Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10])=[O:4].I[C@@:14]1([N:23]2[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]2=[O:25])[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17](O)[C@H:15]1O.CO>ClCCl>[F:1][C:2]([F:11])([F:12])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:29]1[C:27](=[O:28])[NH:26][C:24](=[O:25])[N:23]([CH:30]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[CH2:17][CH2:15]1)=[O:4]
Reactant: C#CCCCNC(=O)C(F)(F)F
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
5-Trifluroacetamido-1-pentyne (59) was coupled for 4 h to 5-iodo-2',3'-dideoxyuridine (47, prepared as described in Example 2A) according to the general procedure described in Example 1C. Chromatography on silica gel (100 g) with a 0-5% methanol in dichloromethane gradient afforded 647.7 mg of alkynylamino nucleoside 58 as a light tan foam. This material was homogeneous by TLC and NMR except for the presence of about 16 mole % of dimethylformamide. Correcting for the presence of dimethylformamide, the yield of desired product was 80%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 175.4 %

Procedure:
To a stirred solution of (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5, 10 mg), (3-methylsulfonylphenyl)boronic acid (58 mg), tetrakis-(triphenylphosphine)palladium (0) (30 mg) in 1,2-dimethoxyethane (2 mL) was added potassium carbonate (90 mg). The mixture was stirred at 80° C. overnight. Water was added, the phases were separated and the inorganic one was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 2:1 to EtOAc) to yield (E)-3-(3′-methanesulfonyl-biphenyl-4-yl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (21 mg, 18%) as a light yellow foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[S:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1>>[C:6]1([C:4]2[C:3](=[O:18])[NH:31][C:29](=[O:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[S:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)SCC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)SCC3)=C1c1c[nH]c2ccccc12

Procedure:
Beginning with (3,4-dihydro-5-thia-2a-aza-acenaphthylen-1-yl)oxoacetic acid methyl ester and (indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]1>>[CH3:12][C:13]1([C:16]([NH:18][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:17])[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC1(C(N)=O)CC1
Product: COC(=O)c1ccnc(NC(=O)C2(C)CC2)c1
Yield: 86 %

Procedure:
The title compound is prepared in 86% yield (0.30 g, a white solid) from methyl 2-chloroisonicotinate (0.25 g, 1.46 mmol) and 1-methylcyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [CH2:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([O:7]C)=[O:6])[CH2:2][CH3:3].[OH-].[Na+].O>C(O)C>[CH2:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3]
Reactant: C=CCCCC(CCC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCC(CCC)C(=O)O
Yield: 75.2 %

Procedure:
A mixture of methyl 2-propyl-6-heptenoate (1.8 g), sodium hydroxide (0.65 g), water (2 ml) and ethanol (100 ml) was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the resulting residue was shaken with water and hexane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated to give oil of 2-propyl-6-heptenoic acid (1.25 g).
Reaction SMILES: CC1C(C2N3C4C=CN(COCC[Si](C)(C)C)C=4N=CC3=[N:9]C=2)CC(N)C1.Cl[S:29]([NH:32][C:33](=[O:38])[O:34][CH2:35][CH2:36]Cl)(=[O:31])=[O:30].CO>C(Cl)Cl>[O:38]=[C:33]1[N:32]([S:29]([NH2:9])(=[O:31])=[O:30])[CH2:36][CH2:35][O:34]1
Reactant: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: O=C(NS(=O)(=O)Cl)OCCCl
Solvent: ClCCl
Solvent: CO
Product: NS(=O)(=O)N1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.50 g, 1.3 mmol) and 2-chloroethyl chlorosulfonylcarbamate (0.288 g, 1.297 mmol, prepared as detailed in Biorg. Med. Chem. Lett, 2006 16, 3367-3370) in DCM (16 mL) was added TEA (0.542 mL, 3.89 mmol) drop-wise. The mixture was stirred at ambient temperature for about 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc (30 mL each). The organic layer was washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified by silica gel chromatography (0% DCM for 5 min, then to 6% MeOH in DCM over the next 30 min.) to yield N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.24 g, 35% yield) as an off-white solid. LC/MS (Table 1, Method a) Rt=2.42 min; MS m/z 535 (M+H)+.
Reaction SMILES: Cl.O.[CH:3]1([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27](OC)[O:28]C)[CH:19]=3)[CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1>[CH:3]1([CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:19]=2)[CH:27]=[O:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(OC)c1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12N HCl (2 mL) and H2O (4 mL) were added to a mixture of cyclohexylmethyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine (0.0055 mol) in THF (17 mL), and the reaction mixture was stirred overnight at room temperature. H2O was added, and the mixture was extracted with diisopropyl ether. The organic layer was washed with a 10% NaHCO3 solution, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by short column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][NH:16][C:17]([CH2:19][NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:17]1[S:2][C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=1
Reactant: CNC(=O)CNC(=O)c1cccnc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CNc1cnc(-c2cccnc2)s1
Temperature: 25 °C
Yield: 23 %

