Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:12]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[C:4]=3[CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
6-(3-Chlorophenyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-chlorophenyl boronic acid according to the procedure of Example 4, as a white solid: mp 150-151° C.; 1H-NMR (CDCl3) δ 8.52 (s, 1H, D2O exchangeable), 7.50 (s, 1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, J=1.5 Hz), 6.89 (d, 1H, J=8.2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, J=7.4 Hz); MS (EI) m/z 315 (M+, 53%). Anal. Calcd. For C18H18ClNO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.16; H, 5.81; N, 4.32.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:24]=[CH:25][N:26]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N(Cc1c[nH]cn1)C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)cn1)C1CCN(Cc2ccccc2)CC1
Yield: 24 %

Procedure:
To a solution of tert-butyl (1-benzyl-4-piperidinyl)((1H-imidazol-4-yl)methyl)carbamate (1.3 g) obtained in Example 83b) in DMF (30 ml) was added sodium hydride (0.22 g) under ice-cooling, and mixed at room temperature for 1 hour. Subsequently, 2-(trimethylsilyl)ethoxymethyl chloride (1.3 ml) was added under ice-cooling, and then mixed at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water, and the organic layer was collected by separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate:hexane=1:1) to obtain the title compound as a pale yellow oil (4.9 g, 24%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][C:39]([NH2:43])=[N:40]2)=[CH:35][CH:34]=1>>[NH2:43][C:39]1[CH:38]=[C:37]([N:44]2[CH2:49][CH2:48][N:47]([C:11]([NH:1][C@H:2]3[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]3=[O:9])=[O:12])[CH2:46][CH2:45]2)[C:36]2[C:41](=[CH:42][C:33]([Cl:32])=[CH:34][CH:35]=2)[N:40]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: N[C@H]1CCCCNC1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCNC3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, (s)-3-amino-azepan-2-one, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 417 (M++1). 1H NMR (CD3OD) δ 7.80 (d, 1H), 7.45 (s, 1H), 7.15 (d, 1H), 6.35 (s, 1H), 4.45 (d, 1H), 3.68 (m, 4H), 3.25 (m, 2H), 3.10 (m, 4H), 2.00 (m, 2H), 1.80 (m, 2H), 1.60 (m, 1H), 1.38 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cccc(CNC(=O)c2c(Cl)ncnc2Cl)c1
Reactant: N
Solvent: C1COCCO1
Product: COc1cccc(CNC(=O)c2c(N)ncnc2Cl)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
4,6-Dichloro-N-(3-methoxybenzyl)pyrimidine-5-carboxamide (523 mg, 1.68 mmol) was dissolved in dioxane (8 ml) and cooled in an ice bath. Ammonia solution (1.2 ml, 8.40 mmol, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h. After evaporation of the solvent under reduced pressure, the residue was suspended in ethyl acetate and filtered, washing several times with ethyl acetate. The organics were evaporated under reduced pressure to yield the final compound as a solid (424 mg, 97% purity, 84% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:23]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:22]=1.BrC1C=C(C2C(=O)N(C)C(Cl)=NC=2C2C=CN=CC=2)C=CC=1>ClCCl>[CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:23]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:22]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC[C@H]1CCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.186 g, 0.86 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.3 mL diisopropylethylamine (1.71 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.2 g, 0.57 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. (This naphthyl chloro-intermediate was synthesized by a similar procedure as that of 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.) The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.21 g as pale yellow solid. MS (ES+): 454 (M+H)+; (ES−): 452 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCN2CCCC2)cc1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (4.56 g, 30 mmol) in dry DMF (60 mL) was added cesium carbonate (31.3 g, 96 mmol, 3.2 eq.) and 1-(2-chloroethyl)pyrrolidine hydrochloride (8.1 g, 48 mmol, 1.6 eq.). The reaction was heated at 80° C. for 20 h. The reaction mixture was cooled to ambient temperature then water (240 mL) was added. The mixture was partitioned with ethyl acetate (250 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined extracts were washed with water (240 mL), brine (50 mL), dried (Na2SO4), filtered then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (90:5:5 hexane:THF:TEA) to give the desired product as an oil (5.3 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]#[N:26])=[CH:4][N:3]=1.[OH-:27].[Na+].OO.O>CCO.CS(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]([NH2:26])=[O:27])=[CH:4][N:3]=1
Reactant: Cc1cn(-c2ccc3c(N)ncc(C#N)c3c2)c2c1C(=O)CC(C)(C)C2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc3c(N)ncc(C(N)=O)c3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A suspension of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile (0.066 g, 0.19 mmol) in EtOH/DMSO (3:1, 2 mL) is treated with an aqueous solution of NaOH (1 M, 0.03 mL) and H2O2 (30%, 0.1 mL). The reaction mixture is stirred at RT for 2 h. The reaction mixture is treated with H2O (20 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-20% MeOH/CH2Cl2) affords 0.02 g (29%) of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carboxylic acid amide. LC/MS m/z=363 [M+H]+, RT=1.93 min.
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[C:21]1([C:35]([OH:36])=[C:31]([N+:32]([O-:34])=[O:33])[CH:30]=[C:26]([N+:27]([O-:29])=[O:28])[CH:25]=1)[N+:22]([O-:24])=[O:23].[Fe:37]>CO>[C:31]1([C:35]([O-:36])=[C:21]([N+:22]([O-:24])=[O:23])[CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[CH:30]=1)[N+:32]([O-:34])=[O:33].[Fe+2:37].[C:31]1([C:35]([O-:36])=[C:21]([N+:22]([O-:24])=[O:23])[CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[CH:30]=1)[N+:32]([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: [Fe]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: [Fe+2]

