Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:33])([CH3:32])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1.CS(C)=O.CC#N.O>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:32])([CH3:33])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C(C)C12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C(=O)O)C12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 100 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
A mixture of methyl 2-{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}propanoate (Intermediate 18; 220 mg, 0.49 mmol) and potassium trimethylsilanolate (315 mg, 2.45 mmol) in THF (5 mL) was heated in a microwave for 35 mins at 100° C. and was then stirred at ambient temperature for 2 days. The solvent was removed under reduced pressure and the residue partitioned between 2M HCl (20 mL) and EtOAc (50 mL) and the aqueous phase was further extracted with EtOAc (50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave a gum. This was dissolved in DMSO/MeCN/H2O (7:2:1) and separated by reverse phase chromatography eluting 5-95% water-acetonitrile 0.2% TFA, providing the title compound (45 mg, 0.104 mmol, 21%) as a white solid; 1H NMR δ 1.01 (d, 3H), 1.49-1.55 (m, 3H), 1.62 (s, 6H), 1.64-1.69 (m, 3H), 1.78-1.81 (m, 6H), 2.12 (q, 1H), 7.05 (s, 1H), 7.40 (d, 2H), 7.65 (d, 2H), 7.99 (s, 1H); MS m/e MH+ 435.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46]([O:53][C:54]1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1.[Si](OCCNC1COC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:54][O:53][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1COC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1COC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (325 mg, 0.72 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (8 g) (248 mg, 1.07 mmol). The yield was 340 mg, 71%, of a colorless sticky mass.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2].C1C=C[C:37]([N:40](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.CN>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:40][CH3:37])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2]
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Agent: CN
Product: CCOC(=O)c1c(NC)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 61 step D from a crude mixture of 6-chloro-4-(2-chloro-benzyl)-8-fluoro-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester and N-phenylbis(trifluoromethanesulfonimide) and methylamine. Off white solid. MS (ESI): 407 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1)#[N:2].[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(C#N)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
To a solution of 83 mg of (7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 80 mg of tert-butyl piperidin-4-yl-carbamate in 10 mL of chloroform, 24 μL of acetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 136 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of ethyl acetate:hexane=1:1 to obtain 76 mg of tert-butyl (1-(2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17].[NH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC(O)C>[CH2:14]([C:13]1[N:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOCCCCNC(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCCc1nc2cnc3ccccc3c2n1OCCCCNC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 76.5 %

Procedure:
N-(4-chloroquinolin-3-yl)valeramide (1.97 g), benzyl (4-aminooxybutyl)carbamate (2.99 g), triethylamine (0.89 g) and 2-propanol (40.69 g) were combined and heated at 80° C. for 3.5 hours. The reaction was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. Dichloromethane (20 mL) was added to the resulting solid and the mixture was stirred for twenty minutes. Undissolved solid was removed by filtration and the filtrate was washed with two 10 mL portions of water that had been made slightly acidic by the addition of 20 drops of hydrochloric acid (1.2 M). The organic fraction was dried and concentrated under reduced pressure. The crude solid was recrystallized from tetrahydrofuran to provide 2.56 g of benzyl 4-{[2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butylcarbamate.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17]CCCC)=[O:16])=[CH:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>O1CCOCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1cc(=O)n(CCCC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCn1c(=O)cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A mixture of 2.04 g (6.77 mmols) of Compound b, 0.54 g of sodium hydroxide, 40 ml of water and 40 mt of dioxane was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=5/1) to give 1.44 g (yield: 87%) of Compound a.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>COCCO.[Pd]>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH2:11][NH:12][CH2:13][CH2:14]2)[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccncc2C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: COCCO
Solvent: O
Product: O=C1C2CCNCC2C(=O)N1Cc1ccccc1
Temperature: 35 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
To a solution of 2-benzyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (3.50 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 35° C. and stirred for 6 h under H2, then cooled to rt, poured into 100 mL of water and extracted with CH2Cl2 (70 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (2.20 g, 60%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 245.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:39][CH3:40])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:27]2)=[CH:21][CH:20]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1)=[O:5].[OH-].[Na+]>C1COCC1>[CH3:1][CH:2]([CH2:39][CH3:40])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:27]2)=[CH:21][CH:20]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:5]
Reactant: CCOC(=O)C1CCC(CNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)C(C(=O)NCC1CCC(C(=O)O)CC1)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1

