Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[C:25]4[S:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:33]3[C:38]4[S:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:37]=4[CH:36]=[CH:35][CH:34]=3)[C:15]=2[OH:46])=[CH:3][CH:2]=1.[CH2:47]1C[O:50][CH2:49][CH2:48]1.C(N(CC)CC)C.C(Cl)(=O)C=C>ClCCl.O>[C:49]([O:46][C:15]1[C:14]([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[CH:19][C:18]([C:20]2[C:25]3[S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]=1[C:33]1[C:38]2[S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:37]=2[CH:36]=[CH:35][CH:34]=1)(=[O:50])[CH:48]=[CH2:47]
Reactant: C1CCOC1
Reactant: Oc1c(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)Oc1c(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Reaction time: 0.5 h
Yield: 59 %

Procedure:
1.5 g of the thus obtained 2,4,6-tris(4-dibenzothiophenyl)phenol is placed in a round bottom flask; 30 mL of THF is added to form a transparent solution; after ice cooling the flask, 0.4 g of triethylamine is added; 0.30 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 30 mL of water is added; the mixture is vigorously stirred; and 100 mL of dichloromethane is then added, thereby separating an aqueous solution. The aqueous layer is washed with dichloromethane and then gathered with the original dichloromethane solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/dichloromethane mixture), thereby obtaining 0.9 g (yield: 59%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.44 (dd=1.2 & 10.4 Hz, 1H), 5.63 (dd=10.4 & 17.2 Hz, 1H), 5.96 (dd=1.2 & 17.2 Hz, 1H), 7.43 to 7.69 (m, 12H), 7.82 to 7.91 (m, 3H), 8.12 (s, 2H), 8.14 to 8.21 (m, 6H)
Reaction SMILES: [N+](=CC([C@@H]1N(CC2C=CC(OC)=CC=2OC)[C:8](=[O:21])[C@H]1CC)=O)=[N-].CO[C:26]([C@H:28]1[C@H:31]([CH2:32][CH3:33])[C:30](=[O:34])[N:29]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1[O:44][CH3:45])=O.[OH2:46]>>[CH3:45][O:44][C:37]1[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:36]=1[CH2:35][N:29]1[C:30](=[O:34])[C@@H:31]([CH2:32][CH3:33])[C@@H:28]1[CH2:26][C:8]([OH:21])=[O:46]
Reactant: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1C(=O)OC
Reactant: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1C(=O)C=[N+]=[N-]
Reactant: O
Product: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1CC(=O)O
Yield: 47.1 %

Procedure:
2.93 g (10 millimole) of trans-4-diazoacetyl-1-(2,4-dimethoxy-benzyl)-3-ethyl-2-azetidinone-which may contain some methyl-trans-1-(2,4-dimethoxy-benzyl)-3-ethyl-4-oxo-2-azetidine-carboxylate too--are dissolved in 100 ml of peroxide-free tetrahydrofuran and to the solution 50 ml of water are added. The solution is irradiated with a high pressure mercury vapor lamp (HPK) under argon in a pyrex apparatus equipped with a submersed lamp for about 4 hours (until the diazoacetyl derivative is converted). From the solution the tetrahydrofuran is evaporated in vacuo, the residue is diluted with water to 150 ml and made alkaline by adding 4 ml of a 10% aqueous sodium hydroxide solution. The alkaline solution is extracted three times with 30 ml of dichloromethane each and the aqueous phase is acidified with concentrated hydrochloride acid to pH 2. The acidic solution is extracted three times with 30 ml of dichloro methane each. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness. On rubbing with ether the residue becomes crystalline. Thus 1.44 g of the desired compound are obtained, yield: 47.1%. M.p.: 131° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].[C:15]([O-:18])([O-])=[O:16].[K+].[K+]>C1COCC1.O.CCOC(C)=O>[C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1)([O:18][C:3]([CH3:8])([CH3:4])[CH3:1])=[O:16]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 174.3 %

