Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1COCC1.[Li+].[OH-].Cl>O.CO>[CH3:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Temperature: 50 °C
Yield: 48.4 %

Procedure:
To a flask charged with (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoate (2.70 g, 8.30 mmol) were added THF (48.5 mL), MeOH (48.5 mL) and water (48.5 mL) respectively. To the resulting turbid solution was added LiOH (0.994 g, 41.5 mmol), and the resulting mixture was heated at 50° C. overnight. The resulting mixture was cooled in an ice water bath and brought to pH˜2 by the addition of 2N HCl (˜15 mL) leading to a light yellow solution to which water was added (˜100 mL). This lead to the formation of a white precipitate which was collected by vacuum filtration and washed with excess water. After drying under high vacuum overnight, (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (1.25 g, 4.02 mmol, 48.4% yield) was obtained as a white solid. NMR indicated that the product formed as a THF adduct with a 3:2 product to THF ratio. 1H NMR (400 MHz, DMSO-d6) δ=12.76 (br. s., 1H), 7.87-7.81 (m, 2H), 7.63-7.57 (m, 2H), 7.41-7.34 (m, 2H), 7.34-7.30 (m, 1H), 7.30-7.19 (m, 2H), 5.51 (s, 1H), 1.63 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:22]2[C:7](=[O:8])[N:6]=[C:4]([C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])[O:5][C:23]2=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: O=c1nc(-c2c(F)cccc2F)oc(=O)n1-c1ccc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
A mixture of freshly prepared 2,6-difluorobenzoyl isocyanate (1.85 g) and 3,4-dichlorophenyl isocyanate (1.89 g) is heated at 120° C. for a period of 16 hours, and then cooled. Recrystallisation of the solid which was obtained from ethyl acetate yielded 3-(3,4-dichlorophenyl)-6-(2,6-difluorophenyl)-3,4-dihydro-2H-1,3,5-oxadiazin-2,4-dione, white crystals, m.p. 196°-197° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]#[CH:5].[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:2]([CH:1]1[S:11][CH2:7][CH2:8][CH2:9][S:10]1)[CH2:3][C:4]#[CH:5]
Reactant: SCCCS
Reactant: C#CCCC=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCCC1SCCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of pent-4-ynal (6.99 g, 85.1 mmol) dissolved in methylene chloride (85 mL) was added 1,3-propanedithiol (8.54 mL, 85.1 mmol). The solution was stirred at room temperature for 1 hour and then cooled to -20° C. Boron trifluoride etherate (10.46 mL, 85.1 mmol) was added and, after warming to room temperature, the solution was stirred for 16 hours. The solution was washed with water (2×20 mL) and the aqueous extract was washed with additional methylene chloride (2×40 mL). The combined organic extracts were washed with 10% potassium hydroxide solution (4×30 mL) and the aqueous extract was washed with additional methylene chloride (2×40 mL). The combined organic extracts were washed with 10% potassium hydroxide solution (4×30 mL) and the aqueous extract was back-extracted with methylene chloride (2×40 mL). The combined organic extracts were washed with brine (2×40 mL) and dried (K2CO3). The solvent was removed by rotary evaporation to afford 9.14 g (62%) of 2-(but-3-ynyl)-1,3-dithiane as a pale yellow oil. 1H NMR (CDCl3)δ: 4.2 (t, 1H), 3.1-2.8 (m, 4H), 2.6-2.4 (m, 1H), 2.3-2.0 (m, 6H); IR (neat): 3286, 2908, 1421, 1272, 907 cm-1 ; GC retention time=3.11 min (88% area); TLC (silica gel, 90% hexane: 10% ethyl acetate) Rf=0.74.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([CH:25]([CH3:28])[CH2:26][OH:27])[C:20]=1[CH3:29])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([CH:25]([CH3:28])[CH:26]=[O:27])[C:20]=1[CH3:29])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Dimethylsulfoxide (625 mg, 8 mmoles) was dissolved in 20 ml of methylene chloride, and the solution was cooled to -78° C. with a dry ice-acetone bath. Oxalyl chloride (762 mg, 6 mmoles) was added to the solution, and the mixture was stirred at the same temperature for 30 minutes. Then, 1.027 g (4 mmoles) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)-2-methylethanol dissolved in 12 ml of methylene chloride was added dropwise to the mixture. The mixture was stirred for 30 minutes, and then 1.6 ml of triethylamine was added dropwise. The mixture was warmed up gradually to room temperature. The reaction mixture was shaken with 50 ml of methylene chloride and 50 ml of water to separate an organic layer. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to form a dark scarlet oil. The oil was chromatographed on a column containing 50 g of silica gel using benzene/ethyl acetate (20/1) as an eluent. The fractions were collected each in an amount of 50 ml. From the 5th to 14th fractions, 500 mg (50%) of compound (502) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][C:6](=[O:8])[C:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[CH:4][CH2:3]1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][C:2]1([CH3:15])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cn1nccc1C1=CCC(C)(C)CC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cn1nccc1[C@H]1CCC(C)(C)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
To a solution of the 5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one (581 mg, 2.84 mmol) prepared in Example 72c in methanol (6.0 mL), sodium borohydride (200 mg, 5.29 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 30 minutes. To the reaction solution, a saturated aqueous solution of ammonium chloride (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=98:2) to yield the title compound (40 mg, 6.8%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-])=O)=[CH:19][C:13]=2[N:12]2[N:23]=[N:24][N:25]=[C:11]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[OH-].[Pd+2].[OH-].CCO>[Si:28]([O:27][CH2:26][C:10]1([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[O:15][C:14]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:13]=2[N:12]2[N:23]=[N:24][N:25]=[C:11]12)([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2-n2nnnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc(N)cc2-n2nnnc21
Reaction time: 6 h

