Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[C:40]([C:44]1[CH:48]=[CH:47][N:46]([C:49]2[CH:54]=[C:53]([Cl:55])[CH:52]=[CH:51][C:50]=2[C@@H:56]([OH:61])[C:57]([F:60])([F:59])[F:58])[N:45]=1)([CH3:43])([CH3:42])[CH3:41]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:61][C@H:56]([C:50]2[CH:51]=[CH:52][C:53]([Cl:55])=[CH:54][C:49]=2[N:46]2[CH:47]=[CH:48][C:44]([C:40]([CH3:43])([CH3:41])[CH3:42])=[N:45]2)[C:57]([F:59])([F:60])[F:58])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CC(C)(C)c1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Product: CC(C)(C)c1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 40).
Reaction SMILES: C([O:8][C@H:9]([CH3:37])[C@@H:10]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[NH2:11])C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[NH2:11][C@H:10]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[C@@H:9]([CH3:37])[OH:8]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)OCc1ccccc1)C(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)C(C)C)C(=O)O
Reaction time: 4 h
Yield: 85 %

Procedure:
One gram of benzyl O-benzylthreonylvalylleucinate hydrochloride is neutralized to provide benzyl O-benzylthreonylvalylleucinate. A hydrogenolysis mixture is prepared containing the benzyl O-benzylthreonylvalylleucinate, 0.5 grams of 10 percent palladium on charcoal per 0.01 mole of the material to be hydrogenated, and absolute ethanol. To the mixture is added 1.1 mole equivalents of acetic acid based on the benzyl ester. The mixture is hydrogenated for 4 hours. The catalyst is removed by filtration and the solvents are removed in vacuo. The residue is washed with anhydrous ether and recrystallized from an ethanol/ether mixture to provide 544 milligrams of the free peptide, threonylvalylleucine (85% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:35]=[C:36]=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:26][C:36](=[O:37])[NH:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:36](=[O:37])[NH:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCN=C=O
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Octyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to afford the title product as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:56][C:57]1[C:58]([OH:68])=[N:59][C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)=[N:61][CH:62]=1>CC#N>[OH:68][C:58]1[C:57]([NH:56][C:16](=[O:18])[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:62][N:61]=[C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)[N:59]=1
Reactant: Nc1cnc(-n2cccn2)nc1O
Reactant: CCOP(=O)(OCC)c1ccc(C(C(=O)O)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)Nc2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-(Diethoxyphosphoryl)phenyl)-2-phenylacetic acid, 14-f, (1.18 g, 3.4 mmol), HATU (1.86 g, 4.9 mmol) and triethylamine (989 mg, 9.8 mmol) in CH3CN (20 mL) was added 5-amino-2-(1H-pyrazol-1-yl)pyrimidin-4-ol (11-e, 577 mg, 3.30 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in EA and water. The aqueous layer was extracted with EA. The combined layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product of 14-1 which was purified by pre-HPLC (766 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ1.18-1.23 (m, 6H), 3.92-4.03 (m, 4H), 6.64 (s, 1H), 7.25-7.35 (m, 6H), 7.47-7.51 (m, 2H), 7.64-7.71 (m, 2H), 7.97 (s, 1H), 8.61-8.52 (m, 1H), 8.63 (br s, 1H); LC-MS: (M+H)+ 508.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](Br)[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([NH2:19])[N:3]=1.[NH3:20]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([NH2:20])[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([NH2:19])[N:3]=1
Reactant: Nc1nc(N)c2nc(Br)n(COC(CO)CO)c2n1
Reactant: N
Solvent: CO
Product: Nc1nc(N)c2nc(N)n(COC(CO)CO)c2n1
Temperature: 125 °C

Procedure:
A mixture of 1.153 g (3.46 mM) of 2-[(2,6-diamino-8-bromo-9H-purin-9-yl)methoxy]-1,3-propanediol and 300 ml of a saturated solution of ammonia in methanol was heated at 125° C. in a Parr bomb for 18 hours. The reaction mixture was purified by flash chromatography on silica gel eluting with a methanol dichloromethane gradient (10→40%) to give a light brown solid. This solid was recrystallized from acetonitrile/methanol to yield the title compound as a light brown powder, mp 206°-208° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].[C:26]([OH:29])(=[S:28])[CH3:27].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:28][C:26](=[O:29])[CH3:27])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cncc1CO
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1cncc1CO

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-[2-(5-hydroxymethyl-imidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (1.63 g) was reacted with thioacetic acid (0.65 ml) and potassium t-butoxide (0.978 g) in substantially the same manner as that of Preparation 14-12) to give (2R,4S)-1-allyloxycarbonyl-4-acetylthio-2-[2-(5-hydroxymethyl-imidazol-1-yl)ethyl]pyrrolidine (884 mg) as an orange paste.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5](Cl)=[O:6].[CH2:10]([OH:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5]([O:12][CH2:10][CH3:11])=[O:6]
Reactant: CCO
Reactant: CC1(C(=O)Cl)CC1(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1(F)F
Yield: 87 %

