Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[S:47](N)([NH2:50])(=[O:49])=[O:48]>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:50][S:47]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)(=[O:49])=[O:48]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Temperature: 130 °C
Yield: 6.9 %

Procedure:
To a solution of N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) (10.0 mg, 0.018 mmol) in 1,4-dioxane (1.0 mL) was added sulfamide (17.1 mg, 0.18 mmol) and the mixture was heated to 130° C. in a microwave for 10 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (0.8 mg, 7% yield). LCMS for C24H27ClN7O3S (M+H)+: m/z=528.2.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14]O>S(=O)(=O)(O)O.CCOC(C)=O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:14])=[O:9])(=[O:3])=[O:4]
Reactant: CO
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 98 %

Procedure:
3-(Aminosulfonyl)benzoic acid (603 mg, 3.0 mmol) was heated at 80° C. in CH3OH (3 mL) with 3 drops of concentrated sulfuric acid for 60 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water, brine, and dried (Na2SO4). The solvent was evaporated to afford the product (630 mg, 98%) as a white solid. MS (ES+) m/z 216 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1.I[CH3:20].O>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:20])[CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2CCC(=O)C2)c2cc(F)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 0.335 g, 8.2 mmol) in dimethylformamide (20 mL) was stirred at room temperature. A solution of 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.5 g, 6.9 mmol) in 10 mL of DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for an additional 30 min, then iodomethane (3.1 g, 21.8 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.6 g of crude product. Flash chromatography on silica gel (50% ethyl acetate/hexane) afforded 1.2 g (81%) of the title compound as a thick oil which solidified on standing. An analytical sample was recrystallized from ethyl acetate/hexane: mp 104-105° C.; MS (ESI) m/z 232 [M+H]+.
Reaction SMILES: C([O:4][CH:5]1[C:9](=[O:10])[C:8]([CH2:11][CH2:12][CH:13]([O:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH2:6]1)(=O)C.CC(C)(O)[C:25]#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:20]([O:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH:8]1[CH:7]([C:25]#[N:26])[CH2:6][CH:5]([OH:4])[C:9]1=[O:10])(=[O:22])[CH3:21]
Reactant: CCCCCC(CCC1=CCC(OC(C)=O)C1=O)OC(C)=O
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CCC1C(=O)C(O)CC1C#N)OC(C)=O
Yield: 96.9 %