Procedure:
A suspension of phosphorus pentasulfide (1.73 g, 7.8 mmol) and N-methylcarbamoylmethyl-nicotinamide (1 g, 5 mmol) in dry toluene (10 mL) was stirred at reflux under nitrogen for 16 h. The mixture was cooled to room temperature and then dry pyridine (4 mL) was added. The mixture was stirred at reflux under nitrogen for 8 h, then it was cooled to room temperature and the organic layer was removed. The dark residue was treated with hot saturated aqueous sodium bicarbonate (Na2CO3, 40 mL) and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate (MgSO4), and purified by silica gel chromatography (1% methanol in dichloromethane) to yield a brown amorphous solid (0.22 g, 22%): mp 141-146° C.; 1H NMR (300 MHz, CDCl3) δ 8.97 (d, J=2.4 Hz, 1H), 8.53 (dd, J=5.0, 1.8 Hz, 1H), 8.06 (ddd, J=7.2, 3.3, 0.6 Hz, 1H), 7.31 (ddd, J=5.5, 4.7, 0.5 Hz, 1H), 6.96 (s, 1H), 2.97 (d, J=5.0 Hz, 3H); ESIMS m/z 192 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[OH-:22].[Na+]>Cl>[OH:15][CH2:14][CH:13]([CH2:18][OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 72 %

Procedure:
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-ethyl]purine (3.74 g, 12 mmol) in hydrochloric acid (2.0M, 12 ml) was heated under reflux for 1.5 hours. The solution was neutralised with aqueous sodium hydroxide (10%) and then allowed to cool. The solution was filtered and the solid washed with water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine as a white crystalline solid (2.18 g, 72%), m.p. 275-277° C.; (Found: C, 47.31; H, 6.02; N, 27.81%; C10H15N5O3 requires C, 47.43; H, 5.97; N, 27.65%).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]([OH:18])=[O:17])[NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+].[CH3:21]O>O>[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]([O:18][CH3:21])=[O:17])[NH:13]2)=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc2ccc(O)cc2[nH]1

Procedure:
0.144 ml (2.70 mmol) of concentrated sulfuric acid is added, at ambient temperature, to a solution of 5.98 g (33.75 mmol) of 6-hydroxy-1H-indole-2-carboxylic acid in 350 ml of methanol. The mixture is refluxed for 9 days and the reaction mixture is then concentrated to dryness under reduced pressure. The residue obtained is taken up in water and alkalinized to pH9 with a 38% potassium hydroxide solution, and the product is then extracted 6 times with ethyl acetate. The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 5.81 g of methyl 6-hydroxy-1H-indole-2-carboxylate in the form of a brown solid.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.CC1NC2C(C=1[CH2:24][N:25](C)[C:26](=[O:29])[CH:27]=[CH2:28])=CC=CC=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][NH:25][C:26](=[O:29])/[CH:27]=[CH:28]/[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1CCCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)/C=C/c1cnc2c(c1)CCCC(=O)N2
Yield: 57.1 %