Procedure:
35 ml of ethanol are added dropwise at 20° C. to 15.45 g (0.1 mol) of 2,2-difluoro-1-methyl-cyclopropanecarbonyl chloride, with stirring. After the addition of 2 drops of concentrated sulphuric acid, the reaction mixture is refluxed for another hour. Excess ethanol is subsequently distilled off, and the residue is dried and distilled under atmospheric pressure. In this manner, 14.2 g (87% of theory) of ethyl 2,2-difluoro-1-methylcyclopropane-carboxylate are obtained in form of a liquid of boiling point 141°-143° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:51]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:73])[CH2:64]P(OCC)(OCC)=O)[CH2:59][CH2:58]1)=[O:56])[CH:52]=[CH2:53].[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:64]/[C:63]([N:60]1[CH2:59][CH2:58][N:57]([C:55]([O:54][CH2:51][CH:52]=[CH2:53])=[O:56])[CH2:62][CH2:61]1)=[O:73])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCN(C(=O)CP(=O)(OCC)OCC)CC1
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCOC(=O)N1CCN(C(=O)/C=C/[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCC=C)CC1
Yield: 92.6 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 1.5 g, 3.26 mmol), dimethyl sulfoxide (0.65 ml, 9.14 mmol), oxalyl chloride (0.42 ml, 4.90 mmol), triethylamine (2 ml, 14.9 mmol), N-allyloxycarbonyl-N'-(diethylphosphonoacetyl)piperazine (1.24 g, 3.92 mmol) and 60% sodium hydride (130 mg, 3.26 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with ethyl acetate) to give the title compound (1.97 g, 92.6% yield).
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[N:8]=[C:9]2[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=3)[N:12]=[CH:11][N:10]2[CH:31]=1)=O)C>CCO>[F:30][C:26]1[N:25]=[C:24]([C:20]2[N:19]([CH2:18][C:13]3[N:12]=[CH:11][N:10]4[CH:31]=[C:7]([C:5]([NH2:1])=[O:4])[N:8]=[C:9]4[C:14]=3[CH2:15][CH2:16][CH3:17])[CH:23]=[CH:22][N:21]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C(=O)OCC)nc12
Reactant: N
Solvent: CCO
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C(N)=O)nc12
Temperature: 90 °C

Procedure:
Ammonia gas is passed through a stirred solution of 7-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-8-propyl-imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (110, above) (1 mmol) in EtOH (7 ml) in a sealed tube for 20 minutes at 0° C. The tube is then sealed and heated at 90° C. for 2 days. The solvent is evaporated and the residue (128) is used directly in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:19]1([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[OH:1][CH:2]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:22]2[CH2:23][CH2:24][N:19]([C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[CH2:20][CH2:21]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)(C)C(O)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)(C)C(O)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-hydroxy-4,4-dimethylpentyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (39% yield). 1H NMR (500 MHz, CDCl3) δ 8.18, 8.05, 7.74, 7.63, 7.56, 7.36, 6.99, 4.05, 3.92-3.67, 3.45-3.32, 3.26, 1.76, 1.55, 0.88. MS (ES+) m/z 494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: Cc1ccc(C#N)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
17.3 g 2-Chloro-4-methyl-benzonitrile were dissolved in 50 ml tetrachloromethane and heated to reflux. A mixture of 24.3 g N-bromosuccinimide and 7.48 g 2,2′-azobis(2-methylpropionitrile) were added in five portions over a period of one hour. The reaction mixture was heated under reflux for additional three hours. The cooled reaction mixture was then filtered through a celite pad. The filtrate was washed with 100 ml saturated NaHCO3 solution, dried over MgSO4 and the solvent was removed in vacuo. The resulting residue was dissolved in 200 ml tetrahydrofuran and cooled in an ice bath to 0° C. 88.0 ml diethyl phosphite were added, followed by the addition of 117.0 ml N,N-diisopropylethylamine. The cooling bath was removed and the reaction mixture stirred at room temperature for four hours. The reaction mixture was poured in 400 ml 50% NaHCO3 solution and extracted with 400 ml diethylether. The organic layer was separated and washed with 200 ml 50% NaHCO3 solution and 200 ml water and then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified on silica gel with the eluent n-heptane:ethyl acetate=19:1 to obtain 13.0 g 4-Bromomethyl-2-chloro-benzonitrile as a solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26](B1OC(C)(C)C(C)(C)O1)[CH:25]=2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:21])=[CH:30]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (200 mg, 0.68 mmol) in DME (5.0 mL) and water (2 drops) was added 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (352 mg, 1.37 mmol), Pd(PPh3)4 (39 mg, 0.03 mmol), and K2CO3 (189 mg, 1.37 mmol) with stirring for 1 hour at 90° C. under atmosphere of nitrogen. The resulting mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (180 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Cl)cc1
Temperature: 65 °C
Yield: 88 %