Procedure:
To a solution of (2-cyano-phenyl)-piperazine (2.4 g, 12.78 mmol) in THF and H2O (25 mL, 1:1) was added K2CO3 (3.9 g, 28.12 mmol). The solution was allowed to stir for about 10 minutes at r.t. Boc-anhydride (3.1 g, 14.06 mmol) was then added and reaction was allowed to stir for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 3.2 g of 1-Boc-4-(2-cyano-phenyl)-piperazine (88%). To a solution of sodium borohydride (2.1 g, 56.03 mmol) in THF (25 mL) at 0° C. was added TFA (4.3 mL, 56.03 mmol) dropwise. 1-Boc-4-(2-cyano-phenyl)-piperazine (3.2 g, 11.21 mmol) was then added slowly at r.t. The reaction was allowed to stir for about 12 hours at r.t. The reaction was quenched with H2O, diluted five-fold with EtOAc and washed with brine. The organic phase was concentrated to dryness yielding about 1.0 g of 1-Boc-4-(2-aminomethyl-phenyl)-piperazine (30%). MS (ESI+) 292.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]=1[NH2:8].[CH:16](Cl)(Cl)Cl.CCOCC>C(O)=O>[CH2:9]([N:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: ClC(Cl)Cl
Solvent: CCOCC
Solvent: O=CO
Product: CCCCCn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
37.4 g of 5,6-diamino-1-pentyl-2,4-(1H,3H)-pyrimidinedione (XXXIX) was refluxed in 50 ml of formic acid for 2 h. 50 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 36.8 g. The amide was refluxed in 50 ml of 5N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 1.8 l of ethanol. Yield 18.3 g (XXXVIII) NMR (see Table I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]=[C:18]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([CH3:26])([CH3:25])[C:19]2=[O:27])[CH:10]=1.[OH:28]O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:18]3([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[O:21][C:22]3([CH3:24])[CH3:23])[O:28]2)[CH:10]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=C1C(=O)C(C)(C)OC1(C)C
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Temperature: 25 °C

Procedure:
To a solution of 4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (2.04 g, 0.0051 mol) in methanol (24 ml) at 55° C. is added hydrogen peroxide solution (0.43 ml, 0.0076 mmol, 50% wt solution), followed immediately by aqueous lithium hydroxide (0.25 ml, 0.0005 mol). The reaction mixture is heated at this temperature for 30 minutes, then is rapidly cooled to room temperature and quenched with saturated sodium thiosulphate. The crude product is extracted with diethyl ether (×3), washed with saturated sodium bicarbonate, then dried over magnesium sulfate. The residue is purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to afford 2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one as a yellow gum.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[C:3]=1[CH3:21].[C:22]12(O)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.B(F)(F)F.CCOCC>CCCCC>[C:22]12([C:19]3[C:2]([OH:1])=[C:3]([CH3:21])[C:4]4[CH2:5][CH2:6][C@@H:7]5[C@@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]5[CH2:9][CH2:10][C:11]3=[O:20])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: Cc1c(O)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: FB(F)F
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1c(O)c(C23CC4CC(CC(C4)C2)C3)cc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65.2 %

Procedure:
To a suspension of the known 3-hydroxy-4-methylestra-1,3,5(10)-trien-17-one (ref. Kaneko et al., 1964; Chemical Abstracts Registry Number [68969-90-4], 30 mg, 0.11 mmol) and 30 mg (0.197 mmol) of 1-adamantanol in 1 mL of anhydrous pentane was added 0.02 mL of boron trifluoride diethyl etherate while cooling with an ice bath and stirring. After stirring at 0° C. for 15 min. the reaction was stirred at room temperature for 45 min. Ice was added and the white solid that formed was filtered, washed with water and dried over P2O5. The crude product was purified by chromatography (silica gel eluted with 7% ethyl acetate in hexanes) to give 30 mg of pure product (68% yield). After recrystallization from methylene chloride-hexanes the product had: m.p. 262-263° C.; 1H NMR(CDCl3) δ 0.90 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.7 (m, 2H, CH2), 7.11 (s, 1H, Ar—H); 13C NMR (CDCl3) δ 11.02, 13.70, 21.44, 26.22, 26.67, 27.54, 28.95 (3×C), 31.56, 35.84, 36.60, 36.98 (3×C), 37.63, 40.82 (3×C), 44.60, 47.91, 50.34, 121.41, 121.51, 131.45, 133.32, 150.79, 221.49. (Anal. calc'd. for C29H39O2: C, 83.21; H, 9.15. Found: C, 83.45; H, 8.94.)
Reaction SMILES: ClCCl.[F:4][C:5]1[C:17]([N:18]2[C:22](=[O:23])[N:21]([CH3:24])[C:20]([CH3:25])=[N:19]2)=[CH:16][C:8]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][CH3:15])[S:11][C:7]=2[CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:31].[OH2:37]>>[F:4][C:5]1[C:17]([N:18]2[C:22](=[O:23])[N:21]([CH3:24])[C:20]([CH3:25])=[N:19]2)=[CH:16][C:8]2[N:9]=[C:10]([S:12]([CH2:13][CH2:14][CH3:15])(=[O:31])=[O:37])[S:11][C:7]=2[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1nc2cc(-n3nc(C)n(C)c3=O)c(F)cc2s1
Reactant: O
Solvent: ClCCl
Product: CCCS(=O)(=O)c1nc2cc(-n3nc(C)n(C)c3=O)c(F)cc2s1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
10 mL dichloromethane solution was charged with 0.001 mol 1-(6-fluoro-2-(propylthio)benzo[d]thiazol-5-yl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.002 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 4 hours, the mixture was poured into 30 mL of water, extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 95% yield.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=[O:14]>C(Cl)Cl>[ClH:12].[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]([N:9]1[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]1)=[O:14])([O-:24])=[O:23]
Reactant: O=C(Cl)Oc1ccccc1[N+](=O)[O-]
Reactant: CCC(CC)N1CCNCC1
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2ccccc2[N+](=O)[O-])CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (175 μl, 1.0 mmol) and dry DCM (10 ml) was added 2-nitrophenyl chloroformate (201 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was dissolved in a 0.5 N HCl solution (15 ml). The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 310 mg (86%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7]O[C:4]=2[CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][C:26]#[N:27]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:4]([CH:3]=1)=[CH:17][NH:7][C:6]=2[CH:9]1[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][C:26]#[N:27])[CH2:11][CH2:10]1
Reactant: N#CCCBr
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1CCC(c2[nH]cc3cc(F)ccc23)CC1
Yield: 31.7 %