Procedure:
A solution of 3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (0.60 g, 2.50 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.85 g, 3.75 mmole), Pd(OAc)2 (0.06 g, 0.25 mmole), tri-ortho-tolylphosphine (0.15 g, 0.50 mmole) and diisopropylethylamine (0.87 mL, 5.00 mmole) in propionitrile (50 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (200 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3). The title compound (0.35 g. 35%) was obtained as a light tan solid after drying in vacuo: MS (ES) m/e 246 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.O.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+]>C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC(O)C1

Procedure:
To a 1-liter 3-necked round bottom flask, equipped with mechanical stirrer and two addition funnels, is added 30 g (0.2966 mole) of 3-hydroxypiperidine and 300 ml of water. The resulting solution is stirred and is cooled to ~0° C. with ice-salt bath. At this point benzyl chloroformate (51 ml, 0.356 mole) is added dropwise from one funnel and the 2N NaOH (178 ml) from the other funnel (at a slightly faster rate) during which time the temp. is maintained at ~0° C. After addition is complete, stir cold for 2 hr, then overnight at ambient temp. After this time an oily residue separates from the reaction solution, ethyl acetate is added (250 ml) to the reaction and is stirred for 1/2 hr. The phases are separated and the aqueous phase is extracted once more with EtOAc (250 ml). All organic phases are combined, washed with 1×150 ml saturated NaHCO3, 1×150 ml H20, 1×150 ml 10% HCl, 1×150 ml H20 and dried over MgSO4. The mixture is filtered and concentrated on roto-evap under reduced pressure to yield a viscous oil which is stored under vacuum to remove any residual solvents as 3-Hydroxy-1-piperidine-carboxylic Acid, Phenylmethyl Ester, a clear oil.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:4]1[O:6][CH2:5]1>>[NH2:2][CH2:5][CH:4]([OH:6])[CH2:3][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCN(CC)CC1CO1
Agent: [OH-]
Product: CCN(CC)CC(O)CN
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To the ice-cold solution of ammonium hydroxide (25 mL, 159 mmole) of 25% (w/w) was added glycidyldiethylamine dropwise (3.2 g, 24.8 mmol) over 10 minutes. The reaction mixture was stirred at 0–5° C. for 1 hour and then room temperature for 14 hours. The resulting reaction mixture was evaporated and distilled (84–90° C. at 500–600 mT) to yield 1-amino-3-diethylamino-propan-2-ol (3.3 g, 92%). MS m/z 147 ([M+1]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].CN(C)C=O.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Yield: 109 %

Procedure:
A solution of 2,6-dichloro-4methylbenzoic acid (7.15 g, 34.9 mmol) in thionyl chloride (133 ml) containing dimethylformamide (1.3 ml) was refluxed 3 hours, evaporated under vacuum, and azeotroped twice with benzene. The residue was triturated with petroleum ether (b.p. 30°-60° C., 200 ml) and filtered. The filtrate was evaporated under vacuum to provide 8.5 g (109% of theory) 2,6-dichloro-4-methylbenzoyl chloride, IR (neat): 1785 cm-1. The crude chloride and chlorobenzene (94 g) were stirred in carbon tetrachloride (235 ml), treated in portions with aluminum chloride (5.35 g, 40.1 mmol), kept 30 minutes at ambient temperature, and refluxed 3 hours. The mixture was cooled, quenched by addition of ice and concentrated hydrochloric acid, and extracted three times with dichloromethane. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (400 g) eluted with 3:2 (v/v) dichloromethane-hexane to provide 7.19 g (69%) of 4-(4-chlorobenzoyl)-3,5-dichlorotoluene, m.p. 111.5°-114° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].Cl[CH2:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:37]>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:23]=1[CH3:37])[CH:11]=[CH:10]2)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(=O)C(Cc1ccc2c(ccn2Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c1)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester [preparation 1] was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2001), WO 01/00603 A1] to give rac-2-ethoxy-3-{1-[4-methyl-2-(4-trifluoromethyl-phenyl )-thiazol-5-ylmethyl]-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[F:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[F:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1F
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1F

