Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:68]=[CH:67][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:43][C@@H:42]([CH2:44][O:45][C:46]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C@H:32]([O:33]C(=O)C3C=CC=CC=3)[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:43][C@@H:42]([CH2:44][O:45][C:46]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)[C@H:32]([OH:33])[CH2:31]2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:67][CH:68]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](OC(=O)c3ccccc3)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Yield: 76 %

Procedure:
Compound 8 was treated by a solution (saturated at −10° C.) of methanolic ammonia (20 mL), at room temperature for 24 h, then the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane (30 mL) and washed with water (20 mL). The aqueous layer was extracted by dichloromethane (2×20 mL) and the combined organic phase was dried, filtered and concentrated. Pure compound 9 (0.50 g, 76% from 7) was obtained as a foam after purification by silica gel column chromatography (0-2% MeOH in dichloromethane): 1H NMR (DMSO-d6): δ 2.2-2.3 (m, 1H, H-2′), 2.8-2.9 (m, 1H, H-2″), 3.1-3.2 (m, 2H, H-5′ and H-5″), 3.64 and 3.65 (2s, 6H, 2×OCH3), 3.97 (pq, 1H, H-4′), 4.4-4.5 (m, 1H, H-3′), 5.36 (d, 1H, OH-3′, JH,OH=4.5 Hz), 6.34 (t, 1H, H-1′, J1′,2′=J1′,2″=6.4 Hz), 6.8-6.9 and 7.1-7.4 (2m, 29H, 2 MMTr and NH-6), 7.81 and 8.32 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 796 [M+H]+, 408 [BH2]+, (FAB−) m/z 794 [M−H]−, 406 [B]−; UV (95% ethanol): λmax 276 nm (ε 42600), λmin 248 nm (ε 23300); [α]D20=+29 (c 1.05, DMSO).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)=[C:5]([CH3:17])[O:4][N:3]=1.[O:18]1CCOCC1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:18])[N:8]=2)=[C:5]([CH3:17])[O:4][N:3]=1
Reactant: C1COCCO1
Reactant: Cc1noc(C)c1-c1ccnc(S(C)(=O)=O)n1
Product: Cc1noc(C)c1-c1cc[nH]c(=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3,5-dimethyl-isoxazol-4-yl)-2-methanesulfonyl-pyrimidine (666 mg, 2.63 mmol) was dissolved in dioxane (20 ml) and then 2N NaOHaq (13.2 ml, 26.3 mmol) was added. After stirring at room temperature for 30 minutes, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was purified by flash chromatography with DCM-MeOH (9-1) to give the title compound. (quantitative yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].C1C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[S:29])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOP(=O)(Cc1ccc(C(=O)N2CCCc3ccccc32)cc1)OCC
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=S)N2CCCc3ccccc32)cc1)OCC
Temperature: 25 °C

Procedure:
0.77 Gram (2.0 mM) of 1-(4-diethoxyphosphinoylmethylbenzoyl)-1,2,3,4-tetrahydroquinoline and 1.0 g (4.6 mM) of phosphorus pentasulfide were suspended in a mixed solvent consisting of 20 ml of anhydrous benzene and 5 ml of anhydrous pyridine This suspension was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, the mixture was poured into 50 ml of ice-water, and the aqueous phase was acidified with 4N hydrochloric acid and then extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate, and concentrated. Thus obtained residue was purified by means of a silica gel column chromatography (eluted with chloroform:ethyl acetate=1:1). The crude crystals were recrystallized from benzene-n-hexane to yield 0.23 g of 1-[(4-diethoxyphosphinoylmethylphenyl)thiocarbonyl]-1,2,3,4-tetrahydroquinoline as yellowish crystals. Melting point 96°-97° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
To a mixture of 4-bromo-2-iodo-phenylamine (2.00 g, 6.71 mmol), 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.40 g, 6.71 mmol) and Pd(PPh3)4 (388 mg, 0.336 mmol) in 40 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (26.8 mL, 53.7 mmol). After stirring at 80° C. for 5 h under Ar, the reaction was cooled to RT. The mixture was treated with EtOAc (100 mL), washed with H2O (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 1.47 g (87%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C12H14BrN, 252.0 (M+H). found 252.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(CCC2COc3ccccc3O2)C1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