Procedure:
A mixture of 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine (127 mg, 0.3 mmol), palladium(II) hydroxide on carbon (Aldrich cat. number 212911) (25 mg) and EtOH (10 mL) was hydrogenated at 30 psi for 6 hr. The mixture was then filtered through a short plug of celite, and the filter cake washed with EtOH (3×10 mL). The filtrate was concentrated under vacuum to give the product (yield assumed quantitative=119 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[K].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>CC(CC)=O>[CH2:2]([N:11]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCC(C)=O
Product: C=CCCN1C(=O)c2ccccc2C1=O

Procedure:
50 g (370 mmol) 4-bromo-1-butene and 68.5 g (370 mmol) phthalimide potassium salt are suspended in 800 ml ethyl methyl ketone and heated under reflux for 14 hours. After cooling, the mixture is filtrated and the filtrate is concentrated under vacuum. The residue is taken up in acetic acid ethyl ester and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum: yield 50 g (67%).
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24](OC)([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)(Cl)Cl>[N:37]([C:24]([C:21]1[N:19]2[CH2:20][C@H:14]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=3[F:6])[CH2:15][CH2:16][C@@H:17]([NH2:29])[C:18]2=[N:23][CH:22]=1)([CH3:25])[CH3:26])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(N=[N+]=[N-])c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Methanesulfonic acid (0.30 mL, 4.63 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (50 mg, 0.115 mmol) and sodium azide (170 mg, 2.62 mmol) in chloroform (10 mL). After 1 h, additional methanesulfonic acid (0.95 mL, 14.65 mmol) was added. After 16 h, the reaction mixture was concentrated. Purification by reverse phase HPLC (100% water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (38 mg). MS 347.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:19]=2)[CH:3]=1.[C:33]1([SH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[C:27]1([C@@H:25]([NH:24][C:20]2[N:19]=[C:18]([C:4]3[CH:3]=[C:2]([S:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:7]=[N:6][C:5]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:23]=[CH:22][N:21]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Sc1ccccc1
Reactant: C[C@H](Nc1nccc(-c2cc(Cl)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(-c2cc(Sc3ccccc3)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 120 °C
Yield: 51 %