Procedure:
A solution of 492 mg (0.90 mmol) of ethyl 4-{[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}pentanoyl)amino]methyl}cyclohexanecarboxylate (Example 150A) in 8 ml of THF and 4.6 ml (4.6 mmol) of 1 N aqueous sodium hydroxide solution was stirred at 60° C. for four days. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 343 mg (0.66 mmol, 73% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][NH:24][CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]4[NH:17][C:18](=[O:20])[NH:19][C:15]=4[CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][N:24]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]4[NH:17][C:18](=[O:20])[NH:19][C:15]=4[CH:14]=3)[N:12]=2)[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: O=c1[nH]c2ccc(-c3nc4c(c(N5CCOCC5)n3)CCNC4)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(-c3nc4c(c(N5CCOCC5)n3)CCN(c3ncccn3)C4)cc2[nH]1

Procedure:
Step 3—Synthesis of compound ug: 5-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.297 g, 0.843 mmol), 2-Chloropyrimidine (0.145 g, 1.27 mmol), N,N-Dimethylformamide (10.0 mL, 129 mmol) and N,N-Diisopropylethylamine (0.588 mL, 3.38 mmol) were combined. The reaction solution was microwaved on 300 watts, 120° C. for 30 minutes on a CEM microwave. The reaction solution was filtered and washed with dichloromethane. LC/MS-m/z+431.2 (M+H)+
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C@@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])=O)(C)(C)C.Cl>CCOCC>[NH2:8][C@@H:9]([CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C@@H:10]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](CO)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H](CC1CCCCC1)[C@H](CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
3(S)-t-Butoxycarbonylamino-2(R)-benzyloxy-4-cyclohexyl-1-butanol (108 mg) (U.S. Pat. No. 4,668,769), Example 1J was dissolved in 0.5 mL ether and cooled to 0° C. Into this solution was introduced excess anhydrous HCl and the solution was stirred at 25° C. for 2 hours and concentrated giving 88 mg of colorless solid, TLC Rf 0.28 in System A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[S:25][C:26]([C:32]2[C:37]([F:38])=[CH:36][C:35]([C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][C:33]=2[F:43])=[CH:27][C:28]=1[C:29]([NH2:31])=[O:30]>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:23][C:24]3[S:25][C:26]([C:32]4[C:33]([F:43])=[CH:34][C:35]([C:39]([OH:42])([CH3:40])[CH3:41])=[CH:36][C:37]=4[F:38])=[CH:27][C:28]=3[C:29]([NH2:31])=[O:30])[N:16]=2)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(C)OC(=O)NCc1cn(Cc2cccc(Br)n2)nn1
Product: CC(C)(C)OC(=O)NCc1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1

Procedure:
The title compound was prepared according to the procedure in Example 1 using tert-Butyl({1-[(6-bromopyridin-2-yl)methyl]-1H-1,2,3-triazol-4-yl}methyl)carbamate (147 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) as the starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)COC1C(Br)=[N:33]C(C)=CC=1)(C)(C)C>>[CH3:19][Si:18]([C:17]#[C:16][C:10]1[C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[CH:14][CH:13]=[C:12]([CH3:11])[N:33]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Reactant: Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)n1
Product: Cc1ccc(OCC(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n1

Procedure:
Following the general method as outlined in Intermediate 2, starting from tert-butyl[(2-bromo-6-methylpyridin-3-yl)oxy]acetate (Intermediate 84), the title compound was obtained as a brown oil after purification by flash column chromatography (silica), eluting with petroleum ether and ethyl acetate (98:2).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[N:40]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:39]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=[N:40]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: c1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccccc43)nc12
Temperature: 110 °C
Yield: 73.7 %

Procedure:
To a stirred solution of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 316 μmol) in toluene (2 mL) was added copper (I) iodide (3.17 mg, 35.4 μmol), sodium iodide (94.7 mg, 631 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (11.5 mg, 80.5 μmol). The reaction mixture was sealed under nitrogen and the mixture heated at 110° C. for 15 h. To the mixture was added 1H-indazole (37.3 mg, 316 μmol) and potassium phosphate tribasic (141 mg, 663 μmol) then the reaction vessel was degassed, filled with nitrogen, and the mixture heated at in sealed tube at 110° C. for 15 h. The mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-(1-Hydroxy-2-methylpropan-2-yl)-2-(1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (112 mg, 74%). 1H NMR (CDCl3) d: 9.21 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.31-7.41 (m, 1H), 5.73 (s, 2H), 3.81 (s, 2H), 3.55-3.66 (m, 2H), 1.55 (s, 6H), 0.89-1.04 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:38][CH:39]=1)=[O:8]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Reactant: Cc1ccsc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Yield: 70.7 %