First 1.96 g (12.5 mmol) of piperidine-3-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g 10 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.82 g (100%) of crude product are obtained which are filtered over 190 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.70 g (96.6%) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a pale yellow oil. The 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 162°-165°.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[O-]CC.[Mg+2].[O-]CC.[CH:16]1(C(O)=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[CH:16]1([C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)C1CCCC1
Reactant: COC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
In 200 mL of methanol, was dissolved 8.91 g (75.4 mmol) of monomethyl malonate, and the resulting solution was mixed with 4.30 g (37.5 mmol) of magnesium ethoxide, and stirred for 4 hours at room temperature. The reaction solution was concentrated and the residue was dried under reduced pressure. In 120 mL of tetrahydrofuran, was dissolved 4.10 mL (37.7 mmol) of cyclopentanecarboxylic acid, and the resulting solution was mixed with 6.69 g (41.2 mmol) of carbonyldiimidazole, followed by stirring for 2.5 hours. The reaction solution was added to a dry magnesium salt and the resulting mixture was stirred at room temperature for 221 hours. The reaction solution was concentrated; the residue was mixed with 150 mL of 2 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and then saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.15 mmHg, 51 to 55° C.) to give 5.72 g (33.4 mmol, 88.8%) of methyl 2-cyclopentanecarbonylacetate as an anhydrous liquid. Similarly to Example 133, 2.32 g (8.39 mmol, 57.0%) of pale yellow crystals were obtained from 5.72 g (33.4 mmol) of methyl 2-cyclopentanecarbonylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[NH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18].C1C(=O)N(Br)C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:5]1[CH:4]=[C:3]2[C:2]([CH:1]=[C:16]([C:17]([F:20])([F:19])[F:18])[NH:15]2)=[CH:7][CH:6]=1)=[O:14]
Reactant: Cc1ccc(NC(=O)C(F)(F)F)cc1NC(=O)C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc2cc(C(F)(F)F)[nH]c2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
A mixture of N,N′-(4-methyl-1,3-phenylene)bis(2,2,2-trifluoroacetamide) (1.02 g, 3.25 mmol), NBS (0.80 g, 4.5 mmol) in CCl4 (6 mL) was stirred overnight at room temperature under irradiation of a 300 W lamp. The precipitate formed was collected by filtration and washed with CCl4. The crude residue was taken up in dry toluene (9.7 mL) in the presence of PPh3 (1.3 g, 4.96 mmol) and stirred at 60° C. for 16 h. The phosphonium precipitate was collected by filtration, then dissolved in dry DMF (10 mL) and stirred at 165° C. until complete conversion to the product (6.5 h). The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (5-25% AcOEt in hexanes) to obtain 2,2,2-trifluoro-N-(2-(trifluoromethyl)-1H-indol-6-yl)acetamide (243 mg, 25%). LC/MS: m/z 297.3 (M+H)+ at 1.68 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[N:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1.[Li+].[OH-].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[N:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:22])([F:21])[F:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a suspension of (S)-methyl 6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylate (0.72 g, 2.00 mmol, Eq: 1.00) in tetrahydrofuran (7 mL) was added a 1M LiOH solution in water (2.59 ml, 2.59 mmol, Eq: 1.3) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove tetrahydrofuran and diluted with water; acidified with 1M hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic phase was dried with MgSO4; filtered, evaporated and dried to constant weight under high vacuum to yield the title compound as white solid (0.70 g, 100%), MS 345.0 (M−H)−.