Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][CH:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CC(O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.7 g (71%) of (RS)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 76°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:31])=[CH:9]2)=[CH:5][CH:4]=1>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:31])=[CH:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=Cc4ccncc4)c4ccccc4)cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2cc(C)c3ccc(C(Cc4ccncc4)c4ccccc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A solution of cis- and trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole (70 mg, Example 22) in a mixture of tetrahydrofuran and methanol (20 ml; 1:1, v/v) was heated at 45-50° C. under an atmosphere of hydrogen in the presence of 6% palladium on activated charcoal then stirred overnight at room temperature. The mixture was filtered through celite then evaporated. The residue was subjected to high pressure liquid chromatography using a hypersilC18 BDS column (250×20 ml, 8 micron) and eluting with methanol containing 0.1% ammonium hydroxide to yield the title compound (13 mg) as an oil. NMR (CDCl3): δ 2.30(s, 3H); 3.30-3.40(m, 2H); 3.70(s, 3H); 4.30-4.40(m, 1H); 5.10(s, 2H); 6.80-7.50 (m, 13H); 8.30-8.35(m, 2H); 8.50(bs, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18](C2CCCCO2)[N:17]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>CO>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](/[CH:15]=[CH:14]/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:17]1
Reactant: C(=C/c1nn(C2CCCCO2)c2ccccc12)\c1ccccc1Nc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1Nc1ccccn1
Yield: 2.7 %

Procedure:
A solution of (E)-3-{2-[2-(2-pyridylamino)phenyl]vinyl}-1-(tetrahydropyran-2-yl)-1H-indazole (49 mg, 1.2 mmol) obtained in Step 2 and trifluoroacetic acid (1.0 mL) in methanol (0.50 mL) was stirred at room temperature for 18 hours. A 2 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=97/3) to obtain Compound 164 (10 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](I)[CH3:35]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH2:34][CH3:35])[C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nc(-c3ccncn3)cc(=O)n2CC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(CC)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 1.8 %

Procedure:
To a solution of 10.00 g (41.27 mmol) of 4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in dry tetrahydrofuran (8 mL) under argon at −78° C. was added 2.00 mL (2.00 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −78° C. for 10 min and 1.28 mL of ethyl iodide (15.86 mmol) was added. The reaction was stirred at −78° C. for 1 h and then at 0° C. for 2 h. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 1% of methanol) to afford 0.100 g of a white solid (18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 8.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol) Piperidine (102 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543 [M+H+]
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]I.Cl>C(OCC)C>[O:1]([CH2:8][CH2:9][CH:10]([OH:11])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: O=CCCOc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(O)CCOc1ccccc1
Yield: 67 %

Procedure:
24.9 g of methyl iodide was reacted with 7.26 g of magnesium in 150 ml of anhydrous diethyl ether to obtain methylmagnesium iodide by Grignard reaction. To a solution consisting of 20 g of 3-phenoxypropionaldehyde and 200 ml of anhydrous diethyl ether was added dropwise the methylmagnesium while maintaining a temperature of not more than 20° C. To the reaction solution was added 25 ml of concentrated hydrochloric acid and the solution was separated into two phases, which phases were then separated from each other. The ether layer was washed with an aqueous sodium bicarbonate solution, washed with water, dried with anhydrous sodium sulfate and then condensed under reduced pressure to obtain 15.0 g of 4-phenoxy-2-butanol having a boiling point of 61° C. to 62° C. at 3 mmHg in a yield of 67%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: N#Cc1ncc(N)cc1Cl
Yield: 48 %

