Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:14][C:10]1[CH:9]=[C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1-c1cccc(F)c1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(-c2ccccc2N=C=S)c1

Procedure:
Reaction of 2-amino-3'-fluorobiphenyl (10 g) and thiophosgene (9.2 g) in a mixture of dioxane (15 ml) and water (70 ml) at ambient temperature for 1.5 hours yielded 3'-fluoro-2-biphenylylisothiocyanate as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([O-])(=[O:14])=[O:13])=[C:8]([CH3:16])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[K+].O=P(Cl)(Cl)[Cl:20]>>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([Cl:20])(=[O:14])=[O:13])=[C:8]([CH3:16])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(C)c(S(=O)(=O)[O-])sc12
Agent: [K+]
Product: COc1cccc2c(C)c(S(=O)(=O)Cl)sc12
Temperature: 60 °C
Yield: 46 %

Procedure:
A mixture of potassium 7-methoxy-3-methylbenzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the crude product was purified on a small amount of silica eluting with CH2Cl2 to give the title compound in 46% yield (43 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:23])[N:4]2[C:16](=[CH:17][C:18]=1[C:19](=[O:22])[CH2:20][CH3:21])[C:7]1=[N:8][C:9]3[C:14]([CH:15]=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>O1CCCC1.[Zn].C([O-])(=O)C.[Ag+].C(O)C>[OH:22][C:19]([C:18]1[CH:17]=[C:16]2[N:4]([CH2:5][C:6]3[C:7]2=[N:8][C:9]2[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:23])[C:2]=1[CH3:1])([CH2:20][CH3:21])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: CCC(=O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(O)(CC)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
A suspension of zinc (1.25 g, 19.1 mmol), 8-methyl-7-propionylindolizino[1,2-b]quinoline-9-(11H)-one (500 mg, 1.43 mmol, as obtained by Kingsburry, W. D., Tetrahedron Lett. 29:6847 (1988)) and silver acetate (250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 ml) is agitated at ambient temperature under an argon atmosphere. After 10 minutes, the reaction mixture is activated by the dropwise addition of a molar solution of chlorodiethylalumninium (10 ml, 10 mmol), then ethyl bromoacetate (1.25 ml, 11.3 mmol) is added dropwise and the resultant mixture is left to react for another 5 hours. The reaction is stopped by the successive addition of ethyl alcohol (10 ml) and a saturated solution of potassium and sodium tartrate (10 ml). The resultant mixture is agitated for another hour, filtered and concentrated under reduced pressure. The residue is taken up in dichloromethane (30 ml), washed with water, dried, concentrated and purified by column chromatography (SiO2, CH2Cl2/MeOH:98/2), which produces 93 mg (15%) of desired product in the form of a pale yellow solid, m.p. 185-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].Cl[C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH3:33])([CH3:32])[O:30][C:29]([CH3:35])([CH3:34])[C:27]=2[N:28]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:23]2[N:24]=[CH:25][C:26]3[C:31]([CH3:33])([CH3:32])[O:30][C:29]([CH3:35])([CH3:34])[C:27]=3[N:28]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: CC1(C)OC(C)(C)c2nc(Cl)ncc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ncc4c(n3)C(C)(C)OC4(C)C)CC2)ccc1OC
Temperature: 25 °C
Yield: 19.3 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h 2-chloro-5,5,7,7-tetramethyl-5,7-dihydro-furo[3,4-d]pyrimidine (15.5 mg, 0.10 mmol, 1.0 equiv) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.5 mg (12%) of the title compound. MS (ISP): 441.5 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH2:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br.C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C@:2]12[CH2:18][CH2:17][C:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C:15]=3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=C(CCC(=O)C3)[C@H]1CC2
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CCC3=C1CC2
Reaction time: 0.02 h
Yield: 31 %

Procedure:
Estra-5(10),16-dien-3-one, 3 (0.38 g, 1.5 mmol), in pyridine (5.0 mL, 62 mmol) was cooled in an ice-salt bath to -13° C. and pyridinium bromide perbromide (1.58 g, 4.94 mmol) was added in small portions so that T<-4° C. After swirling 1 min. phenol (0.25 g, 2.7 mmol) was added and reaction continued 24 h at room temperature. See FIG. 12. Ethyl acetate (50 mL) was added and the reaction mixture was washed with 25 mL of 1N HCl, two 25 mL portions of saturated copper sulfate, 25 mL of 5% sodium hydroxide, and 25 mL of brine. After drying over magnesium sulfate, filtration, and concentration under reduced pressure the residue was taken up in 10 mL of abs. ethanol, granular zinc (0.33 g, 5.0 mg-atom) was added, and the mixture was refluxed 1/2 h. The supernatant was removed, the residue was washed with 10 mL of abs. ethanol, and the combined supernatants were concentrated under reduced pressure. The resulting resin was flash chromatographed on silica gel using 15% ethyl acetate/hexane as eluent. Appropriate fractions were pooled, concentrated, and then recrystallized from hexane to give solid product (117.5 mg, 0.4619 mmol, 31%), m.p. 87°-92° C. (NA-1993A-62, 65B)
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[CH:22]=O)/[N:7]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[NH:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][OH:40].C(O)(=O)C>ClCCl.CO>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=2[CH2:22][N:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[CH2:39][OH:40])/[N:7]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2C=O)s1
Reactant: OC[C@@H]1CCCN1
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2CN2CCC[C@H]2CO)s1
Yield: 38 %

