Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)(O)=O.Cl.C(N=C=NCCCN(C)C)C.O[N:29]1C(=O)C[CH2:31][C:30]1=[O:35].Cl.[CH3:37][S:38][S:39]CC[NH-].CSSCCN.Cl.CSSCCN>CN(C)C=O.O.C(N(CC)CC)C>[CH3:37][S:38][S:39][CH2:31][C:30]([NH:29][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)=[O:35]
Reactant: CSSCC[NH-]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)Cc1cccc(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CSSCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CSSCC(=O)NCOc1cccc(CC(C)=O)c1
Reaction time: 8 h

Procedure:
To a solution of m-(carboxymethoxy)phenyl acetone (6.1 g, 0.029 mmole) in N,N-dimethylformamide (56 ml, dried over molecular sieves, 3A) were added under nitrogen at 5° powdered 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 6.1 g, 0.032 mole) and N-hydroxysuccinimide (3.7 g, 0.032 mole). The resulting reaction mixture was then allowed to stir at 5° overnight. The complete formation of N-hydroxysuccinimic ester was observed. To the methyldithioethylamide hydrochloride (4.7 g, 0.029 mole, prepared in D above) in water (20-50 ml) was added triethylamine to adjust the pH to 8.5. Then the N-hydroxysuccinimic ester of m-(carboxymethoxy)phenyl acetone was added dropwise to the methyldithioethylamine solution with the adjustment of pH to 8.5, and the resulting solution was allowed to stir at 5° for 1 hour. Additional reagents, methyldithioethylamine hydrochloride (2 g, 0.0125 mole) and EDCI (3.0 g, 0.0156 mole), were added and the pH of the resulting solution was adjusted to 6.5 and the reaction mixture was allowed to stir at 5° overnight.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:29])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[N:36]1([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>CCOC(C)=O.CCCCCC>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:48][C:45]4[CH:44]=[CH:43][C:42]([CH2:41][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:47][CH:46]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])[CH:15]=1)=[O:29]
Reactant: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-2-methyl-benzamide (prepared below, 100 mg, 0.251 mmol) and THF (2.5 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (44.2 mg, 0.251 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with acetone (˜5 mL) to afford the title compound in 56% yield (0.078 g, 0.1401 mmol).
Reaction SMILES: C([O:4][CH2:5][C:6]12[O:26][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][N:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH2:21]4)[CH2:15][CH2:14]3)[CH2:12][CH:11]1[C:10](=[O:27])[CH2:9][CH:8]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:7]2)(=O)C.O.NN>C(O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]2([CH2:12][CH:11]3[C:6]([CH2:5][OH:4])([CH2:7][CH:8]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:9][C:10]3=[O:27])[O:26]2)[CH2:14][CH2:15]1)[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH2:25]1
Reactant: CC(=O)OCC12CC(C(=O)OCc3ccccc3)CC(=O)C1CC1(CCN(CN3C=CN=CC3)CC1)O2
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)C1CC(=O)C2CC3(CCN(CN4C=CN=CC4)CC3)OC2(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of the compound obtained in Step 5 (400 mg) in ethanol (8 ml) was added hydrazine monohydrate (0.38 ml) under cooling with ice. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (eluent; methylene chloride:methanol=50:1–25:1) to obtain the title compound (329 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:53])=[CH:31][C:32]([NH:46][CH2:47][C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[C:33]([CH:45]=1)[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43]Cl)=[O:41])=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:53])=[CH:31][C:32]([NH:46][CH2:47][C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[C:33]([CH:45]=1)[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:41])=[O:35])(=[O:27])=[O:28]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of the free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.025 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (315) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-[4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoyloxymethyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (620). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:15]([OH:16])[C@H:14]([CH2:17][OH:18])[O:13][CH2:12]2)=[CH:5][CH:4]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:18][CH2:17][C@@H:14]2[O:13][CH2:12][C@H:11]([S:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C@H:15]2[OH:16])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc(CS[C@H]2CO[C@@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a 0° C. solution, under argon, of 0.580 g of product from Example 323 in 10 ml of pyridine is added 0.430 g of p-toluenesulfonyl chloride. The reaction is stirred at room temperature overnight. The mixture is quenched with water, extracted with diethyl ether, washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica gel: 50% ethyl acetate/hexane) to give 0.520 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH:7]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:8][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[H-].C[O:35]CCO[Al+]OCCOC.[Na+].[H-].[OH-:47].[Na+]>C1(C)C=CC=CC=1>[C:30]([OH:31])(=[O:35])[C:3]([OH:2])=[O:47].[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH:7]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COCCO[Al+]OCCOC
Reactant: [OH-]
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7,8-dimethoxy-1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (15 g, 40 mmole), phenol (3.6 g, 40 mmole) and triphenylphosphine (10.8 g, 41 mmole) in benzene (400 ml), cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (7.2 g, 42 mmole) in benzene (100 ml). After stirring three hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine (6.2 g, 94%, m.p. 132°-134° C.), then was concentrated to an oil (35 g) which was purified by column chromatography (silica gel, ether) to give 16 g, (88%) of an oil. A solution of the resultant 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (15 g, 33 mmole) in toluene (65 ml) was added to a solution of sodium bis (2-methoxyethoxy) aluminum hydride (40 g, 0.2 mole, 70% in toluene). The reaction mixture was stirred at ambient temperature for two days, then at 70° C. for three hours. The reaction mixture was then cooled and poured slowly into 1 liter of dilute NaOH and extracted with ethyl acetate. The organic extracts were washed twice with water, dried (saturated NaCl, anhydrous MgSO4), filtered and converted utilizing the procedure of Example 1 to the oxalate salt (8 g, 62%, m.p. 100° C.). This material was recrystallized from a 20:1 solution of ethyl acetate/methanol to give 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine oxalate, d 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[O:32]C(C)(C)O[C:28](=[O:29])[CH:27]=1>>[C:28]([O:24][CH2:23][CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:32]
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Product: COc1ccc(-n2nc(CCCOC(=O)CC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
5-(4-Chlorophenyl)-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)pyrazole (1.71 g, 0.005 moles) and 2,2,6-trimethyl-1,3-dioxen-4-one (0.71 g, 0.005 moles) were disolved in 100 ml of xylenes. The solution was stirred under reflux for 16 hours. At that time, the solution was cooled to room temperature, and concentrated in vacuo to a yellow oil. The oil was flash chromatographed on silica gel to afford 59 (1.7 g, 80%) as a pale yellow oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[C:31]([NH:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1
Reactant: NNc1cccc2cnccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:53]([C:57]1[CH:58]=[C:59]([NH2:64])[C:60]([NH2:63])=[CH:61][CH:62]=1)([CH3:56])([CH3:55])[CH3:54].CN(C)C=O>>[NH2:64][C:59]1[CH:58]=[C:57]([C:53]([CH3:55])([CH3:54])[CH3:56])[CH:62]=[CH:61][C:60]=1[NH:63][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl}uronium Hexafluorophosphate (0.44 g, 1.2 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (460 mg. 0.77 mmol) and N,N-Diisopropylethylamine (0.44 mL, 2.6 mmol) and 4-tert-butylbenzene-1,2-diamine (0.15 g, 0.93 mmol) in N,N-Dimethylformamide (5 mL, 60 mmol). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 and concentrated. Purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield a solid (0.24 g).