Procedure:
3-Chloro-2-cyano-5-nitropyridine (0.35 g, 1.9 mmol), iron powder (0.56 g, 10 mmol, 325 Mesh) and calcium chloride (0.06 g, 0.55 mmol) were combined in 10 mL of 90% ethanol and as described in example 772B. Purification of the crude product via silica gel chomatography using 10% ether/CH2Cl2 as the eluent gives compound 775D (0.14 g, 43%) as a light brown solid. HPLC: 95.5% at 1.69 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 154.03 [M+H]+.
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[CH3:12][C:13]1([CH2:16][NH:17][C:18](=[O:28])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:15][O:14]1.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:15][C:13]1([CH2:16][NH:17][C:18](=[O:28])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[O:14][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: CC1(CNC(=O)OCc2ccc(Cl)cc2)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(CNC(=O)OCc2ccc(Cl)cc2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 16.4 %

Procedure:
2,4-Dinitro-1H-imidazole (0.518 g, 3.28 mmol) and 4-chlorobenzyl (2-methyloxiran-2-ylmethyl)carbamate (2.097 g, 8.20 mmol) and sodium acetate (0.538 g, 6.56 mmol) in ethanol (6 ml) was stirred under reflux for 1 hour. To the solution, water was added and the precipitates were filtered off. The resulting solid was treated with diethyl ether to afford 4-chlorobenzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.197 g, yield 16%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:39])[O:14][CH2:15][C@@H:16]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[Cl:37])=[O:27])[CH2:17][C:18]([F:24])([F:23])[CH2:19][N:20]=[N+]=[N-])=[CH:5]2.C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:39])[O:14][CH2:15][C@@H:16]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[Cl:37])=[O:27])[CH2:17][C:18]([F:23])([F:24])[CH2:19][NH2:20])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(F)(F)CN=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(F)(F)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a mixture of (S)-5-azido-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 6-fluoroisoquinolin-3-ylcarbamate (25.0 g, 0.0441 mol), THF (300 mL) and water (100 mL) was added triphenylphosphine (13.9 g, 0.0529 mol) and aq. HCl solution (53 mL, 2N, 0.106 mol). The resulting mixture was stirred at RT for 1 h and concentrated down to about 200 mL. Water (200 mL) was then added. The resulting mixture (pH<4) was extracted with EtOAc (300 mL) and the EtOAc solution was discarded. The remaining aq. solution was adjusted to pH>8 by adding NaOH (2N) and extracted with DCM (200 mL×3). The organic layer was washed with water and brine, dried over Na2SO4. The organic layers were combined and concentrated. The resulting residue was purified on silica gel column (DCM/MeOH) to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 6-fluoroisoquinolin-3-ylcarbamate (12.1 g, 50.7%). LRMS (M+H+) m/z 542.5.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (0.70 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloro-perbenzoic acid (70%, 0.39 g) in dichloromethane (10 ml) and the mixture was stirred at −78° C. for 1 hour. To a reaction system was added an aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The resultant was concentrated under reduced pressure, after which the residue was separated and purified with column chromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate 1:19), followed by recrystallization (ethyl acetate-diisopropyl ether) to give 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl] phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (579.7 mg) as yellow crystals (Compound 51).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>C(N(CC)CC)C>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][Si:21]([CH3:23])([CH3:22])[Cl:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(O[Si](C)(C)Cl)c(C(C)(C)C)c1