Procedure:
Compound 10 (100 mg, 0.220 mmol), thiophenol (˜200 μL), and diisopropylethylamine (100 mL) were combined under Ar and heated at 120° C. for 3 h. The mixture was purified by flash column chromatography (hexane:ethyl acetate 70:30) to afford a foam. Crystallization from hexane:ethyl acetate afforded 59 mg (0.112 mmol, 51%) of Compound 86.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([N:11]([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:32]N>>[Cl:1][C:2]1[C:3]([C:9]([N:11]([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])=[N:4][C:5]([NH:8][CH3:32])=[N:6][CH:7]=1
Reactant: CN
Reactant: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(N)ncc2Cl)c1
Product: CNc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2cccc(OC)c2)n1

Procedure:
This was prepared in the same manner as the product of example 249, using methylamine as the amine, to give the title compound as a foam, 0.24 g, (88%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)CCl)C=CC=CC=1.[Mg].[CH2:33]([N:40]1[C:44]([CH:45]=[O:46])=[CH:43][N:42]=[CH:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(OCC)C>[CH2:33]([N:40]1[C:44]([CH:45]([OH:46])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:43][N:42]=[CH:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cl[Mg]CC(c1ccccc1)c1ccccc1
Reactant: O=Cc1cncn1Cc1ccccc1
Agent: Cl
Agent: ClCC(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(CC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1

Procedure:
The Gringnard reagent, diphenylethanyl magnesium chloride, is prepared by the usual way from diphenylethanylchloride (0.01 mol) and magnesium turnings (0.01 mol) in dry diethylether (30 ml). 1-benzyl-5-imidazole aldehyde (0.005 mol) is dissolved in dry diethylether and the Grignard reagent is added dropwise to the solution. The reaction mixture is refluxed for 3 hours. The reaction is then poured into 2N hydrochloric acid and extracted with diethylether. The water phase is made basic with sodium hydroxide and then extracted with ethyl acetate. The ethyl acetate phase is dried and evaporated. The residue is purified by flash-chromatography eluating with methylene chloride-methanol mixture (9.5:0.5). M.p. of the product as base is 188°-190° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:16])[N:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:9]1=O>C1COCC1>[CH3:14][N:13]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1([CH3:16])[CH3:7]
Reactant: CN1CCNC(=O)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNCC1(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
LiAlH4 (1 M in THF, 47 mL, 47 mmol, 1.5 equiv) was added to a solution of 3,3,4-trimethyl-piperazin-2-one (Step 107.3) (4.5 g, 32 mmol) in THF (50 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 2 h at 50° C., quenched by addition of acetone, filtered through a pad of celite and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 1.9 g of the title compound as a yellow oil. Title compound: ESI-MS: 129.1 [M+H]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](O)=[O:33]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:28]5[CH2:29][CH2:30][CH2:31][O:27]5)=[O:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (87 mg, 82%), MS (ISP) m/z=427.4 [(M+H)+], mp 160° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-2-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
According to the method of J. C. S. Perkin Trans. I, 1979, 135, p-cyanoaniline (6.894 g, 58.4 mmol) was added to a solution of 4-chloro-3-nitropyridine (9.26 g, 58.4 mmol) in ethanol (200 ml) and the mixture was stirred at room temperature for 18 hours. The resulting yellow suspension was poured into 500 ml of ice-cold dilute ammonia and filtered. The solid was treated with 150 ml of boiling ethanol, cooled in ice, and filtered to give the title compound as a bright yellow powder, (12.15 g), m.p. 210°-211° C.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.[NH2:37][C:38](=[O:42])[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[C@@H:26]([NH:28][C:39]([C:38]([NH2:37])=[O:42])=[O:40])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:13][CH:14]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: NC(=O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
N,N-Diisopropylamine (0.049 mL, 0.30 mmol) was added to a suspension of (1R,2S)-1-(1-(4-fluorophenyl)indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (53 mg, 0.14 mmol), 2-amino-2-oxoacetic acid (12 mg, 0.14 mmol) and HBTU (62 mg, 0.16 mmoL) in dichloromethane (2 mL). The mixture was stirred at r.t. overnight. The clear solution was concentrated and purified by HPLC to give the title compound (43 mg, 69%).
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH2:20][CH2:21][CH3:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:23]1([C:2]2[NH:6][CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=2[CH2:20][CH2:21][CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccccc1
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+]
Product: CCCc1c(C(=O)OC)c[nH]c1-c1ccccc1
Yield: 80.2 %

