Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:30][C:26]4[CH:25]=[C:24]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:29]=[CH:28][CH:27]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccccc5)c4)ncnc3[nH]2)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (60.0 mg, 0.179 mmol) and biphenyl-3-ylamine (30.5 mmol, 0.180 mmol) in nBuOH (3 mL) was heated to 80° C. (bath temp.) for 17 h. The solvent was evaporated, water/NaHCO3 solution was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, the filtrate was concentrated, and the residue was chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-9)→1% MeOH in CH2Cl2 (10-19)→2% MeOH in CH2Cl2 (20-30)]. Fr.17-26 were combined and dried in vacuo overnight. One obtained the title compound as off-white solid. MS (ES+): m/z 468.1 (100) [MH+]. HPLC: tR=3.2 min (ZQ2000, nonpolar—5 min). 1H NMR (CDCl3, 400 MHz): δ=1.50 (s, 9H), 2.44-2.55 (brs, 2H), 3.61-3.71 (m, 2H), 4.13-4.22 (m, 2H), 6.15 (s, 1H), 6.24 (s, 1H), 7.11 (brs, 1H), 7.37 (t, J=7.4 Hz, 1H), 7.40-7.52 (m, 4H), 7.60-7.67 (m, 3H), 7.80 (t, J=1.6 Hz, 1H), 8.43 (s, 1H), 11.83 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:31][CH2:30][CH2:29][N:28]2[N:32]=[C:33]([NH2:35])[N:34]=[C:27]12>>[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:31][CH2:30][CH2:29][N:28]2[N:32]=[C:33]([NH:35][CH:11]3[CH2:12][CH2:13][N:8]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=4)[CH2:9][CH2:10]3)[N:34]=[C:27]12
Reactant: Nc1nc2n(n1)CCCC2c1ccc(C(F)(F)F)cc1F
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Product: Cc1cc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(C(F)(F)F)cc3F)CC2)ncn1

Procedure:
Prepared in analogy to example 1h employing 1-(6-methylpyrimidin-4-yl)piperidin-4-one and 8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 1d-g). The title compound was obtained as light yellow foam. MS ISP (m/e): 476.2 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[O:19]([CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)C>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cc1ccccc1OCCCCOc1ccccc1

