Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[Cl:33]>C(OCCO)C>[Cl:33][C:27]1[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(O)cc1Cl
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3Cl)c2cc1OC
Yield: 84.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 270.1 mg (1.5 mmol) of 4-amino-3-chlorophenol to give 299.2 mg (84.3%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 355.8, 357.8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[C:30]([NH2:34])(=[O:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:32][CH2:31][C:30]([NH2:34])=[O:33])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: C=CC(N)=O
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(N)=O)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
A solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), acrylamide (24 mg, 0.33 mmol) and DIEA (87 μL, 0.5 mmol) in NMP (1 mL) was stirred at 80° C. for 10 h. LCMS at this point shows the reaction was not complete, so additional acrylamide (2×36 mg) was added and the reaction continued until LCMS shows the reaction was complete. The crude product was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)propanamide as a white powder; ESMS m/z 483.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:32]=[O:33])[CH:39]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: O=Cc1cccc(B(O)O)c1
Product: COC(=O)c1c(-c2cccc(C=O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 3-formylphenylboronic acid. Colorless crystals (140 mg).
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:22][C:23]([NH2:25])=[S:24]>CCOC(C)=O.CO>[NH2:25][C:23]1[S:24][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:11]2[N:10]([CH3:9])[CH:14]=[CH:13][N:12]=2)[N:22]=1
Reactant: NC(N)=S
Reactant: COC(=O)CC(=O)c1nccn1C
Agent: O=C1CCC(=O)N1I
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(N)nc1-c1nccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
N-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41 mmol) methyl 3-(1-methyl-1H-imidazol-2-yl)-3-oxopropanoate (Intermediate 63) and 7.5 g Amberlyst-15 resin in 400 ml EtOAc followed by stirring for 1 hour at room temperature. The resin was filtered off and rinsed with EtOAc. Solvent was removed from the filtrate and the residue was taken up in diethyl ether. Insoluble material was filtered off and rinsed with additional ether. Solvent was removed from the filtrate and the residue was dissolved in 200 ml MeOH before addition of 4.7 g (62 mmol) thiourea. The mixture was heated at reflux for 1 hour, then the solvent was removed and the residue was taken up in aqueous Na2CO3. Insoluble material was collected by filtration and rinsed well with water. The solids were dried in vacuo affording 4.51 g of the title compound: MS (ES) (M+H)+: 239 for C9H10N4O2S; NMR: 3.48 (s, 3H), 3.57 (s, 3H), 6.90 (s, 1H), 7.12 (s, 1H), 7.98 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>N1C=CC=CC=1>[S:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)([CH3:25])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a stirred solution of 5-amino-3-[(7-azaindol-3-yl) methylene]-2-oxindole (2.773 g, 10 mmol) in pyridine (10 ml) was added gradually mesylchloride (1.146 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 5 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 70% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11]O1)([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:22].O>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][S:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Reactant: NC(N)=S
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(CC2CS2)cc(C(C)(C)C)c1O

Procedure:
A solution of 26.2 g [0.10 mol] of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane [Example 1] and 8.4 g [0.11 mol] of thiourea in 100 ml of methanol is stirred for 12 hours at room temperature and subsequently poured into water. Extraction of the aqueous phase with chloroform, drying over sodium sulphate and evaporation of the solvent yields crude 3,5-di-tert.-butyl-4-hydroxybenzyl-thiirane, which after recrystallization from petroleum ether melts at 62°-63° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[O:12])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27])=[O:17])[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][C:10]1=[O:12])=[O:27])=[O:17])[CH3:14]
Reactant: CCOC(=O)CCCCCCCN=C=O
Reactant: O=c1[nH]cc(-c2ccccc2)o1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCCNC(=O)n1cc(-c2ccccc2)oc1=O
Reaction time: 24 h