Procedure:
A mixture of 2,6-di-t-butyl-4-methylphenol (110 g, 0.5M), acetonitrile (500 ml), triethylamine (70 ml, 0.5M) and dichlorodimethylsilane (61 ml, 0.5M) was refluxed for 16 hours. The solvent was evaporated and the residue extracted with toluene (500 ml). The toluene extract was evaporated and the residue recrystallised from acetonitrile to give the title compound (90 g, 57%) m.p. 119°-121° (Found: C, 65 65; H, 9.4%. C17H29ClOSi requires C, 65.2; H, 9.3%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([CH:26]=[O:27])=[CH:3][C:4]=2[N:5]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cnc2c(N3CCOCC3)nc(Cl)nc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (3.0 g, 0.0091 mol—Preparation 3) and dry THF (15 mL) were added under nitrogen atmosphere and then cooled to −78° C. To the reaction flask, 2.5 M n-butyl lithium (4.4 mL, 0.0109 mol) was slowly added and the reaction mixture was stirred at −78° C. for 30 minutes. To the reaction mixture, N,N-dimethylformamide (1.27 mL, 0.0164 mol) was added and the reaction mixture allowed to warm to 0° C. The reaction mass was quenched with 10% aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 10-40% ethyl acetate) to provide the title compound as a light yellow solid (0.8 g, 31%). 1H NMR (300 MHz, CDCl3): δ 10.24 (s, 1H), 9.11 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 3.91 (t, J=4.8 Hz, 8H): LC-MS (ESI): Calculated mass. 278.06, Observed mass [M+H]+: 279.0 (RT=0.66 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1.C=O.N1CCCC[CH2:19]1>C(O)C>[CH3:1][C:2]1([CH3:15])[C:11](=[CH2:19])[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1
Reactant: C1CCNCC1
Reactant: CC1(C)CC(=O)c2cc(C#N)ccc2O1
Agent: C=O
Solvent: CCO
Product: C=C1C(=O)c2cc(C#N)ccc2OC1(C)C

Procedure:
A solution of 24 g of the chromanone, 12 g of paraformaldehyde and 24 ml of piperidine in 300 ml of ethanol is heated at 70° for 3 hours and evaporated. The residue is taken up in dichloromethane/petroleum ether 1:1, the mixture is filtered through silica gel and evaporated, and 2,2-dimethyl-3-methylene-6-cyano-4-chromanone is obtained as an unstable oil.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25])([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:1]([S:3]([C:6]1[N:7]=[CH:8][C:9]([C:19]2[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[C:17]([F:25])[CH:18]=2)=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: CCS(=O)(=O)c1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(F)c2)cn1

Procedure:
Procedure VV: To a stirring solution of 2-Ethanesulfonyl-5-iodo-pyridine (1.0 mmol) and (4-carboxy-3-fluorophenyl)boronic acid (1.3 mmol) in dioxane (0.1M), add dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (0.03 mmol) and 2M aqueous sodium carbonate (3.0 mmol). Heat the reaction to reflux for 4 hours. After this time, remove the heat and concentrate in vacuo. Wash with dichloromethane while extracting with water. Acidify the aqueous layer with 1N hydrochloric acid and extract with 10% isopropanol/dichloromethane four times. Combine the organics, dry with sodium sulfate, decant and concentrate in vacuo. MS (m/e): 310.3 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][NH:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][N:29]([S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:17])=[O:16])[O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1cccc(OCc2ccccc2)c1)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A mixture of 3-benzyloxybenzenesulfonyl chloride (65 mg; 0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately one hour. An additional quantity of 3-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) was added and the reaction was heated at reflux for approximately 1 hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The phases were separated and the organic layer was then washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[3-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (140 mg, 89%). H1-NMR (chloroform-D3): 1.22 (m, 6H), 1.62 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.11 (b, 1H), 3.66 (m, 2H), 3.87 (m, 4H), 4.18 (m, 1H), 4.77 (m, 1H), 4.95 (m, 1H), 5.10 (m, 2H), 5.60 (d, 1H), 7.29 (m, 14H). MS(ESI): 703(M+Na).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:19]([CH:26]=[O:27])=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([CH:26]=[O:27])[C:18]([O:17][CH2:2][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][N:22]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: COc1cccc(-c2ncccc2CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(-c2ncccc2COc2cnc(OC)cc2C=O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(3-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH3CN (30 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20% MeCN up to 40% in 10 min, up to 95% in 2 min, down to 20% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 100.8 mg (17%) of 2-methoxy-5-[[2-(3-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([N:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:13][O:12][C:11]1=[O:14])=[O:21]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1NC(c2ccc(F)c(F)c2)CO1
Product: O=C(CCCCCl)N1C(=O)OCC1c1ccc(F)c(F)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 5-chloropentanoyl chloride.