Procedure:
28.2 g (0.17 mole) of methyl 2-hydroxyphenylacetate, 25.8 g (0.19 mole) of potassium carbonate and 38.9 g (0.17 mole) of 4-phenoxybutyl bromide in 400 ml of dimethylformamide are stirred for 24 hours at 70° C. Thereafter, the solvent is stripped off and the residue is taken up in diethyl ether. The solution is extracted several times with water and saturated sodium carbonate solution and the organic phase is dried over MgSO4. The oil obtained after removal of the solvent is purified by chromatography over silica gel (cyclohexane/ethyl acetate). Yield: 31 g (58%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:11].[SH:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=1.C(N(CC)CC)C.CCOCC>C(O)C>[Cl:11][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH2:9][CH3:10])[C:3]=1[CH2:2][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([C:20]([F:23])([F:21])[F:22])[N:14]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: CCc1cncc(Cl)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1cncc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of crude 4-(bromomethyl)-3-chloro-5-ethylpyridine (2.5 g, 10.66 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.35 g, 6.92 mmol) in anhydrous ethanol (50 mL) at 0° C. was added triethylamine (3.77 g, 37.31 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrochloride salt. The solid was filtered and washed with ether several times. The combined ether layers were evaporated to provide a crude residue, which was purified by Combiflash using 0-10% MeOH in dichloromethane to provide 2-{[(3-chloro-5-ethylpyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol as a white solid (1.5 g, 40% yield); 1H NMR (400 MHz, CDCl3): δ 1.17 (t, 3H), 2.24 (s, 3H), 2.84 (q, 2H), 4.65 (s, 2H), 6.72 (s, 1H), 8.41 (s, 1H), 8.50 (s, 1H); M+350.1
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][C:4]([NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[S:8])=[O:5].[C:15](=O)([O-])[O-].[Na+].[Na+].IC>O1CCCC1>[CH3:15][S:8]/[C:7](=[N:6]\[C:4](=[O:5])[CH:3]=[C:2]([CH3:14])[CH3:1])/[N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=CC(=O)NC(=S)N1CCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
A mixture of 3-methyl-N-(pyrrolidine-1-carbonothioyl)but-2-enamide (230 mg, 1.08 mmol, Eq: 1.00), sodium carbonate (121 mg, 1.14 mmol, Eq: 1.05) and iodomethane (769 mg, 339 μl, 5.42 mmol, Eq: 5) in tetrahydrofuran (7 ml) was stirred for 18 hours at 70° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 50-100% as eluent affording 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide (119 mg/48.5%) as a light yellow liquid. MS: m/e=227.1 (M+H+)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1)=[O:7].[I-].[K+].[ClH:34].[Cl:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][C@H:40]([CH2:44][O:45][CH3:46])[CH2:39]1.C(N(CC)C(C)C)(C)C>O.C(OCC)(=O)C.CN(C)C=O>[OH2:7].[ClH:35].[ClH:34].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][C@H:40]([CH2:44][O:45][CH3:46])[CH2:39]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1)=[O:7].[OH2:7].[OH2:7].[F:31][C:2]([C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][C@H:40]([CH2:44][O:45][CH3:46])[CH2:39]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1)=[O:7])([F:1])[F:30].[ClH:35].[ClH:35]
Reactant: COC[C@@H]1CN(CCCl)CCO1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(O)c3)C2)CCO1
Temperature: 52.5 °C
Yield: 191.8 %

Procedure:
Into N,N-dimethylformamide (33.5 ml) were charged (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (6.7 g), potassium iodide (8.0 g), (2S)-4-(2-chloroethyl)-2-(methoxymethyl)morpholine hydrochloride (4.3 g) and N,N-diisopropylethylamine (4.8 g). The temperature was raised to 50 to 55° C. and allowed to react for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Ethyl acetate (33.5 ml) and water (33.5 ml) were added and mixed. After mixing was completed, layers were separated. The organic layer was washed by adding water (33.5 ml), layers were separated and the organic layer was concentrated. Ethyl acetate (33.5 ml) was added to the obtained oil of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine to effect dissolution and then the solution was concentrated. The obtained concentrate was diluted with acetone (100 ml), clarified and filtered, and washed with acetone (34 ml). Concentrated hydrochloric acid (3.9 g) was added dropwise to the combined filtrate and washings at room temperature and crystallization was effected under ice-cooling for 8 hours. Crystals were collected by filtration, washed with acetone (33.5 ml), dried under reduced pressure and moistured to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methyl-benzyl)piperazine dihydrochloride sesquihydrate (8.1 g, yield: 76.7%) in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=1[CH3:14].CCO/[C:19](/[CH3:26])=[CH:20]/[C:21](OCC)=[O:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:15]=[C:19]([CH3:26])[CH:20]=[C:21]([OH:22])[C:11]2=[CH:12][C:13]=1[CH3:14]
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: Cc1ccn(N)c1-c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-3-methyl-1H-pyrrol-1-amine (2.34 g, 9.69 mmol), ethyl trans-3-ethoxycrotonate (1.58 g, 10.0 mmol) and p-toluenesulfonic acid (0.095 g, 0.50 mmol) in CHCl3 (100 mL) is refluxed with a Dean-Stark tube charged with molecular sieves for 24 h. After cooling down to room temperature, the mixture is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 1.88 g (63%) of light yellow solid as the title compound: mp 234–237° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=2.1 Hz, 1H), 7.52 (dd, J=2.1, 8.3 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 5.94 (s, 1H), 2.20 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 153.0, 149.0, 134.2, 135.2, 132.0, 128.2, 127.6, 125.7, 121.2, 119.0, 118.8, 96.0, 92.5, 20.0, 10.5; IR (diffuse reflectance) 3075, 3008, 2997, 2989, 2353, 2327, 2216, 2190, 2105, 1555, 1367, 1314, 1185, 828, 814 cm−1; MS (EI) m/z 308 (M+), 306 (M+); HRMS (FAB) calcd for C15H12Cl2N2O+H 307.0405, found 307.0414; Anal. Calcd for C15H12Cl2N2O: C, 58.65; H, 3.94; N, 9.12. Found: C, 58.68; H, 3.91; N, 8.96.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][OH:12]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CO
Product: COC(=O)c1ccc(C)cc1