Procedure:
In a vial (5 mL), a mixture of Example 375C (88 mg, 0.200 mmol), support-bound cyanoborohydride resin (0.256 g, 0.599 mmol), (S)-pyrrolidin-2-ylmethanol (60 mg, 0.593 mmol), and acetic acid (18 mg, 0.300 mmol) in dichloromethane (1 mL) and methyl alcohol (1 mL) was shaken on an orbit shaker for 2 hr. The reaction was filtered, concentrated and the residue was purified by preparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) in 38% yield as TFA salt. 1H NMR (300 MHz, CD3OD) δ ppm 1.41 (s, 9H) 1.72-1.81 (m, 1H) 1.88-1.99 (m, 2H) 2.05-2.20 (m, 3H) 2.27-2.41 (m, 1H) 3.34-3.42 (m, 1H) 3.52-3.66 (m, 1H) 3.67-3.82 (m, 4H) 3.85-3.96 (m, 1H) 4.36-4.46 (m, 3H) 4.57 (d, J=12.69 Hz, 1H) 4.86-4.93 (m, 2H) 7.28 (s, 1H) 7.76-7.82 (m, 1H) 7.87-7.94 (m, 1H) 8.73-8.75 (m, 1H); MS (DCI/NH3) m/z 526 (M+H)+. Anal. calcd calcd C26H34F3N3O3S.1.9 CF3CO2H: C, 48.22; H, 4.87; N, 5.66. Found: C, 48.28; H, 4.63; N, 5.67.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd].[C]>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CC1CCOCC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 78.1 %

Procedure:
To a mixture composed of ethyl 2-(2H-pyran-4(3H,5H,6H)-ylidene)acetate (10 g, 58.75 mmol) and ammonium formate (37 g, 587.54 mmol) in methanol (150 ml) was added 10% Pd-carbon (1.0 g) at room temperature, and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, and the catalyst was collected by filtration through Celite pad and was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=94:6) to give the title compound as an oil (7.9 g, yield 78%).
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:30]=2)([OH:4])[CH:2]([CH3:41])[CH3:1])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2cccnc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2cccnc2)c1)c1c[nH]cn1
Yield: 92.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[3-(3-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (0.57 g) and pyridine hydrochloride (208 mg), the title compound (288 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][C:2]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:3]=[CH:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl>>[CH3:1][C:2]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC=C=C(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C=CC=C(C)CCCC(C)CCCC(C)C
Yield: 93 %