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[C:11]12([CH2:25][CH2:24][CH2:23][CH2:22]1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:13]([CH:20]=[O:21])=[CH:12]2.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CCCCCC.O1CCCC1.O>[C:26]([NH:30][CH2:1][CH:20]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:12]=1)[OH:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: [Li]CCCC
Reactant: CC(C)(C)N
Reactant: O=CC1=CC2(CCCC2)c2ccccc21
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)NCC(O)C1=CC2(CCCC2)c2ccccc21
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexane (6 ml of a 2 M solution) is added dropwise under nitrogen to a stirred suspension of powdered trimethylsulphonium iodide in anhydrous tetrahydrofuran (30 ml) at 0° C. After stirring for 5 minutes, a solution of spiro(cyclopentane-1,1'-indene)-3'-carbaldehyde (2.0 g) in tetrahydrofuran (25 ml) is added. Stirring is continued at 0° C. for 1 hour, whereupon tert.-butylamine (1.0 g) is added and the mixture is allowed to come to about 20° C. After 24 hours, water (200 ml) is added and the solution is extracted three times with diethyl ether. The combined extracts are washed, dried and concentrated to about 50 ml. An excess of hydrogen chloride is added and the precipitated salt is collected and crystallized from ethanol; m.p. 292° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:14]([OH:16])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[CH3:17]O>ClCCl>[CH:5]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CO
Reactant: O=C(O)C1CCc2ccccc21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 100 %

Procedure:
Thionyl Chloride (0.95 mL, 13.0 mmol) was added to a room temperature solution of indane-1-carboxylic acid dissolved in 20 mL of dichloromethane. The reaction mixture was stirred at room temperature for 35 minutes after which time the volume was reduced by approximately 50% via a rotovap. Then 20 mL of methanol was added and the reaction was stirred at room temperature for 3 hours. Evaporation of the solvent and column chromatography (9/1 hexanes/EtOAc) afforded of methyl indane-1-carboxylate (2.2 g, 100%) as a colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1
Reactant: COc1ccc(C(F)(F)F)cn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ncc(C(F)(F)F)cc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To butyl lithium (7.2 ml, 1.6M in hexanes, 11.5 mmol) in tetrahydrofuran (12.0 ml) at −78° C. was slowly added diisopropylamine (1.14 g, 11.3 mmol) in tetrahydrofuran (4.0 ml), and the resulting solution allowed to warm to 0° C. over 45 mins. A mixture of 2-methoxy-5-trifluoromethylpyridine (2.00 g, 11.3 mmol) and trimethylsilyl chloride (3.2 ml, 25.2 mmol) in tetrahydrofuran (8.0 ml) was then slowly added and the mixture stirred for 30 mins. at 0° C., before being quenched with water (50 ml). The mixture formed was extracted with ethyl acetate (2×70 ml), and the extracts washed with brine (50 ml), dried (Na2SO4) and concentrated to give the product as an orange oil (1.36 g, 48% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])[CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[O:13]1.C(=O)(O)[O-].[Na+]>>[F:5][C:6]1[C:11]([CH:12]2[CH2:16][CH2:15][C:14](=[O:17])[O:13]2)=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1CCC(c2ccc(NC(=O)c3ccccn3)cc2F)O1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2cc([N+](=O)[O-])c(NC(=O)c3ccccn3)cc2F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fuming nitric acid (3 ml) was added to N-(3-fluoro-4-(5-oxotetrahydrofuran-2-yl)phenyl)pyridine-2-carboxamide (600 mg) obtained in (step 4), and the reaction liquid was stirred at room temperature for 2 hours. With cooling with ice, aqueous saturated sodium bicarbonate was added to the reaction liquid to make it basic, and extracted with ethyl acetate. This was dried with anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was washed with chloroform/hexane mixed solvent to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([OH:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([O:12][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)[CH3:11]