Procedure:
5-Acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone (15.5 g.) [prepared as described in (h) above] acetone cyanohydrin (6.0 g.), aqueous sodium carbonate solution (10.0% w/v; 5 ml.) and methanol (75 ml.) were stirred together and heated at reflux for 4 hours. Methanol was removed in vacuo, water (50 ml.) was added and the mixture extracted with diethyl ether. The ethereal extract was washed with water, dried with magnesium sulphate and evaporated in vacuo to give 2-(3-acetoxyoctyl)-3-cyano-5-hydroxycyclopentanone (14.3 g.) which was used as starting material in the following preparation (k) of 3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentane carbonitrile without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:34])=[O:36])=[CH:31][CH:32]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-ethanol (500 mg, 1 mmol) in methanol (50 mL) and water (10 mL) was added sodium metaperiodate (440 mg, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfinyl-phenyl)-ethanol (512 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C26H25FN2O4S2 [M+H]+ 513.63, observed 512.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][C:26]1([CH3:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:29]2[CH2:30][CH2:31][C:26]([CH3:32])([CH3:25])[CH2:27][CH2:28]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC1(C)CCNCC1
Product: CC1(C)CCN(CCCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (100 mg, 0.23 mmol) and 4,4-dimethyl-piperidine (45.0 mg, 0.28 mmol). The title compound was afforded as a solid (30.0 mg, 26% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.43 (1H, s), 3.23 (2H, m), 2.95 (4H, m), 1.82 (2H, m), 1.35 (4H, m), 1.23 (2H, m), 0.94 (6H, s). MS m/z: 503.34, 505.37 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([N:16](CC)CC)C.ClC(OCCC)=O.N>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([NH2:16])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CCC2(CC1)OCCO2
Agent: CCCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (823 mg, 4.42 mmol) in tetrahydrofuran (22 mL), triethylamine (5.87 mL, 42.1 mmol) and n-propyl chloroformate were added at 0° C., and the obtained solution was stirred at the same temperature for 1 hour. After adding dropwise, the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, 28% aqueous ammonia (1.5 mL) was added, and the obtained solution was stirred at room temperature for 1 hour. The organic layer was separated from the reaction solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (694 mg, 3.75 mmol, 85%) as a colorless amorphous product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:23]1[CH2:28][CH2:27][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:27][CH2:28]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CC(OCCN2CCOCC2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCOCC2)CC1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.2 g, 0.67 mmol), 4-(2-(piperidin-4-yloxy)ethyl)morpholine (79) (0.144 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (0.055 g, 16.6% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.60-1.48 (1H, m), 1.83-1.64 (2H, m), 1.94-1.88 (1H, m), 2.59-2.57 (4H, m), 2.64 (2H, t), 3.14-3.05 (1H, m), 3.49-3.37 (1H, m), 3.58-3.51 (1H, m), 3.66-3.60 (3H, m), 3.74-3.72 (4H, m), 4.06-3.94 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.32-7.26 (2H, m), 7.77-7.70 (3H, m), 8.48-8.44 (1H, m), 10.77 (1H, s); m/z (LC-MS, ESI+), RT=1.57 (M+H 495).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]([CH:37]1[CH2:40][NH:39][CH2:38]1)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][O:34][C:35]([CH:37]1[CH2:40][N:39]([C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])[CH2:38]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), azetidine-3-carboxylate methyl ester hydrochloride (200 mg, 1.32 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to yield 1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid methyl ester (26 mg, 10.7%). The ester was taken directly to the hydrolysis step by dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid (11.8 mg, 46.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H27Cl2F2N3O3+H [(M+H)+]: 550.1471. found: 550.1471.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[I-].[K+].[CH2:29]([NH2:32])[CH:30]=[CH2:31]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:32][CH2:29][CH:30]=[CH2:31])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: C=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 31, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran is reacted to give 8-nitro-1-[(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C([N:25]([C:33]1[S:42][CH2:41][C@H:40]2[C@:35]([C:43]3[CH:48]=[C:47](Br)[CH:46]=[CH:45][C:44]=3[F:50])([CH2:36][O:37][CH2:38][CH2:39]2)[N:34]=1)C(OC(C)(C)C)=O)(=O)C1C=CC=CC=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:50][C:44]1[CH:45]=[CH:46][C:47]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:48][C:43]=1[C@@:35]12[N:34]=[C:33]([NH2:25])[S:42][CH2:41][C@@H:40]1[CH2:39][CH2:38][O:37][CH2:36]2
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@@]2(c3cc(Br)ccc3F)COCC[C@H]2CS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)COCC[C@H]2CS1
Temperature: 90 °C
Reaction time: 6 h
Yield: 38.6 %

