pentoxy)phenol (18.0 g; 0.1 mol; from Example C above) and 1,2-dibromoethane (100 ml; 1.16 mol). Following work up the residue was chromatographed on silica gel with diisopropyl ether as eluent to yield 26.1 g (91%) of the tide compound as an oil which subsequently crystallised (96% purity). MW=287 (GCMS)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:61][CH3:62])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@@H:4]([CH2:3][C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[CH:41]([CH3:40])[CH2:61][CH3:62])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A solution containing the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 36E (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.025 g, 64% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.57 (d, J=6.62 Hz, 3 H), 0.71 (t, J=7.17 Hz, 3 H), 0.82 (m, 12 H), 1.26 (m, 1 H), 1.54 (m, 2 H), 1.73 (m, 1 H), 2.33 (m, 4 H), 2.76 (m, 3 H), 3.51 (s, 3 H), 3.59 (m, 1 H), 3.82 (d, J=18.38 Hz, 1 H), 4.01 (m, 2 H), 4.18 (s, 1 H), 4.67 (m, 2 H), 4.87 (d, J=5.15 Hz, 1 H), 6.82 (d, J=9.56 Hz, 1 H), 7.02 (m, 6 H), 7.12 (d, J=7.72 Hz, 1 H), 7.30 (d, J=8.46 Hz, 3 H), 7.64 (m, 2 H), 7.87 (m, 4 H), 8.09 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([NH:12]C(=O)C)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:16])[CH2:3]1>Cl.CCO>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:17])([CH3:1])[CH2:3][C:4](=[O:16])[NH:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)CC2(C)C
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc(N)ccc21

Procedure:
N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-acetamide (1.50 g, 6.46 mmol) in 10 ml of HCl (concentrated, 37%) and 30 ml of EtOH was stirred at 75° C. for 4 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc/H2O, neutralized with NaHCO3, washed with brine, dried with Na2SO4, filtered, and condensed to give the titled compound as an off-white solid. MS (ES+): 191.2 (M+H)+. Calc'd for C11H14N2O—190.24.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:14])[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCOCc1ccccc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(OCCOCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
Sodium hydride (50% in mineral oil; 0.54 g, 11.35 mmol) was added portionwise to a solution of 2-benzyloxylethanol (1.72 g, 11.4 mmol) in THF (15 mL) at r.t. under nitrogen. After 15 min. 2-chloro-4-nitro-pyridine (1.20 g, 7.57 mmol) was added and the reaction mixture stirred at r.t. overnight. The reaction mixture was quenched by slowly pouring onto ice and concentrated to remove the organic solvent. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate, filtered and concentrated. The crude material was subjected to column chromatography over silica gel (60-120 mesh) using 5%-25% ethyl acetate in petroleum ether as eluent to afford 4-(2-benzyloxy-ethoxy)-2-chloro-pyridine (1.91 g, 96%) as an oily liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH:12]3[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]3)[N:7]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)[C:6]=2[CH:26]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:25][C:21]1[N:20]=[C:19]([N:7]2[C:6]3[CH:26]=[C:2]([C:36]#[C:35][C:33]([C:30]4[CH:29]=[C:28]([CH3:27])[O:32][N:31]=4)([OH:37])[CH3:34])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[CH:24]=[CH:23][N:22]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: CC1(C)OCC(COc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC4COC(C)(C)O4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
A mixture of 4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.32 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (300 mg, 1.98 mmol), bis(triphenylphosphine)palladium(II) dichloride (300 mg, 0.43 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1 h at 70° C. under a nitrogen atmosphere. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 27 mg (17%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid: 1H NMR (400 MHz, DMSO) delta 8.38 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.09 (s, 2H), 7.02 (d, J=5.2 Hz, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.69-4.54 (m, 3H), 4.11 (t, J=7.4 Hz, 1H), 3.89 (t, J=7.2 Hz, 1H), 2.41 (s, 3H), 1.81 (s, 3H), 1.32 (d, J=16 Hz, 6H); LC-MS: m/z=+491 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:3]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: Nc1cccc(O)c1
Product: Nc1nc(Nc2cccc(O)c2)ncc1Br

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 4-amino-5-bromo-2-chloropyrimidine and 3-aminophenol were reacted to give 4-amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.33 (br s, 1H), 8.27 (s, 1H), 7.14-6.06 (m, 2H), 7.01 (d, 1H, J=1.7 Hz), 6.54 (td, 1H, J=1.7 Hz and 7.0 Hz).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([OH:31])[CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39]CC)(=[O:38])[CH2:36]O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([CH:30]=2)[O:31][CH2:36][C:35]([OH:39])=[O:38])=[CH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)c(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CO
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)c(OCC(=O)O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 63F and ethyl glycolate were processed as described in Example 62A to provide the title compound.
Reaction SMILES: [OH-:1].[Na+].C([O:7][C:8]([CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[C:12]1=[O:33])=[O:9])(C)(C)C>C(O)C>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][C:8]([OH:7])=[O:9])[C:12]2=[O:33])[CH2:18][CH2:19]1)=[O:24])(=[O:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CN1CCCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous 4N sodium hydroxide solution (10 mL) was added to a solution of benzyl 4-[3-(tert-butoxycarbonylmethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (1.7 g) obtained in Example 35a) in ethanol (20 mL), and the mixture was stirred at room temperature overnight. Ethanol was distilled off under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust pH to 3, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.5 g, quantitative) as a white powder.