Procedure:
Using methyl 5-bromo-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate (3.96 g), phenylboronic acid (2.5 g), tetrakis(triphenylphosphine)palladium (1.79 g) and sodium carbonate (3.28 g), a procedure as in Reference Example 56 was performed to give the title compound as a pale-yellow oil (yield 2.0 g, 80%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([F:26])([F:25])[C:4]([F:24])([F:23])[C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[C:8]([F:16])([F:15])[C:9]([F:14])([F:13])[CH2:10][CH2:11]I.[P:29]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[O:30]CC>>[F:13][C:9]([F:14])([C:8]([F:15])([F:16])[C:7]([F:17])([F:18])[C:6]([F:19])([F:20])[C:5]([F:21])([F:22])[C:4]([F:23])([F:24])[C:3]([F:26])([F:25])[C:2]([F:28])([F:27])[F:1])[CH2:10][CH2:11][P:29](=[O:30])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 120 °C

Procedure:
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-iododecane (1.02 g, 1.78 mmol) and P(OEt)3 (15 ml, excess) was added to 50 ml round bottom flask. The mixture was heated to 120° C. under nitrogen for 40 hours and then purified with FluoroFlash® SPE cartridge. The remaining light yellow oil was chromatographed with Ethyl Acetate/Hexane to give product. (0.96 g, 92%). 1H NMR (600 MHz, CDCl3): δ (ppm) 4.10-4.00(m, 4H, CH2CH3), 2.35-2.23 (m, 2H, CH2CF2), 1.92-1.86 (m, 2H, PCH2), 1.25 (t, J=7.2 Hz, 6H, CH2CH3). 13C NMR (150 MHz, CDCl3): δ (ppm) 121-106 (m, C—F coupling unsolved), 62.28 (d, 2Jcp=6 Hz, CH2CH3), 25.33 (t, 2JcF=23 Hz, CH2CF2), 17.24 (d, 2Jcp=148 Hz, PCH2), 16.38, 3Jcp=6 Hz, CH2CH3), HRMS calcd for C14H14F17O3P: [M+H]+, 585.0487; found: 585.0433
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:6]=[C:7]([NH:13][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(OC)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
trans-2-(3-Methoxy-4-propoxy-5-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran (50 mg, 0.12 mmole) and potassium carbonate (1.0 g) were suspended in 2 mL of DMF. Benzyl bromide (205.1 mg, 1.2 mmole) was added and the suspension was stirred at room temperature for 20 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to an oil that was purified by column chromatography with hexane/ethyl acetate solvent (yield 50.2 mg, 82.6%).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(C(=O)N2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)cc1
Yield: 53 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4-methylbenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 53%.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O>C(O)C>[CH3:2][C:1]1[S:3][CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:4]=1
Reactant: CC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Solvent: CCO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cs1
Yield: 2.2 %

Procedure:
Thioacetamide (120 mg) was added to an ethanol (6 mL) solution of tert-butyl 4-(bromoacetyl)piperazinecarboxylate (340 mg) obtained in the above 1), and heated under reflux for 3 hours. The reaction liquid was restored to room temperature, then the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 7 mg of the entitled compound.