Procedure:
According to one method aspect of the present invention, additives may be prepared by the steps of (i) combining EDTA and amine in a suitable solvent such as methanol; (ii) adding picric acid to a suitable solvent such as methanol to make a solution of picric acid; (iii) adding a source of +2 iron to the picric acid solution of step (ii) with stirring to obtain a green iron picrate solution; and (iv) adding portions of the solution of step (i) to the green iron picrate solution of step (iii) with agitation until the green color disappears and a clear yellow solution is obtained. The color change of step (iv) is rapid, taking place immediately upon sufficient addition of the solution of step (i).
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCc1ccccc1
Reactant: c1ccc(NC2CCNC2)cc1
Product: c1ccc(CCN2CCC(Nc3ccccc3)C2)cc1

Procedure:
3-Anilinopyrrolidine and 2-bromoethylbenzene are reacted under the same conditions as in Starting Material Synthetic Example 4 to give 3-anilino-1-(2-phenylethyl)pyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32][CH3:33])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][N:18]([C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:35]=2[Cl:34])[C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Yield: 87.4 %

Procedure:
4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (133 mg, 0.28 mmol) was dissolved in 1,2-dichloroethane (2.8 mL) and was treated with 2,4-dichlorobenzoyl chloride (60 μL, 0.43 mmol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 4-{[(2,4-Dichloro-benzoyl)-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (0.156 g, 85% yield).
Reaction SMILES: [CH2:1]([P:5](Cl)([CH2:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:12]([Mg]Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>O1CCCC1>[CH2:1]([P:5](=[O:6])([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CP(=O)(Cl)CC(C)C
Reactant: CCCCCCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCP(=O)(CC(C)C)CC(C)C
Temperature: 25 °C

