Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:17][CH2:16]2)[CH:5]=[N:6][CH:7]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (4 g, 17.4 mmol) in DMF (80 mL), cooled at 0° C. with an ice bath, was added 60% NaH in mineral oil (0.918 g, 38.3 mmol) and the reaction mixture was stirred at 0° C. for 15 min. Then, a solution of 1,2-dibromoethane (3.27 g, 17.4 mmol) in DMF (16 mL) was added at 0° C. After the addition, the mixture was stirred at room temperature for 1 h. Two other portions of 60% NaH in mineral oil (2×0.2 g) were added sequentially, until conversion was complete. Then, the reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (3×125 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (4.764 g, 99%) as a brown oil, which was used with no further purification. MS: 256.0 and 258.0 (M+H+).
Reaction SMILES: CC1C=CC(C2C=CC=CN=2)=C(C=1)C(OC)=O.Br[C:19]1[C:20]([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[C@H:29]2[CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[O:27])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C([Sn](CCCC)(CCCC)[C:52]1[N:57]=[CH:56][CH:55]=[CH:54][N:53]=1)CCC>>[CH3:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:26](=[O:27])[C:20]2[C:19]([C:52]3[N:57]=[CH:56][CH:55]=[CH:54][N:53]=3)=[CH:24][CH:23]=[C:22]([CH3:25])[N:21]=2)[C@@H:29]1[CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46]
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: COC(=O)c1cc(C)ccc1-c1ccccn1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(pyridin-2-yl)benzoate in Example A9, using 2-(((2S,3R)-1-(3-bromo-6-methylpicolinoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-(tributylstannyl)pyrimidine. ESI-MS (m/z): 456, [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.F[C:30](F)(F)[C:31]([OH:33])=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=[O:38])C.[Na+]>ClC(Cl)C.CC1(C)OCC(=O)CO1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:30]([CH2:31][OH:33])[CH2:36][OH:38])[CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OCC(=O)CO1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1C(CO)CO
Reaction time: 0.33 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (50 mg, 0.13 mmol) was dissolved in dichloroethane (0.20 mL) and 2,2-dimethyl-1,3-dioxan-5-one (0.20 mL). Trifluoroacetic acid was added (0.039 mL) and the resulting solution was allowed to stir for 20 minutes. Sodium triacetoxyborohydride was added (55 mg, 0.26 mmol) and the reaction mixture was stirred for 30 minutes. The crude reaction mixture was then evaporated to dryness, dissolved in N,N-dimethylformamide and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=1.[H][H].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br>CN(C)C=O>[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][CH2:14][N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:13][CH2:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:4][CH3:3])=[CH:6][CH:7]=2)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:7][CH:6]=1
Reactant: CSc1ccc(N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: BrCCCCCBr
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(N(CCCN(CCCCCN(CCCN(C(=O)OC(C)(C)C)c2ccc(SC)cc2)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Suspend sodium hydride (48 mg, 2 mmol) in anhydrous dimethylformamide (2 mL), cool to 0° C. and place under a nitrogen atmosphere. Add, by dropwise addition, a solution 1-(4-methylthiophenyl)-1,5-bis(t-butyloxycarbonyl)-1,5-diazapentane (1.58 g, 4 mmol) in dimethylformamide (2 mL). Stir until evolution of hydrogen ceases. Add, by dropwise addition, a solution of 1,5-dibromopentane (460 mg, 2 mmol) in dimethylformamide (2 mL). Stir overnight at room temperature then carefully quench with saturated ammonium chloride. Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatogaphy to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[CH:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N+]([CH3:16])([O-])=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:10]#[N:11])[CH2:16][CH:5]1[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C(C#N)=CCC(C)C
Solvent: CC#N
Product: COC(=O)C1(C#N)CC1CC(C)C