Reactant: CC(O)C(=O)c1ccc(F)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(OC1CCCCO1)C(=O)c1ccc(F)cc1F
Yield: 97.7 %

Procedure:
2',4'-Difluoro-2-hydroxypropiophenone (61 g) was dissolved in methylene chloride (500 ml), to which was added, under ice-cooling, p-toluene sulfonic acid.hydrate (1.0 g). To the mixture was added, under ice-cooling while stirring, 3,4-dihydro-2H-pyran (41.4 g) during 10 minutes. The mixture was stirred, under ice-cooling, for one hour, to which was added a 5% aqueous solution of sodium hydrogen carbonate (240 ml). The mixture was stirred for 10 minutes under ice-cooling. The methylene chloride layer was separated and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residual oily product was purified by means of a silica gel column chromatography (hexane: ethyl acetate=5:1) to afford 2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (86.5 g) as a pale yellow oily product.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].CN(C)C=O.CO[C:17](OC)([CH3:19])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:18][C:17]1([CH3:19])[O:5][CH2:4][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)(CO)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCC(CO)(CO)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 5 L round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were charged 254 g of pentaerythritol and 2,500 g of N,N-dimethylformamide, and they were heated and dissolved at 80° C. After cooling to 25° C., 195 g of 2,2-dimethoxypropane and 3.6 g of p-toluenesulfonic acid monohydrate were placed therein and, with introduction of nitrogen thereinto, a reaction was carried out at 25° C. without further treatment. Neutralization was performed by adding 9.5 g of triethylamine and the reaction solution was concentrated. After concentration, the resulting powder was dispersed in 1 kg of hexane, followed by stirring and filtration. The hexane-washing step was repeated four times. The resulting cake was dissolved in 1 kg of ethyl acetate at 50° C. and, after insoluble matter was filtrated, 250 g of Kyoward 2003 was added to the filtrate and adsorption treatment was performed at 50° C. for 1 hour. The filtrate was concentrated to obtain 2,2-dimethyl-5,5-bis(hydroxymethyl)-1,3-dioxane. 1H-NMR (D2O, internal standard H2O=4.65 ppm) δ (ppm): 1.40 (6H, s, —CH3), 2.69, 3.64 (4H, 4H, s, s, —O—CH2—C—, —CH2OH)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH3:14])[CH:16]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=CCOCc1ccccc1
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: Cn1cc([C@@H](CC=O)COCc2ccccc2)c2ccccc21
Yield: 87.2 %

Procedure:
Prepared according to the general procedure from 4-benzyloxy-but-2-enal (286 mg, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidm-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.85 mL) and isopropanol (0.15 mL) at −83° C. for 18.5 h to provide, after silica gel chromatography (50:50 Et2O/hexanes), the title compound as a colorless oil (134 mg, 84% yield, 96% ee). IR (film) 3056, 2957, 2894, 2830, 2722, 1717, 1618, 1600, 1582, 1550, 1478, 1451, 1370, 1331, 1309, 1272, 1223, 1173, 1110, 1070, 1024, 772, 740, 714 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.77 (dd, J=2.1, 2.1 Hz, 1H, CHO), 8.04 (d, J=7.2 Hz, 2H, ArH), 7.75 (d, J=8.1 Hz, 1H, ArH), 7.61-724 (m, 5H, ArH), 7.17 (ddd, J=1.5, 6.6, 8.1 Hz, 1H, ArH), 6.96 (s, 1H, NCH), 4.73 (dd, J=5.1, 11.1 Hz, 1H, CH2O). 4.42 (dd, J=8.7, 11.1 Hz, 1H, CH2O), 4.12 (m, 1H, ArCH), 3.76 (s, 3H, NCH3), 3.06 (ddd, J=2.1, 6.3, 16.8 Hz, 1H, CH2CO); 2.96 (ddd, J=2.7, 8.4, 16.8 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 201.5, 166.4, 137.1, 133.1, 129.9, 129.6, 128.5, 126.8, 126.4, 122.1, 119.3, 119.0, 112.9, 109.6, 68.1, 46.5, 33.0, 31.2; HRMS (CI) exact mass calcd for (C20H19NO) requires m/z 321.1365, found m/z 321.1354. [α]D=−2.0 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (4:96 ethanol/hexanes, 1 mL/min); S isomer tr=42.9 min and R isomer tr=53.2 min.