Procedure:
To 200 ml of methanol at 0° was added, with stirring, 48.4 g (0.312 mole) of 4-methylbenzoyl chloride over 20 minutes. Following the addition, the reaction mixture was stirred at room temperature for one hour. The methanol was evaporated and the residue was distilled to give 43 g of the title compound as a colorless liquid: boiling point 103°-108° C. at 20 mm of Hg.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](/[C:16]([O:18][CH3:19])=[O:17])\[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)(Cl)Cl>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(C)=C/c1ccc(C(=O)OC(C)(C)C)s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
5-[(1E)-2-(methoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylic acid tert-butyl ester (13.77 g, 0.049 mol) was dissolved in ethyl acetate (60 mL), methanol (20 mL), and chloroform (10 mL), palladium hydroxide (2.8 g) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, palladium hydroxide was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (13.14 g, 0.046 mol, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)(O)[O-:27].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:16])[CH2:17][OH:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: O=C([O-])O
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3cccnc3)CO2)CCN(C)C1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CO)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,8-dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.3 mmol) in 20% aq. TFA (2 mL) was stirred at RT overnight. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with EtOAc (2×30 mL) to remove the impurities. The aqueous layer was lyophilized to obtain the crude product that was purified by reverse phase HPLC to obtain 5 mg of 3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propane-1,2-diol as the TFA salt. 1H NMR (CD3OD, TFA) δ (ppm): 8.75 (s, 1H), 8.6 (m, 2H), 7.83 (m, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 4.62 (d, 1H), 4.45 (dd, 2H), 4.3 (t, 1H), 4.05 (t, 1H), 3.8 (m, 2H), 3.5 (m, 3H), 3.1 (s, 3H), 2.3 (s, 3H). Separation by chiral HPLC provides enantiomers II-257a-b.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41]C)=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([OH:41])=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)c(OC)c1)OCC
Yield: 67.2 %

Procedure:
To a mixture of methyl 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.38 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.25 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 148-149° C.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([NH2:11])=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)[CH3:13].C([O-])(=O)C.[Na+]>CN(C)C=O>[CH2:8]([C:9]1[N:11]=[C:12]([CH3:13])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cc2ccccc2)nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To 100 ml of N,N-dimethylformamide, 17.1 g (100 mmol) of 2-phenylacetoamidine hydrochloric acid salt, synthesized in accordance with a method described in “Tetrahedron”, page 887 (1984), 18.6 g (100 mmol) of ethyl 2-acetyl-3-ethoxyacrylate and 9.0 g (110 mmol) of sodium acetate were suspended, followed by stirring at 100° C. for 3 hours. The reaction liquid was cooled and then poured into ice water, and extracting with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 22.8 g (yield: 89%) of ethyl 2-benzyl-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14](=[O:30])[CH2:15]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:12].C1OCCOCCOCCOCCOCCOC1.[C:49]1([CH3:57])[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=O)[CH:50]=1>C1COCC1>[CH2:11]([O:13][C:14](=[O:30])[CH:15]=[CH:57][C:49]1[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=1)[CH3:12]
Reactant: Cc1cccc(C=O)c1
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(C)c1
Reaction time: 0.5 h