Procedure:
To 0.193 g (1.2 mmol) of 3-methylthiophene-2-carbonyl chloride in 3 ml of dichloromethane, cooled to 0° C., is added 209 μl of triethylamine. The mixture is stirred and 0.30 g (1 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine is added. The mixture is stirred at room temperature overnight and then concentrated under vacuum. To the residue is added 30 ml of ethyl acetate and the mixture washed with 2 ml each of water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried (Na2SO4) and the solvent removed to give 0.30 g of solid. The solid is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 150 mg of product as a yellow foam.
Reaction SMILES: Br[C:2]1[C:3]([C:14]#[N:15])=[N:4][N:5](C(OC(C)(C)C)=O)[CH:6]=1.CC1(C)C(C)(C)OB([C:24]2[C:25]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[NH2:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][C:25]2[C:24]([C:2]3[C:3]([C:14]#[N:15])=[N:4][NH:5][CH:6]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2cccnc2Oc2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)n1cc(Br)c(C#N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(N)cc1
Temperature: 100 °C

Procedure:
Dioxane (2.0 mL) was added to a 20 mL sealed tube. The tube was purged with nitrogen for 5 minutes. To this was added tert-butyl 4-bromo-3-cyano-1-H-pyrazole-1-carboxylate (0.100 g, 0.368 mmol), 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine (0.229 g, 0.735 mmol), and sodium carbonate (2.0 M in water)(0.667 mL). Palladium(II) acetate (0.008 g, 0.037 mmol) and tri-t-butylphosphonium tetrafluoroborate (0.021 g, 0.074 mmol) was added and the tube was purged with nitrogen, sealed, and heated to 100° C. for 17 hours. The reaction was cooled to RT, concentrated and passed through a pad of silica with the aid of 90:10:1 (CH2Cl2:MeOH:NH4OH). The eluent was concentrated to yield 4-(2-(4-aminophenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile as light brown solid. MS m/z=278 [M+1]+. Calc'd for Cl5H11N5O: 277.28.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:18]>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:18][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A clear solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (150 g, 0.69 mol), ethanol (300 mL) and ammonium hydroxide (28.0-30.0% solution, 690 mL, 10.5 mol) in a 2 L 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, and a further 230 mL of ammonium hydroxide (3.5 mol) was added. The resulting solution was heated to reflux for another 3.5 h, then allowed to cool to RT and stirred for overnight. A solid product had separated, and was collected by suction filtration. Thus, 95 g of 3-benzyloxy-2-methyl-1H-pyridin-4-one (64% yield) was obtained as a first crop. HPLC Method 4 (Example 24), RT=10.7 min, HPLC purity (peak percent area): 99% at λ=280 nm)). 1H NMR (DMSO-d6) δ ppm: 11.3 (br s, 1H), 7.46 (s, 1H), 7.35, (m, 5H), 6.13 (s, 1H), 5.04 (s, 2H), 2.05 (s, 3H); 1H NMR (DMSO-d6+D2O) δ ppm: 7.47 (d, J=7.0 Hz, 1H), 7.39, (m, 5H), 6.20 (d, J=7.0 Hz, 1H), 5.01 (s, 2H), 2.03 (s, 3H).
Reaction SMILES: [Cl:1]CCCC[CH:6]1[O:10][C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]1.Cl.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:17].[I-].[K+].Cl>C(O)C.CCOCC>[ClH:1].[CH2:16]([O:18][C:19]1[CH:21]=[CH:20][CH:19]=[CH:24][C:24]=1[CH2:23][CH2:22][CH2:21][CH:20]([CH:7]1[CH2:6][O:10][C:9](=[O:11])[N:8]1[CH:12]([CH3:13])[CH3:14])[N:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1)[CH3:17]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: CC(C)N1CC(CCCCCl)OC1=O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOc1ccccc1CCCC(C1COC(=O)N1C(C)C)N1CCNCC1
Yield: 60 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-(1-methylethyl)-2-oxazolidinone (5.2 g, 0.0137 mol), 1-(2-ethoxyphenyl)-piperazine hydrochloride (5.76 g, 0.0237 mol) and potassium iodide (1.0 g) in N-butanol (200 mL) gave an oil. The oil was dissolved in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ether and filtration gave a solid which was dried under high vacuum at 70° C. to give 6.62 g (60% yield), mp 199°-205° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: N#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
A solution of 1,5-dichloro-2,4-dinitrobenzene (5.0 g), glycolonitrile (1.81 g) and anhydrous potassium carbonate (2.19 g) in dimethylformamide (20 g) was stirred at 25° to 30° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and washed with ether to give crude crystals (4.16 g), which were recrystallized from methanol to give 2,4-dinitro-5-chlorophenoxyacetonitrile (3.18 g; yield, 58.5%). M.P., 117°-118° C.