Procedure:
2-Fluoropyridine-3-boronic acid (25.6 mg), tetrakis(triphenylphosphine)palladium (10.5 mg) and a 1 N sodium carbonate solution (182 μl ) were added to a solution of (±)-N-benzoyl-N-(tert-butyloxycarbonyl)-[(4aR*,8aS*)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (50 mg) in DMF (5.0 ml). After replacement with nitrogen, the mixture was stirred at 90° C. for six hours. The reaction solution was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (12.7 mg).
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH2:5][CH2:4]1.[Br:24]Br>C(O)(=O)C>[BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=3[CH:12]([Br:1])[CH:13]([Br:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(=C2c3ccccc3C(Br)C(Br)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
1-Methyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide, 18.40 g. (0.05 mole) is dissolved with warming in 750 ml. of glacial acetic acid. This solution is cooled to room temperature and 8.0 g., 2.6 ml., (0.05 mole) of bromine dissolved in 75 ml. of glacial acetic acid is added dropwise with stirring. After completion of the addition the mixture is stirred overnight. The crystals are collected, washed with a small amount of cold glacial acetic acid, then with dry ether, and then dried for 2 hours in a vacuum oven at 70° to give 1-methyl-4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide. Recrystallization from acetonitrile gives an analytical sample, m.p. 185°-186°C.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][OH:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH:71]=[O:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCO
Product: O=CCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
PDC oxidation of 10-(2,3.4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (220 mg, 0.585 mmol) was added to a dry methylene chloride solution (6 mL) of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanol (275 mg, 0.395 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 16 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 204 mg (0.294 mmol, 74%) of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanal as a clear oil. Rf =0.40 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.75 (t, J=1.8 Hz, 1H), 7.32 (m, 20H), 4.98 (dd, J=10.8, 9.6 Hz, 2H), 4.84 (t, J=10.5 Hz, 2H), 4.75 (d, J=10.8 Hz, 1H), 4.61 (d, J=8.4 Hz, 1H), 4.56 (dd, J=10.8, 6.0 Hz, 1H), 4.43 (d, J=7.8, 1H), 4.00 (m, 1H), 3.8-3.4 (m, 8H), 2.40 (dt, J=7.2, 1.5 Hz, 2H), 1.70 (m, 6H), 1.31, (m, 10H); MS (FAB+): 701.0 ((M+Li)+, 100), 609.0 (4), 455.0 (5), 423.1 (7), 181.1 (35), 160.0 (10), 107.0 (4), 105.0 (5).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([CH3:6])[C:8]=1[N+:15]([O-:17])=[O:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(COS(C)(=O)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
At 10°-15° C., 27 g (0.23 mol) of methanesulfonyl chloride dissolved in 20 ml of CH2Cl2 is dripped into a mixture of 34 g (0.2 mol) of 3-methyl-2-nitrobenzyl alcohol and 27 g (0.27 mol) of triethylamine in 100 ml of CH2Cl2. The reaction mixture is stirred for 1 hour at room temperature and is then extracted with water. The organic phase is dried over MgSO4 and evaporated down. There is obtained as residue 48 g of the title compound as a yellow oil, containing about 10% of the corresponding benzyl chloride as impurity. The crude product is used for the next reaction without any further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[S:9])[NH:7][NH2:8])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[CH:13](OCC)=O>CO>[SH:9][C:6]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=[N:8][N:7]=1
Reactant: CCOC=O
Reactant: CCCCNC(=S)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1cnnc1S
Reaction time: 24 h
Yield: 55 %

Procedure:
4-n-Butylthiosemicarbazide (20.0 g. or 0.136 mole) was heated to reflux with a solution of methanol (100 ml.), sodium methoxide (7.55 g. or 0.140 mole) and ethyl formate (20.7 g. or 0.280 mole). After 8 and 16 hours, 10 ml. and 5 ml. of ethyl formate was added to the refluxing solution. After 24 hours total reflux, the solvent was removed under reduced pressure and the residue was dissolved in water (100 ml.). The pH of the solution was adjusted to about 12 with 50% sodium hydroxide solution. This solution was then heated on a steam bath for 45 minutes, cooled and acidified with dilute hydrochloric acid. The resulting oil was extracted into ether. The ether was dried over sodium sulphate and removed under vacuum. The resulting oil was crystallized from ether-hexane to give 11.8 g. (55% yield) of 3-mercapto-4-n-butyl-1,2,4-triazole, m.p. 67°-69° C. The structure was confirmed by its nuclear magnetic resonance spectrum and its mass spectrum.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8]1.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1CC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1CC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Yield: 69.7 %

Procedure:
As presented in the following reaction formula, a solution of potassium nitrate (KNO2; 6.2 g, 0.06 mol) in sulfuric acid (30 mL) was added dropwise at 0° C. to a mixture of 3-methyl-2,3-dihydro-1H-inden-1-one (9.0 g, 0.06 mol) in sulfuric acid ic (H2SO4; 40 mL). Then, the mixture was stirred at 0° C. until the completion of reaction. The mixture obtained after the reaction was added to ice water and filtered. The cake was washed with water and purified by silica gel (100 g) column chromatography (product of Merck Co., Ltd.) using an eluent of pentane (PE):ethyl acetate (10:1 (by volume)) to give 3-methyl-6-nitro-2,3-dihydro-1-H-inden-1-one (8 g, yield: 69%) as a yellow solid.