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:13]([O:15][C:16](=[O:22])[CH:17](Cl)[O:18][CH2:19][CH3:20])[CH3:14]>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH3:20])[N:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]1=[O:3])[CH3:14]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OCC)n1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.228 g=0.74 g NaH) was suspended in DMF (45 ml) under an argon atmosphere. The stirred suspension was cooled to 0° C. and 2-hydroxy-3-nitropyridine (4 g) was added portion wise over a period of 45 min. The mixture containing a compact yellow precipitate was then stirred at r.t. for 30 min and was cooled again to 0C. A solution of 2-chloro-2-ethoxyacetic acid ethyl ester (4.99 g) in DMF (5 ml) was then added and stirring at r.t. was continued for 2 h 30. The mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane=>cyclohexane/EtOAc 3:2) to give (RS)-ethoxy-(3-nitro-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (4.32 g) as yellow solid. MS 270.1 ([M]+)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]([CH3:33])[C:11]([C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([OH:31])[C:14]=1[OH:32])=[O:12].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:31][C:15]1[C:14]([OH:32])=[C:13]([C:11](=[O:12])[N:10]([CH3:33])[CH3:9])[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
Benzyl bromide (3.94 mL, 33.2 mmol) was added to a stirred suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (10.5 g, 30.1 mmol), potassium iodide (5.50 g, 33.2 mmol) and K2CO3 (4.58 g, 33.2 mmol) in DMF (100 mL). The reaction was allowed to stir at 80° C. for 24 h. The reaction mixture was poured into water (200 mL), washed with Et2O (2×200 mL), and the combined organic layers were washed with 1M HCl (aq.) (400 mL), brine (2×400 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g, 0-50% EtOAc in toluene) to afford ethyl 3-(benzyloxy)-5-(dimethylcarbamoyl)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (41) (4.36 g, 33%) as a pale yellow solid: m/z 439 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.53-7.47 (m, 2H), 7.42-7.29 (m, 3H), 7.08-7.01 (m, 2H), 6.90-6.84 (m, 2H), 5.09 (s, 2H), 3.96 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.82 (br s, 6H), 0.97 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[N:17]=[C:16](Cl)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[N:17]=[C:16]([NH:25][C:24]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nn(Cc3ccccc3)c(=O)c3ccccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 19 h
Yield: 28.6 %

Procedure:
A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol), 3,4,5-trimethoxyaniline (1.10 g, 6 mmol), bis(dibenzylideneacetone)palladium(II) (0.46 g, 0.5 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (0.62 g, 1 mmol) and potassium tert-butoxide (0.84 g, 7.5 mmol) in anhydrous toluene (20 mL) was degassed and heated to reflux with stirring for 19 h. After that time, the mixture was cooled to rt and quenched with saturated aqueous NH4Cl (20 mL). Ethyl acetate (20 mL) and water (20 mL) were added and the organic phase was separated, washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 60:40 hexanes/ethyl acetate) followed by recrystallization from CHCl3/hexanes to give 2-benzyl-4-((3,4,5-trimethoxyphenyl)amino)phthalazin-1(2H)-one (0.598 g, 29%) as a white solid: mp 206-207° C.; 1H H NMR (400 MHz, CDCl3) δ 8.57-8.55 (m, 1H), 7.84-7.76 (m, 3H), 7.41 (d, J=6.8 Hz, 2H), 7.32-7.22 (m, 3H), 6.69 (s, 2H), 6.40 (s, 1H), 5.38 (s, 2H), 3.81 (s, 3H), 3.70 (s, 6H); ESI MS m/z 418 [M+1]+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O-:15])(=[O:14])[C@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8].[Ca+2]>>[C:6]([OH:15])(=[O:14])[C@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
Sulfuric acid is added in calcium D-(-)-tartarate to precipitate calcium sulfate and D-(-)-tartaric acid is separated in water. D-(-)-tartaric acid can be obtained by concentrating the aqueous solution. Refined D-(-)-tartaric acid can be obtained by recrystallizing from water.