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq) in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography over a silica gel column (SiO2, 120 g). The product thus purified weighed 8.94 g. Recrystallization from ethanol yielded the nitrile as white crystals 4.3 g, m.p. 100°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.CN.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH3:39])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CN
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 522.19 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH2:25]([O:27][CH:28](O)[C:29]([F:32])([F:31])[F:30])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:25]([O:27][CH:28]([NH:24][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=4)[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)[C:29]([F:32])([F:31])[F:30])[CH3:26]
Reactant: CCOC(O)C(F)(F)F
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 68.7 %

Procedure:
A mixture of 12 (Scheme 3) (500 mg, 1.47 mmol), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL, 2.94 mmol) and 4-toluenesulfonic acid monohydrate (280 mg, 1.47 mmol) in ethanol (25 mL) was heated to reflux for 48 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 5:95 to 8:92) to afford title compound 318 (470 mg, 1.01 mmol, 68% yield). NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.5 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.08-7.02 (m, 2H), 3.86 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=5.5 Hz, 1H), 5.68 (qd, J=10.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.76-3.59 (m, 2H), 1.15 (t, J=7.0 Hz, 3H). LRMS (M+1) 467.0 (100%).
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2.[Cl-].[NH4+]>C1COCC1.O.[Fe]>[C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:2][CH2:3]2
Reactant: O=[N+]([O-])c1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.5 %