Procedure:
The product from Example 305E and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:21])[CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[NH2:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:9](=[O:21])[CH2:10][CH2:11]2
Reactant: CN1CCC(N2C(=O)CCc3cc([N+](=O)[O-])ccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(N2C(=O)CCc3cc(N)ccc32)CC1

Procedure:
A suspension of 1-(1-methylpiperidin-4-yl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.04 mmol) and palladium on activated carbon (10% wt, 55 mg, 0.05 mmol) in 20 mL ethanol/4 mL THF was stirred under a balloon of hydrogen overnight. The suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL methanol, and the filtrate was concentrated to give a viscous oil. The crude product was used without further purification. (250 mg, 92.6%). 1H-NMR (CDCl3) δ 7.06 (d, J=9.3 Hz, 1H), 6.54-6.49 (m, 2H), 4.46-4.36 (m, 1H), 3.42 (brs, 2H), 2.97-2.94 (m, 2H), 2.73-2.49 (m, 6H), 2.31 (s, 3H), 2.27-2.05 (m, 2H), 1.27-1.21 (m, 2H). MS (ESI): 260.2 (M+1, 100%).
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:21][C:22]4[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[CH2:25][O:24][C:23]=4[N:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:21][C:22]4[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[CH2:25][O:24][C:23]=4[N:35]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 0.01 h
Yield: 123.3 %

Procedure:
Ethyl 2-(6-(4-(1-(tert-butoxycarbonylamino)cyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)acetate (22 mg, 0.039 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (22 mg, 98% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:33]#[N:34])#[N:28]>>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:29]([C:27]#[N:28])[C:30]2[CH:31]=[C:32]([CH:35]=[C:36]([CH3:38])[CH:37]=2)[C:33]#[N:34])[C:12]([CH:23]([CH3:25])[CH3:24])=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: CC(C)c1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Product: Cc1cc(C#N)cc(C(C#N)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1

Procedure:
5-Isopropyl barbtric acid (Lancaster) was reacted with phosphorus oxychloride to provide 2,4,6-trichloro-5-isopropylpyrimidine. The 2,4,6-trichloro-5-isopropylpyrimidine was then reacted with benzyl alkoxide to form 2,4-bis(benzyloxy)-6-chloro-5-isopropylpyrimidine. The 2,4-bis(benzyloxy)-6-chloro-5-isopropylpyrimidine was then reacted with 3-(cyanomethyl)-5-methylbenzonitrile to form 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl)(cyano)methyl)-5-methylbenzonitrile. The 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl)(cyano)methyl)-5-methylbenzonitrile was treated with NaH and O2 to form ketone 3-(2,6-bis(benzyloxy)-5-isopropylpyrimidine-4-carbonyl)-5-methylbenzonitrile, which was then catalytically hydrogenated to form Compound 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:15]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Cl)ncnc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.13 g, 0.58 mmol, 1.0 eq.) and DMF (3 ml). The mixture was cooled to 0° C. followed by the addition of NaH (0.028 g, 0.70 mmol, 1.2 eq) with stirring. After stirring for 10 minutes SEM-CL (0.106 g, 0.64 mmol, 1.1 eq) was added and the reaction was allowed to warm to room temperature with stirring for 1 hour. The reaction was diluted with ethyl acetate (50 ml), washed (2×) water, (1×) NaHCO3, (2×) 5% LiCl, (1×) brine, and dried over sodium sulfate, and concentrated in vacuo to give 4-chloro-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a cream solid (0.17 g, 84%). MS (ESI) for C15H22ClN3O3Si: 356 (MH+).