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:36]1(/[CH:42]=[CH:43]/[C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[C:44](=[O:45])/[CH:43]=[CH:42]/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)c(C(=O)OC)c2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)c(C(=O)OC)c2)C(=O)/C=C/c2ccccc2)cc1

Procedure:
The title compound was prepared following the procedure G using the hydrochloride salt of methyl 5-{[(4-dec-1-ynylbenzyl)amino]methyl}-2-(2-methoxy-2-oxoethoxy)benzoate and (2E)-3-phenylacryloyl chloride (purification by flash chromatography on SiO2, DCM/MeOH 98:2) as a pale yellow oil (82%). M+ (ESI): 610.0. HPLC, Rt: 6.0 min (purity: 99.5%). 1H NMR (CDCl3) δ: 7.85 (d, J=15.4 Hz, 1H), 7.70 (m, 1H), 7.47-7.12 (m, 10H), 6.86 (m, 2H), 4.74 (s, 2H), 4.61 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 2.41 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.30 (m, 8H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:17][C@H:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[C:11]=3[CH2:10]2)=[CH:5][C:4]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][N:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:35]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)=[O:36])[CH2:19]4)[C:11]=3[CH2:10]2)=[CH:5][C:4]=1[C:25]([F:28])([F:26])[F:27]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: Cn1cc(C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5cnn(C)c5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (44 mg, 0.11 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (15 mg, 0.12 mmol), benztriazol-1-ol (19 mg, 0.12 mmol) in CH2Cl2 (1.0 mL) was added EDC (34 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 18 h. Partitioned between CH2Cl2 (10 mL) and sat. NaHCO3(aq) (2.0 mL) and the organic layer separated by filtering through a phase separation tube. Concentrated in vacuo and purified by flash chromatography through Biotage® amino silica gel eluting with cyclohexane/EtOAc, 100/0 to 0/100 to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone as a white lyophilized powder (44 mg, 75% yield). 1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.26-2.45 (m, 2H) 3.04-3.10 (m, 2H) 3.49-3.57 (m, 2H) 3.89-4.00 (m, 7H) 4.01 (s, 3H) 4.10-4.18 (m, 2H) 5.78-5.83 (m, 1H) 7.60-7.62 (m, 1H) 7.76-7.89 (m, 2H) 8.04-8.07 (m, 1H) 8.61-8.66 (m, 1H) MS: [M+H]+=504.2, Rt(3)=1.59 min. Example 55 was prepared using procedures analogous to those used in example 54 using appropriate starting materials.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[F:13][C:14]1([F:31])[CH2:16][CH:15]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=2)[NH2:27])[N:18]=1.CCCP(=O)=O>C(OC(=O)C)C.C(=O)(O)[O-].[Na+]>[F:31][C:14]1([F:13])[CH2:16][C@@H:15]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[C:26]([NH:27][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:12])[CH:28]=2)[N:18]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1cc(C)c(-c2noc(C3CC3(F)F)n2)cc1N
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2noc([C@H]3CC3(F)F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 65 °C

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (25 mg, 0.154 mmol) and 5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2,4-dimethylaniline (150) (41 mg, 0.154 mmol) in ethylacetate (1 mL) was added propylphosphonic anhydride solution 50 wt % in ethyl acetate (184 uL, 0.308 mmol). The reaction was heated at 65° C. overnight. The reaction was cooled to room temperature and diluted with a solution of saturated sodium bicarbonate. The organic was separated and washed with water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography and then by a 20×250 mm ChiralPak AD-H column to give (R)—N-(5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2,4-dimethylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F108). 1H NMR (400 MHz, d4-MeOD) δ 10.04 (s, 1H), 9.46-9.44 (m, 1H), 8.57 (s, 1H), 7.95 (s, 1H), 7.79-7.76 (m, 1H), 7.53-7.49 (m, 1H), 7.36 (s, 1H), 7.18-7.15 (m, 1H), 3.74 (m, 1H), 2.55 (s, 3H), 2.47-2.35 (m, 2H), 2.31 (s, 3H). MS m/z 409.14 (M+1)+.