Procedure:
A solution of di-isobutylphosphinyl chloride* (3.9g., 0.02 mole) in tetrahydrofuran (50 ml.) was added dropwise to a refluxing solution of n-heptylmagnesium bromide (prepared from magnesium turnings (1.2g., 0.05 mole), n-heptyl bromide (9.0g., 0.05 mole) and tetrahydrofuran (100 ml.)). The mixture was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured onto ice and 2N HCl (300 ml.), and extracted with methylene dichloride (4 × 200 ml.). The combined extracts were washed with lithium hypochlorite solution, 2N NaOH solution and finally with water, then dried (MgSO4). The solvent was removed by distillation and the residual yellow oil (8g.) was eluted with chloroform down a silica gel column. The product (Rf = 0.1- 0.2 on silica t.l.c. (CHCl3)) was finally distilled to yield diisobutyl-n-heptyl-phosphine oxide as a colourless liquid, bp. 120°-2°/0.03 mm. (Found C 68.8; H 13.0; C15H33OP requires C 69.3; H, 12.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39]C(O)[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH:29]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OC1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCOCC4)cc3)c2cc1OC
Yield: 83.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, tetrahydro-2H-4-pyranol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 83%).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:5][CH:4]=1)=[O:2].[C:18](C1NC=CN=1)([C:20]1[NH:21][CH:22]=[CH:23]N=1)=O.C(NCC)C>CN(C=O)C.C(OC(=O)C)C>[C:15]([N:21]([CH2:22][CH3:23])[CH2:20][CH3:18])(=[O:17])[CH:14]=[CH2:13].[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=Cc1ccc(C=CC(=O)O)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: C=CC(=O)N(CC)CC
Product: O=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of 4-formylnaphthalene acrylic acid (210 mg, 0.92 mmol) in DMF (4 mL) was added carbonyl diimidazole (180 mg, 1.10 mmol). The mixture was stirred at room temperature for 1 hr, and diethylamine (0.1 mL, 71 mg, 0.97 mmol) was added. After stirring at room temperature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3×5 mL), dried (MgSO4) and concentrated. After flash chromatography using hexane/ethylacetate 1:1, 115 mg (43%) of a yellow oil was obtained.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].NC1N=C(O)C=C(O)N=1.Br[C:26]1[S:30][C:29]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=1>O.CN1C(=O)CCC1>[N:1]1([C:26]2[S:30][C:29]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCCCC(=O)c1ccc(Br)s1
Agent: Nc1nc(O)cc(O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Temperature: 157.5 °C

Procedure:
Charged Benzimidazole (12.11 mmoles), cesium carbonate (14.11 mmoles), cuprous oxide (0.4 mmoles), 2-Amino-4,6-dihydroxypyrimidine (1.5 mmoles), PEG (catalyst), keto thiophene (XXI) and NMP (5 ml) to the RB flask fitted with thermo well and condenser. The reaction mixture was heated to 155-160° C. and the temperature was maintained for 10-12 hrs at 155-160° C. After completion of reaction, cooled to room temperature, added water (25 ml), extracted with ethyl acetate (2×100 ml), washed with 10% brine solution, dried the ethyl acetate layer over sodium sulfate and distilled off the solvent completely at reduced pressure to get crude compound. The crude compound was purified by using silica gel 60-120 silica gel column chromatography and DCM: methanol: 100-5% as mobile phase to get the pure compound (84).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O

Procedure:
In pyridine (30 ml) is dissolved R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (7 g), and methanesulfonyl chloride (2.9 ml) is added dropwise, with stirring, under ice-cooling over the period of 5 minutes. The mixture is stirred under ice-cooling for 1.5 hours, and water (5 ml) is added dropwise to the mixture. The reaction mixture is stirred for 30 minutes, diluted with ethyl acetate (300 ml) and washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and water. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (8.2 g) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1.C([Li])CCC.[B:18]([O:27]C(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][B:18]([OH:27])[OH:23])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOCc1ccc(OB(O)O)cc1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis(triphenylphosphine)palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([CH2:45][C:46]([OH:48])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[NH2:4][C:46](=[O:48])[CH2:45][CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CC(N)=O)C1
Yield: 57.5 %

Procedure:
PyBOP (1.946 g, 3.74 mmol) was added to a solution of [1-(tert-Butoxycarbonyl)azetidin-3-yl]acetic acid (0.805 g, 3.74 mmol) in DMF (10 mL). The mixture was stirred in an ice-bath, ammonia gas was bubbled in for 3 mins and then the mixture was stirred at rt overnight. The reaction mixture was concentrated, water (15 mL) and saturated, aqueous NaHCO3 (5 mL) were added, and the mixture was extracted with EtOAc (20 mL×3). The extracts were combined, washed with water (20 mL) and brine (10mL), dried (Na2SO4) and evaporated. Column chromatography of the residue (ISOLUTE SI, 50 g/150 ml), eluting with EtOAc and heptane (50:50), then EtOAc and then MeOH and EtOAc (1:99, 2:98 and 5:95), gave the title compound (0.461 g, 57.5%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.42 (s, 9H), 2.53 (d, 2H), 2.85-2.96 (m, 1H), 3.60 (dd, 2H), 4.09 (t, 2H), 5.78 (s, br, 2H); 13C NMR (100 MHz, CDCl3): 25.4, 28.3, 39.7, 54.3 (br), 79.4, 156.3, 173.2.