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-cyano-5 methyl-hex-2-enoic acid methyl ester (20.2 g, 121 mmol) in dry acetonitrile (110 mL) was added nitromethane (9.8 mL, 181 mmol) and a portionwise addition of alumina-supported potassium flouride (40% wt, 39.3 g). The reaction mixture was stirred under reflux for 2 hours and cooled to room temperature. The solid was removed by filtration through a short pad of celite and washed with acetonitrile. Excess of solvent was removed in vacuo and the residue was re-dissolved in ether. The ether layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes/EtOAc (8:2) as an eluent to give 15 g (69%) of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid methyl ester as colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=2.9 Hz, 3H), 1.00 (d, J=3.0 Hz, 3H), 1.35–1.42 (m, 2H), 1.65 (m, 1H), 1.79–1.94 (m, 3H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 19.3, 22.3, 22.4, 25.5, 27.9, 30.1, 39.0, 53.4, 117.3, 168.5.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:43]([O:47][C:48](=[O:70])[C@H:49]([CH2:68][SH:69])[NH:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([CH3:46])([CH3:45])[CH3:44]>C(Cl)(Cl)Cl>[C:43]([O:47][C:48](=[O:70])[C@H:49]([CH2:68][S:69][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([CH3:44])([CH3:45])[CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC(=O)CCCCCCCCCCCCCCC)C(=O)OC(C)(C)C

Procedure:
Palmitic acid (2.5 g, 9.6 mmol), dimethylaminopyridine (130 mg, 0.9 mmol) and dicyclohexylcarbodiimide (9.6 mmol) are dissolved in 100 ml of chloroform. The solution is stirred for half an hour and N-palmitoylcysteine tert.-butyl ester (2 g, 4.8 mmol), which has previously been dissolved in 50 ml of chloroform, is added dropwise to the other solution. After 11/2 h, the solvent is removed in a rotary evaporator, and the residue is taken up in 100 ml of chloroform/methanol 1:5. The product forms a voluminous precipitate at -20 degrees C. It is filtered off with suction and dried under high vacuum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=[O:21])[CH2:15][CH2:14]1
Reactant: CON1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CON1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (23.8 g, 189 mmol) in 100 ml of methylene chloride, DMSO (29.6 g, 380 mmol) was added slowly and the mixture was stirred for 0.5 h at the same temperature. Then, a solution of 2-(1-methoxy-piperidin-4-yl)-ethanol (12 g, 75 mmol) in 50 ml of methylene chloride was added. After stirring for 30 minutes, triethylamine (44 g, 430 mmol) was added to the mixture. After the addition, the reaction mixture was warmed to room temperature and diluted with methylene chloride. The organic solution was washed with water and aqueous NaHCO3. The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel. Yield: 11.5 g of (1-methoxy-piperidin-4-yl)-acetaldehyde as an oil.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:32]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:32]1([CH:38]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CCOC(=O)N2CCC(c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 2.10 g, 6.79 mmol) was dissolved in DMF (30 mL). DIPEA (2.37 mL, 13.59 mmol) and 3-phenylpyrrolidine (1.00 g, 6.79 mmol) were added and the reaction mixture was stirred at room temperature for 4 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with 1M aq Na2CO3 solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (2.0 g) was added, the reaction mixture shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (60 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo, to give 2-(4-methylpiperazin-1-yl)ethyl 3-phenylpyrrolidine-1-carboxylate (1.03 g, 48.0%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][OH:20])=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-hydroxymethyl-[1,2,4]triazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (from Step 2 above, 0.181 g, 0.641 mmol) and triethylamine (0.134 mL, 0.961 mmol) in dichloromethane (5 mL) at 0° C. was added methanesulfonylchloride (0.055 mL, 0.705 mmol). The resulting solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to yield the desired product as a light yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18]CC)=[O:17])=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]2[C:21]3[CH:22]=[C:23]([C:28]([O:30]CC)=[O:29])[CH:24]=[CH:25][C:26]=3[NH:27][C:4]=12.[OH-].[K+].Cl>CCO.O.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:16]([OH:18])=[O:17])=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]2[C:21]3[CH:22]=[C:23]([C:28]([OH:30])=[O:29])[CH:24]=[CH:25][C:26]=3[NH:27][C:4]=12
Reactant: CCOC(=O)c1ccc2[nH]c3c(OC)c4[nH]c5ccc(C(=O)OCC)cc5c4cc3c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1c2[nH]c3ccc(C(=O)O)cc3c2cc2c1[nH]c1ccc(C(=O)O)cc12
Temperature: 95 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
A mixture of diethyl 6-methoxy-5,7-dihydroindolo[2,3-b]carbazole-2,10-dicarboxylate (10 g, 23.23 mmol) and KOH (3.7 g) in EtOH/H2O/THF(120/40/10 mL) was heated to 90-100° C. under Ar and stirred for 4-6 h until all starting material disappeared. The reaction mixture was neutralized with 1N aq. HCl. The white ppt was collected by filtration and washed with small amount of water, dried under vacuum to give 6-methoxy-5,7-dihydroindolo[2,3-b]carbazole-2,10-dicarboxylic acid (8.3 g, 95%).