Procedure:
16.1 g (0.1 mol) of 5-phenyl-4-oxazolin-2-one are dissolved in 100 ml of absolute DMF and 25.6 g (0.12 mol) of ethoxycarbonylheptyl isocyanate are added. The mixture is stirred for 24 hours at 50°-60° C., water is added and the oily/crystalline precipitate which is formed is separated, washed with water and dried in vacuo at room temperature. The crude product is recrystallised from ethanol.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:39]([NH:38][CH2:36][CH3:37])=[O:40])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CCN=C=O
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(NC)nc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 g (0.5 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was dissolved in dry dichloromethane (10 ml). Triethylamine (0.28 ml, 2 mmol) was added followed by the addition of ethylisocyanate (0.06 ml, 0.753 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.17 g, 72%) MS (EI): 459.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, □ (ppm)): 0.96 t (3H); 0.88-1.13 m (4H); 1.13-1.31 m (1H); 1.54-1.85 m (6H); 2.74 s (3H); 2.98 q (2H); 2.89-3.16 m (4H); 3.19-3.33 m (1H); 3.34-3.58 m (4H); 4.12-4.30 m (2H).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C1CCN2C(=NCCC2)CC1.[Cl:24][C:25]1[C:30]2[CH:31]=[C:32]([CH2:34][CH3:35])[O:33][C:29]=2[C:28]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])=[C:27]([F:46])[CH:26]=1.Cl>CN(C)C=O>[Cl:24][C:25]1[C:30]2[CH:31]=[C:32]([CH2:34][CH3:35])[O:33][C:29]=2[C:28]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[C:27]([F:46])[CH:26]=1
Reactant: CCc1cc2c(Cl)cc(F)c(NC(=O)Oc3ccccc3)c2o1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
80 ml of N,N-dimethylformamide was added to 5.8 g (32 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate and 6.6 g (43 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene, and 9.6 g (29 mmol) of 4-chloro-2-ethyl-6-fluoro-7-phenoxycarbonylaminobenzofuran was gradually added thereto at room temperature. After stirring at 60° C. for 8 hours, the reaction solution was poured into a 10% hydrochloric acid aqueous solution and acidified, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 4.8 g (yield: 44%) of the desired product as white crystals. Melting point: 154-155° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:27])=[CH:4][C:5]2[O:26][CH2:25][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH:18]4[CH2:23][CH2:22]OCC4)[C:9]3=[O:24])[C:6]=2[CH:7]=1.[CH3:28][C:29]1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2O[N:30]=1.BrCC1C=CC=CN=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[C:3]([CH3:27])=[CH:4][C:5]2[O:26][CH2:25][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[CH:23]=[CH:22][CH:28]=[CH:29][N:30]=4)[C:9]3=[O:24])[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCc1ccccn1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: mp 165-168° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ8.67 (d, J=6.0 Hz, 1H), 8.12-8.06 (m, 1H), 7.59-7.55 (m, 2H), 7.26-7.23 (m, 1H), 7.21-7.20 (m, 1H), 7.03-6.98 (m, 2H), 6.76 (s, 1H), 6.55 (s, 1H), 5.18 (s, 2H), 4.74 (ABq, 2H), 2.13 (s, 3H), 2.01 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.5, 159.1, 154.0, 146.7, 142.6, 141.5, 138.3, 132.6, 129.1, 126.7, 124.5, 124.4, 124.1, 123.7, 123.5, 111.3, 109.7, 79.5, 57.8, 43.7, 20.2, 19.2; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: C(ON1C(=O)C2=CC=CC=C2C1=O)(=[O:3])C.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N1C=CC=C(C)C=1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:16]([OH:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: CC(=O)ON1C(=O)c2ccccc2C1=O
Reactant: O=Cc1cccnc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1cccnc1
Product: O=C(O)c1cccnc1

Procedure:
In the presence of an oxidation catalyst (N-acetoxyphthalimide (NAPI)) and a metal catalyst (cobalt acetate and manganese acetate) with nicotinaldehyde as a co-oxidizing agent, β-picoline was oxidized in acetic acid solvent at 140° C. and 2 MPa with air to produce nicotinic acid. From the reaction mixture, acetic acid was removed and to a condensate was added 2-ethylhexanol. The mixture was cooling-crystallized to 25° C. at atmospheric pressure and filtrated, and the residue washed with methanol and filtrated to separate nicotinic acid. The filtrate and washing liquid were combined and the solvent was removed therefrom. The components in the condensed residue were analyzed, and as a result, 92 g of nicotinic acid, 160 g of 2-ethylhexanol, 1.0 g of N-acetoxyphthalimide (NAPI), 1.8 g of N-hydroxyphthalimide (NHPI), 108 g of phthalic acid (PA), 67 g of phthalimide (PI), 24 g of phthalic anhydride (APA), 11 g of total cobalt, 11.4 g of total manganese were contained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.NC1C=CC([CH2:35][CH2:36][CH2:37][CH2:38][PH:39](=[O:43])[O:40][CH2:41][CH3:42])=CC=1OC>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:35][CH2:36][CH2:37][CH2:38][PH:39](=[O:43])[O:40][CH2:41][CH3:42])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1
Reactant: CCO[PH](=O)CCCCc1ccc(N)c(OC)c1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 1E replacing compound 1F with ethyl (4-amino-3-methoxybenzyl)propylphosphinate (Compound 37D, 0.971 g, 3.58 mmol). The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 1.08 g of a white foam (67%). MS (ESI): m/z 452.10 [M+H]+. UPLC: tR=1.10 min (polar—2 min).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:16][CH2:17][OH:18])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]([CH3:19])([CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7]
Reactant: CC(C)(CCO)CCC12C=CC=CC1C(=O)NC2=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)CCC12C=CC=CC1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.57 g (6.0 mmol) of 1-(3,3-dimethyl-5-hydroxypentyl)phthalimide and 0.92 ml (6.6. mmol) of triethylamine in 30 ml of dichloromethane was added, at 0° C., 0.51 ml (6.6 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes at room temperature, to which was added a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with dichloromethane. The extract was dried, followed by distilling off the solvent to give 1-(3,3-dimethyl-5-methanesulfonyloxypentyl)phthalimide.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)=[O:2].[F-].[Cs+].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O.C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[C:3]=1[CH:1]=[O:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(C=O)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C=O)c(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Combine trifluoromethanesulfonic acid 1-formyl-6-methoxy-naphthalen-2-yl ester (2.53 g, 7.6 mmol) with dichlorobis(triphenylphosphine)palladium (II) (0.53 g, 0.8 mmol), cesium fluoride (5.75 g, 37.8 mmol), and 2,4-difluorophenylboronic acid (2.39 g, 15.1 mmol) in acetonitrile (25 mL). Heat to reflux for 1 hour. Cool to room temperature, add DARCO, and filter. Concentrate in vacuo, dilute with dichloromethane and wash with saturated aqueous sodium carbonate. Dry the organic layer over magnesium sulfate, filter, add silica gel, and concentrate in vacuo. Purify the residue by column chromatography using an eluent of 1.5:1 hexanes:dichloromethane to give 1.4 g of the title compound (62%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C:13]2=[N:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC[C@@H]1OC[C@]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])NOC[C@@H]2C1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C@:13]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])[NH:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Reactant: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Product: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12