Procedure:
2-(2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-yloxy)-5-nitropyrimidine (Intermediate 222, 91 mg, 0.304 mmol) was dissolved in 9.0 mL of a 2/1 THF/water solution. Then iron (85 mg, 1.52 mmol) and ammonium chloride (81 mg, 1.52 mmol) were added and the reaction mixture was stirred at room temperature for 10 h. After dilution with AcOEt and filtration over a celite pad (washing with AcOEt), the organic phase was washed (two times) with an aqueous saturated solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (52 mg).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:35][CH:36]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)[C@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>C(Cl)Cl>[CH2:56]([O:55][C:52]1[CH:53]=[CH:54][C:49]([C@@H:36]([NH:35][C:8](=[O:10])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:11])[C@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[CH:50][CH:51]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)c1ccc(OCc2ccccc2)cc1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](C(=O)N[C@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
(S)-2-Phenylpropanoic acid (107 mg, 0.713 mmol), EDC (137 mg, 0.713 mmol), HOBt (109 mg, 0.713 mmol), and Hunig's base (249 μL, 1.426 mmol) in DCM (6480 μL) were stirred at room temperature for 10 min. (2R)-tert-Butyl 2-(amino(4-(benzyloxy)phenyl)methyl)pyrrolidine-1-carboxylate (248 mg, 0.648 mmol) was added and the solution stirred at room temperature for 4 h. The reaction was quenched with 10% aqueous citric acid and extracted with DCM (3×). The combined organic layers were washed with 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10%→60% ethyl acetate in hexanes). Two diastereomers were obtained. (R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (78 mg, 0.114 mmol, 17.54% yield) was obtained as a colorless oil (peak 1). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=6.29 Hz, 1H), 7.33-7.43 (m, 6 H), 7.11-7.23 (m, 4H), 7.06 (d, J=8.56 Hz, 2H), 6.82 (d, J=8.56 Hz, 2H), 4.99 (s, 2H), 4.50 (dd, J=10.83, 6.04 Hz, 1H), 4.01-4.11 (m, 1H), 3.28-3.49 (m, 3H), 1.76-2.07 (m, 2H), 1.53-1.68 (m, 2H), 1.50 (s, 9H), 1.40 (d, J=7.05 Hz, 3H); LRMS (ESI) m/e 515.40 [(M+H)+, calcd for C32H39N2O4 515.29]; m/e 513.60 [(M−H)−, calcd for C32H32N2O4 513.28]. (R)-tert-Butyl 2-((S)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (122 mg, 0.183 mmol, 28.2% yield) was obtained as a colorless oil (peak 2). 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=6.30 Hz, 1H), 7.23-7.44 (m, 10H), 7.02 (d, J=8.56 Hz, 2H), 6.84 (d, J=8.56 Hz, 2H), 5.01 (s, 2H), 4.68-4.76 (m, 1H), 4.02-4.09 (m, 1H), 3.54 (q, J=7.13 Hz, 1H), 3.09-3.22 (m, 1H), 2.41-2.54 (m, 1H), 1.94-2.07 (m, 1H), 1.64-1.74 (m, 1H), 1.49 (d, J=7.05 Hz, 3H), 1.47 (s, 9H), 1.30-1.40 (m, 2H); LRMS (ESI) m/e 515.30 [(M+H)+, calcd for C32H39N2O4 515.29]; m/e 513.50 [(M−H)−, calcd for C32H32N2O4 513.28].
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-fluoroaniline as starting materials, the title compound was obtained as white prismatic crystals (yield 25%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.O>[CH3:24][S:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty g. of 6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene was dissolved in 400 ml. of pyridine, together with 23.4 g. of methanesulfonyl chloride and 50 mg. of 4-dimethylaminopyridine. The mixture was stirred under a nitrogen blanket overnight at ambient temperature, and was then poured into 2 liters of water and stirred vigorously. The solids were collected by filtration, and washed successively with water, methanol and diethyl ether. The washed solids were then vacuum dried at 60° C. to obtain 32.5 g. of the desired intermediate product, m.p. 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[CH3:12][C:13]1([CH3:22])[CH2:18][CH:17]([OH:19])[CH2:16][C:15]([CH3:21])([CH3:20])[NH:14]1.[OH-].[Na+]>O.Cl.ClCCl>[CH3:12][C:13]1([CH3:22])[CH2:18][CH:17]([OH:19])[CH2:16][C:15]([CH3:21])([CH3:20])[N:14]1[N:8]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: Nc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1N=Nc1ccccc1
Temperature: 23 °C
Yield: 66.7 %

Procedure:
9.31 g Aniline is added to a mixture of 50 g ice and 29.4 ml aqueous HCl (32% w/w). Then, a solution of 6.90 g NaNO2 in 30 ml water is slowly added while keeping the temperature between −5 and 0° C. To this solution, a cold (−5° C.) solution of 15.7 g 2,2,6,6-tetramethyl-4-hydroxypiperidine in 30 ml water and 9.8 ml aqueous HCl (32% w/w) and a cold solution of 16 g NaOH in 40 ml water are slowly added sequentially while keeping the temperature in the range from −5 to 0° C. The thick brown suspension is allowed to warm up to 23° C. and is then diluted with 100 ml dichloromethane. The organic phase is separated, evaporated and chromatographed on silica gel with hexane-ethylacetate (2:1) to afford 17.4 g of 2,2,6,6-tetramethyl-1-phenyldiazenyl-piperidin-4-ol as a slightly yellow oil which solidifies on standing. A sample of this material is recrystallized from dichloromethane-hexane to afford light yellow solid, m.p. 68-70° C.
Reaction SMILES: BrCC[CH:4]1[CH2:9][CH2:8][N:7]([CH:10]=[O:11])[CH2:6][CH2:5]1.[C-:12]#[N:13].[Na+].[CH2:15](O)[CH3:16]>>[C:12]([CH2:15][CH2:16][CH:6]1[CH2:5][CH2:4][CH2:9][CH2:8][N:7]1[CH:10]=[O:11])#[N:13]
Reactant: [C-]#N
Reactant: CCO
Reactant: O=CN1CCC(CCBr)CC1
Agent: [Na+]
Product: N#CCCC1CCCCN1C=O
Yield: 50 %

Procedure:
4-(2-Bromoethyl)-1-piperidinecarboxaldehyde (47 g, 0.213M) and NaCN (24 g) in ethanol (470 ml) was refluxed for 4 hours. Solvent was removed, added water (30 ml) and extracted with methylene chloride (4×200 ml). The extracts, dried over NaSO4, were stripped to dryness and then purified on silica gel columns eluted with ethyl acetate to give 4-(2-cyanoethyl-1-piperidinecarboxaldehyde (16 g, 50% yield).