Reaction SMILES: N([O-])=O.[Na+].[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N-:30]=[N+:31]=[N-].[Na+]>O.C(O)(=O)C.C(OCC)(=O)C>[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[CH:26][C:27]([N:29]=[N+:30]=[N-:31])=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(N=[N+]=[N-])ccc32)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 12 mg of NaNO2 in 0.5 mL of H2O was added to a 5° C. solution of 56 mg of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine in 2 mL acetic acid. The solution was cooled to 0° C. and stirred for 0.5 hours. A solution of 16.5 mg NaN3 in 0.5 mL H2O was added and stirred for one hour. The solution was diluted with 100 mL of ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 53 mg of the title compound. RF: 0.6 (5% MeOH in CH2Cl2). 1H NMR (400 MHz, 1:1 CD3OD/CDCl3): δ 1.60 (d, J=7.0 Hz, 3H), 5.12 (q, J=7.0 Hz, 1H), 6.8 (m, 1H), 6.95 (d, J=6 Hz, 1H), 7.2-7.45 (m, 6H), 7.72 (m, 1H), 8.33 (br s, J=6.5 Hz, 1H), 8.74 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 357.1 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[C:41]([CH:42]=[O:43])=[CH:40][N:39]=[CH:38]1.C([Li])(CC)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:42]([C:41]2[N:37]([CH3:36])[CH:38]=[N:39][CH:40]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1cncc1C=O
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Li]C(C)CC
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3cncn3C)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl) silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3), 1-methyl-imidazole-5-carbaldehyde (116 mg, 1.06 mmol) and sec-butyllithium.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:11][C@H:12]([OH:26])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:3]([OH:5])=[O:4].C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CCCCN(C(OCC1C=CC=CC=1)=O)C[C@@H](O)CCNC(OCC1C=CC=CC=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:11][C@@H:12]([OH:26])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CCCCN(C[C@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCN(C[C@@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Yield: 62 %

Procedure:
According to the method described for the preparation of 17a, 16b (78 mg, 0.12 mmol) was reacted with trifluoroacetic acid (704 mg, 6.20 mmol) and triethylsilane (140 mg, 11.92 mmol) in CH2Cl2 (0.98 mL) to give 17b (37 mg, 62%) as a colorless oil: 1H NMR δ 1.20-2.10 (m, 8H), 3.05-3.70 (m, 7H), 3.82 (m, 1H), 5.05 (s, 2H), 5.10 (s, 2H), 7.20-7.60 (m, 10H); HRMS m/z calcd for C26H36N3O7 502.2553, found 502.2546. [α]23D+3.6° (c 1.00, CH3OH).
Reaction SMILES: [CH3:1][C:2]([NH2:22])([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:34]=1[C:35](Cl)=[O:36]>CN(C=O)C>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:34]=1[C:35]([NH:22][C:2]([CH3:3])([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH3:1])=[O:36]
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Reactant: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2c(F)ccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of {1-Methyl-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine (II-1, 43 mg, 0.13 mmol) in DMF (0.7 mL) was treated with i-Pr2NEt (0.066 mL, 0.38 mmol) and 2-chloro-3,6,-difluorobenzoyl chloride (0.2 mL, 0.8 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was purified directly by reverse phase HPLC to afford 2-chloro-3,6-difluoro-N-{1-methyl-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (II-2). Analytical LCMS: single peak (214 nm), 2.803 min. 1H NMR (CD3OD, 300 M ) δ 8.67 (d, J=3.9 Hz, 1H), 8.51 (s, 1H), 8.15 (ddd, J=1.8, 7.8, 8.1 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.60 (dd, J=5.5, 6.9 Hz, 1H), 7.34 (ddd, J=4.8, 9.3, 14.1 Hz, 1H), 7.21 (ddd, J=4.2, 8.4, 12.3 Hz), 1H), 3.76-3.65 (m, 2H), 2.86-2.78 (m, 4H), 2.69-2.54 (m, 2H), 2.25-2.15 (m, 2H), 1.76-1.63 (m, 2H), 1.43 (s, 6H), 0.98 (t, J=7.2 Hz, 3H); RMS m/z 500.1572 (C22H28ClF2N3O3S+H+ requires 500.1581).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH:13]1[CH:14]=[CH:15][C:16]([C@H:19]2O[C@@H:20]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:16]1([C:19]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1oc2ccccc2c(O)c1C(=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flame-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 1.0 g of commercially available trans-stilbene oxide in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is flash column chromatographed with 50% to 66% ethyl acetate in hexane to yield 880 mg of the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10]Cl)=[C:4](Cl)[N:3]=1.[OH-:13].[Na+].O>C(O)(C)(C)C>[Cl:8][C:6]1[C:5]2[CH2:9][CH2:10][O:13][C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)c(CCCl)c(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1nc(Cl)c2c(n1)OCC2

Procedure:
A suspension of 6.0 g of 2-amino-5-(2-chloroethyl)-4,6-dichloropyrimidine, 29 ml of 2 N aqueous sodium hydroxide solution, 35 ml water and 75 ml of t-butanol was heated to reflux (60°) for 24 hours then cooled. The solid was collected by filtration, rinsed with water and dried to yield 2.4 g of 4-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-2-amine, m.p. 258°-263°. The product showed characteristic triplet absorption bands at 3.40 and 5.10 ppm in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:22])[CH2:7][C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)=[O:9])C>C1COCC1.O>[C:16]1([C:13]2[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][C:6]([OH:22])=[O:5])[O:15][N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2ccccc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(=O)Nc1cc(-c2ccccc2)no1
Reaction time: 8 h
Yield: 65.3 %

Procedure:
NaOH (57 mg, 1.4 mmol) was added to a stirred solution of N-(3-phenyl-isoxazol-5-yl)-malonamic acid ethyl ester (78 mg, 0.28 mmol) in a mixture of THF (12 mL) and H2O (12 mL) and stirring was continued at ambient temperature overnight. The reaction mixture was concentrated. The residue was diluted with water, washed with diethyl ether, acidified with concentrated HCl. The precipitate was filtered to afford 45 mg (64.28% Yield) of N-(3-phenyl-isoxazol-5-yl)-malonamic acid.