Procedure:
Thionyl chloride (200 ml) was added to 4-methoxyphenylacetic acid (78 g, 0.47 mole) followed by one drop of dimethylformamide. The reaction was heated at 65° C. for 4 hours and the solvent was removed under vacuum. The residue was distilled in vacuo (water aspirator) at 135° C. to give the product as a red oil (75.9 g, 88%).
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]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[I:21]N1C(=O)CCC1=O>ClCCl>[I:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:18]([CH3:20])[CH3:19])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Solvent: ClCCl
Product: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1.1 g, 3.8 mmol) and 10 mL of dichloromethane were combined in a round bottom flask and stirred for 10 minutes. A slurry of N-iodosuccinimide (1.0 g, 4.6 mmol) in 5 mL of dichloromethane was added and stirred at room temperature overnight. The reaction was quenched with sodium thiosulfate (20 mL, 1M in water) and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a light yellow oil (9, 1.2 g, 75%). MS (ESI) [M+H+]+=415.08.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Br:11]NC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][Br:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)cc1CBr
Yield: 40 %

Procedure:
To a stirred solution 4-Chloro-2-methyl-benzonitrile 1(5.0 g, 33.0 mmol) in carbon tetrachloride (150 mL) was added N-bromosuccinamide (7.6 g, 42.9 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield a white solid (40%). 1H NMR (400 MHz, CDCl3) δ7.61 (d, J=8.3 Hz, 1 H, Ar), 7.57 (d, J=2.2 Hz, 1 H, Ar), 7.41 (dd, J=8.3, 2.0 Hz, 1 H, Ar), 4.59 (s, 2 H, CH2).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[Br:20]Br>Br.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][C:3]1([Br:20])[CH2:18][CH3:19]
Reactant: BrBr
Reactant: CCC1Cc2cc(OCC(=O)O)c(C)c(C)c2C1=O
Agent: Br
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)c(C)c(C)c2C1=O

Procedure:
By following substantially the same procedure as described in Example 1, Step B, using as the reactants (1-oxo-2-ethyl-6,7-dimethyl-5indanyloxy)acetic acid (10.5 g., 0.04 mole), bromine (6.4 g., 0.04 mole), acetic acid (125 ml.) and 48% aqueous hydrobromic acid (2 drops), there is obtained 8.6 g. (63%) of (1oxo-2bromo-2-ethyl-6,7-dimethyl-5-indanyloxy)acetic acid which melts at 136°-139° C. after recrystallization from butyl chloride (200 ml.).
Reaction SMILES: [NH2:1]N.Br[C:4]1[N:5]([C:14]2[N:15]=[C:16]([NH2:22])[NH:17][C:18](=[O:21])[C:19]=2[N:20]=1)[C@@H:6]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.CO>O>[NH2:1][C:4]1[N:5]([C:14]2[N:15]=[C:16]([NH2:22])[NH:17][C:18](=[O:21])[C:19]=2[N:20]=1)[C@@H:6]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1
Reactant: NN
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Solvent: CO
Product: Nc1nc2c(nc(N)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Hydrazine is added to a suspension of 8-bromodeoxyguanosine in water:methanol (150 mL, 1:2) and the resulting solution is heated at reflux for 24 hours. The resulting precipitate is removed by filtration and the filtrate is evaporated to a solid. After repeated evaporations from ethanol, the product is recrystallized from methanol. The purified 8-azido-2'-deoxyguanosine (1.3 g) is dissolved in a mixture of methanol:water (160 mL, 5:3), Raney nickel (10.0 g) is added, and the mixture is heated at reflux for 18 hours. The catalyst is removed by filtration through celite and after washing with water and methanol the filtrate is evaporated to dryness. The resulting solid is recrystallized from methanol to yield 8-aminodeoxyguanosine.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].[Br:16][C:17]([CH2:19]Br)=[CH2:18]>C1COCC1>[Br:16][C:17](=[CH2:18])[CH2:19][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:7]
Reactant: C=C(Br)CBr
Reactant: CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1CCN(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
1-Methyl-2-pyrrolidinone (3.87 mL, 40.3 mmol) was combined with 25 mL of THF and cooled to −78° C. Lithium diisopropylamide (26.9 mL, 40.3 mmol) (1.5M in THF) was added slowly and the mixture was agitated for 30 minutes. 2,3-Dibromopropene (4.93 mL, 40.3 mmol) was added and the mixture was agitated overnight and allowed to warm up to ambient temperature. The reaction was quenched with sodium bicarbonate solution and extracted twice with ether. The extracts were washed with brine and evaporated. The crude product was purified by chromatography on silica gel, eluting with 30-50% ethyl acetate/hexane, to provide the title compound (5.01 g, 56.9% yield) as clear oil.