Procedure:
The product, obtained as a yellow oil, was prepared from (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C16) according to the general procedure for the synthesis of (3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C5) in Preparation P1. Yield: 21.5 g, 57.2 mmol, 48%. LCMS m/z 376.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.98 (ddd, J=9.1, 9.1, 6.8 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=11.9, 8.6, 2.6 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=19.9 Hz, 2H), 3.99-4.06 (m, 1H), 3.97 (dd, half of ABX pattern, J=12.9, 2.0 Hz, 1H), 3.80-3.88 (m, 2H), 3.56 (dd, half of ABX pattern, J=10.2, 6.3 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.1 Hz, 1H), 2.81-2.87 (m, 1H), 2.04 (ddd, J=14.2, 7.6, 2.8 Hz, 1H), 1.48-1.59 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O)(C)(C)C.[NH2:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[NH2:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[C:17]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccncc1)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: NC(Cc1ccncc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of N-(tert-butoxycarbonyl)-3-(pyridin-4-yl)-D,L-alanine [J. Gen. Chem. USSR, 40, 2488 (1970)]and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by acidic hydrolysis there were obtained (S or R)-α-amino-N-[(1S,2R,3 S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-4-yl)propionamide, MS: 267 (M+H)+, and (R or S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-4-yl)propionamide, MS: 267 (M+H)+, each as a colourless foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:12](Br)[C:13]#[CH:14]>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCn1ncc2ccccc21
Reaction time: 0.17 h

Procedure:
Indazole (530 mg, 4.49 mmol) was dissolved in dimethylformamide (4 mL). Sodium hydride (60% suspension in mineral oil, 231 mg, 5.78 mmol) was added slowly, and the mixture was stirred for 10 minutes. Propargyl bromide (80% wt in toluene, 5.0 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed excessively with water, absorbed on silica gel, and purified by silica gel chromatography eluting with a gradient of 5-30% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 157.1 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[N:4]([CH3:13])[C:3]2=[O:14].N[C@H](C(O)=O)C[SeH].[Li]CCCC.C1CCCCC1.[C:33](=[O:35])=[O:34]>C1COCC1>[CH3:13][N:4]1[C:3](=[O:14])[C@@:2]2([CH3:1])[C:9]([CH3:10])([CH3:11])[C@:6]([C:33]([OH:35])=[O:34])([CH2:7][CH2:8]2)[C:5]1=[O:12]
Reactant: CN1C(=O)C2CC[C@@](C)(C1=O)C2(C)C
Reactant: O=C=O
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN1C(=O)[C@@]2(C(=O)O)CC[C@@](C)(C1=O)C2(C)C
Temperature: -95 °C
Reaction time: 0.25 h

Procedure:
To a solution of step 2 intermediate (2 g, 10.2 mmol) in THF maintained at −95° C. under N2 atmosphere, 1.2N Sec.BuLi in cyclohexane (9.5 mL, 13.3 mmol) was added. After stirring for 15 min at −95° C., small pieces of dry ice (2 g) were added and the reaction mixture was kept at this temperature for 1 h before quenching with water (3 mL). The reaction mixture was allowed to warm to room temperature. To this 5% NaHCO3 solution (100 mL) and diethyl ether (50 mL) was added, the aqueous layer was separated and acidified with KHSO4 to pH 2. This was extracted again with diethyl ether, washed with brine, dried with anhydrous Na2SO4 and concentrated. (1.85 g). 1H NMR (400 MHz, CDCl3) δ ppm: 1.0 (s, 3H), 1.1 (s, 3H), 1.26 (s, 3H), 1.88-1.98 (m, 2H), 2.64-2.72 (m, 1H), 2.8 (m, 1H), 3.13 (s, 3H). m/z (M−H): 238.