Procedure:
KHMDS (4.0 g, 20.0 mmol) was added to a solution of ethyl[bis(2,2,2-trifluoro-ethoxy)phosphinyl]acetate (4.7 mL, 20.0 mmol) and 18-crown-6 (10.6 g, 40.0 mmol) in THF (200 mL) at −78° C., and stirred for 30 minutes. m-Tolualdehyde (2.1 mL, 18 mmol) was added and the reaction mixture was stirred for 3 hours from −78° C. to room temperature. The reaction was quenched with aqueous hydrochloric acid (1 M solution, 100 mL), and the product was extracted with EtOAc (3×100 mL). The organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C12H14O2+H: 191, observed: 191.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[N:12]=[C:13]([Cl:17])[CH:14]=[C:15](Cl)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[N:12]=[C:13]([Cl:17])[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccc(Br)cc3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 2-(4-bromo-phenyl)-5,7-dichloro-pyrazolo[1,5-a]pyrimidine (217 mg, 0.633 mM), then morpholine (110 μL, 1.27 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture and the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts obtained were combined together, dried over anhydrous sodium sulfate, the solvent was distilled off and then the resulting solid was washed with methanol to thus give the title compound (240 mg, yield: 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22]([OH:24])=O)([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:31].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([CH3:21])([CH3:20])[C:22]([NH:31][CH:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:39])=[O:28])=[O:24])=[CH:16][CH:17]=2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)NC(Cc3ccccc3)C(=O)O)cc2)c1

Procedure:
Using RSR13 acid (1.6 g, 4.7 mmol), phenylalanine methyl ester hydrochloride (1.08 mg, 4.7 mmol) and 1-hydroxybenzotriazole hydrate (697 mg, 5.2 mmol), N-methylmorpholine (711 mg, 7.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.08 g, 5.3 mmol) in dimethylformamide (40 mL), the two isomers were prepared in 2.2 g yield (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1([NH:1][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2cccnc21
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(Nc2c[nH]c3ncccc23)cc1

Procedure:
A 1 dram vial was charged with aniline (2-3 equiv), and 10 mg of 3-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 583 in 0.4 mL toluene (dry, degassed). A catalyst stock solution containing 3 mmol Pd(OAc)2, 3 mmol biphenyl-2-yl-di-tert-butyl-phosphane and 15 mL of toluene was prepared. To the reaction mixture, 0.050 mL of the catalyst solution was added. Excess NaOtBu was added as a solid to the reaction. The vial was then placed in a 75° C. oven for 60 minutes (shaken several times over an hour). After cooling, the reaction was neutralized with 0.100 mL of TFA. After 30 minutes the sample was evaporated and re-solvated in 0.300 mL of DMSO. The desired compound was isolated by preparative HPLC/MS.
Reaction SMILES: Br[C@H:2]([C@H:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1>CCOCC>[O:14]1[C@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C@H:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@@H](O)[C@@H](Br)C(=O)OCC
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
2a (38.1 g, 142 mmol) was dissolved in anhydrous Et2O (100 ml) and DBU (32.3 g, 212.4 mmol, in Et2O [50 ml]) was added dropwise at 0° C. for 1 h. The reaction was allowed to warm to r.t. and stirred for an additional 4 h. Reaction was quenched with cold 1N HCl to pH˜5. The resulting aqueous layer was extracted with Et2O (3×150 ml). The combined organic extracts were washed with brine (2×100 ml), dried over Na2SO4, and concentrated to give the pure product as faintly yellow oil (21.5 g, 80.7% yield). Product purity typically reflects that of the bromohydrin starting material. If necessary, fractional vacuum distillation can be used for purification. 1H NMR (CDCl3, 400 MHz): δ 4.36-4.22 (m, 4H); 3.67 (s, 2H); 1.35-1.31 (t, 6H). 13C NMR (CDCl3, 100 MHz): 166.75, 62.21, 52.01, 14.01.