Procedure:
20 g of ethyl 5,9,13-trimethyl-3,4-tetradecadienoate and 1 g of potassium carbonate were heated at 40° to 45°C. for 3 hours in the absence of a solvent to effect the rearrangement reaction. Then, the reaction mixture was neutralized with 4N HCl and subjected to distillation under reduced pressure. Ethyl 5,9,13-trimethyl-2,4-tetradecadienoate was obtained in a yield of 93% from a fraction boiling at 143 to 145°C. under 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.O[CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: OC1CCOC1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OC3CCOC3)c2)sc2ccc(Cl)cc12
Yield: 63 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 3-hydroxytetrahydrofuran (8.8 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 63% yield (15.6 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.07 (ddddd, J=13.81, 6.79, 4.51, 1.93, 1.05 Hz, 1 H) 2.25 (dddd, J=13.81, 8.43, 8.43, 6.32 Hz, 1 H) 2.47 (s, 3 H) 3.86-3.96 (m, 3 H) 3.97 (dd, J=10.65, 4.64 Hz, 1 H) 5.46-5.50 (m, 1 H) 7.00 (s, 1 H) 7.37 (dd, J=8.05, 7.69 Hz, 1 H) 7.44 (ddd, J=8.05, 2.35, 1.17 Hz, 1 H) 7.44 (dd, J=8.72, 1.95 Hz, 1 H) 7.70 (dd, J=2.35, 1.57 Hz, 1 H) 7.72 (dd, J=8.72, 0.57 Hz, 1 H) 7.72 (dd, J=1.95, 0.57 Hz, 1 H) 7.82 (ddd, J=7.69, 1.57, 1.17 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: Br[C:2]1(Br)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][O:15][CH3:16])[NH:3]1.[C:18]([N:22]1[C:26]([NH2:27])=[CH:25][C:24]([CH3:28])=[N:23]1)([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:18]([N:22]1[C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][O:15][CH3:16])[N:3]=2)=[CH:25][C:24]([CH3:28])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COCCN1NC(Br)(Br)c2ccccc2C1=O
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COCCn1nc(Nc2cc(C)nn2C(C)(C)C)c2ccccc2c1=O
Temperature: 130 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
4-Bromo-2-(2-methoxyethyl)-4-bromo-2H-phthalazin-1-one (0.57 g, 2.0 mmol), 1-(tert-butyl)-3-methyl-1H-pyrazol-5-ylamine (0.46 g, 3.0 mmol), Cs2CO3 (0.98 mg, 3.0 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.092 g, 0.1 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.17 mg, 0.3 mmol) were dissolved in degassed dioxane (10 ml). The reaction mixture was heated with stirring to 130° C. for 8 hours and then cooled to RT. H2O (100 ml) was added and the precipitated solid was filtered and washed with EtOAc and H2O. The raw product was purified over silica gel (EtOAc:heptane 0%-60% EtOAc) to give the title compound (0.46 g, 65% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.22-8.31 (3H, m), 7.95 (1H, t), 7.86 (1H, t), 5.91 (1H, s), 4.05 (1H, t),3.55 (1H, t), 3.17 (3H, s), 2.14 (3H, s), 1.54 (9H, s); MS (ESI+)=356.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][C@@H:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C@H:14](O)[CH2:13]3)[C:8]2=[O:27])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][C@H:14]1[C@H:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:16][CH2:17][N:12]([CH:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]2=[O:27])[CH2:13]1
Reactant: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)C[C@H]2O)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)C[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one from step B (2.5 g, 6.3 mmol) in 50 mL DCM was added DAST (4.1 mL, 31 mmol) and the reaction was stirred at ambient temperature for 1 h. The reaction was then quenched with a sat.bicarbonate solution (200 mL) and the mixture was extracted with 200 mL of DCM. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via silica gel chromatography eluting with 28% ethyl acetate in hexane to give (±)-rel-3-((3S,4S)-3-fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one (900 mg, 1.6 mmol) as a mixture of four diastereomers. LCMS (method P) RT 0.89 min, m/z 401.2 (M+H+).
Reaction SMILES: [CH2:1]([CH:11]1[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[BrH:20].BrBr>O>[Br:20][C:11]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19]
Reactant: Br
Reactant: CCCCCCCCCCC1C(=O)NC(=O)NC1=O
Agent: BrBr
Solvent: O
Product: CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-decylbarbituric acid (0.537 g) in 2.9 ml of water are added under stirring at room temperature 0.29 ml of 48% hydrobromic acid. The mixture is cooled to 0° C. and 0.113 ml of bromine are dropped. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. then the white precipitate is filtered and it is washed with water. The solid is partitioned between water and diethyl ether, the organic phase is separated, washed with brine and finally dried over sodium sulfate. By evaporation of the solvent under reduced pressure 0.62 g of the product are recovered.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20]O)[N:18]=3)=[CH:10][CH:9]=2)[N:3]=[CH:2]1.Cl.[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:20][CH2:19][C:17]1[N:18]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[CH:13][CH:12]=2)[O:15][CH:16]=1
Reactant: C[C@@H]1CCCN1
Reactant: OCCc1coc(-c2ccc(OCc3cscn3)cc2)n1
Agent: Cl
Product: C[C@@H]1CCCN1CCc1coc(-c2ccc(OCc3cscn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Example 53 from 2-{2-[4-(Thiazol-4-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol (See Intermediate 68) and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 370.2 (M+1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:16]=[CH:17][CH:18]=1)([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Yield: 96.2 %

Procedure:
To a solution of 1-(bromomethyl)-3-nitro-benzene (4.50 g, 0.021 mol) and tert-butyl (3-aminophenyl)carbamate (4.34 g, 0.021 mol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.32 g, 0.03 mol). The resultant mixture was stirred at room temperature overnight and the reaction was complete. The reaction mixture was filtered first to remove K2CO3, and then quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gel (6.94 g, 97%). LCMS for C18H22N3O4 (M+H)+: m/z=344.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14](OC)=[S:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>O1CCCC1.CN(C)C=O>[OH:22][C:8]1[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:14]=2[S:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: COC(=S)c1ccncc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1c(-c2ccccc2)sc2cnccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 4.8 g (19 mmol) of methyl 3-phenylmethylthiopyridine-4-carboxylate in 10 mL of tetrahydrofuran was added to a slurry of 2.40 g (60 mmol) of 60% sodium hydride in 10 mL of N,N-dimethylformamide and the resulting mixture was stirred at 60° C. for 3 hours. The solution was poured onto ice water and acidified with glacial acetic acid. The filtrate was collected to afford 1.6 g (38%) of white solid.
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]=2[CH:32]=1.[I-].[K+]>O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][NH:8][CH2:7][CH:4]4[CH2:6][CH2:5]4)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]=2[CH:32]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: NCC1CC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine and potassium iodide in tetrahydrofuran to give 8-chloro-1-[[(cyclopropylmethyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(C=C)=O.C1(C=CC(O)=CC=1)O.[CH3:13][P:14]([O:18][CH2:19][CH3:20])[O:15]CC.[CH2:21]([O:23][CH:24]([O:31][CH2:32][CH3:33])[CH2:25][CH2:26]P(C)(=O)[O-])[CH3:22]>C(O)C>[CH2:21]([O:23][CH:24]([O:31][CH2:32][CH3:33])[CH2:25][CH2:26][P:14]([CH3:13])(=[O:15])[O:18][CH2:19][CH3:20])[CH3:22]
Reactant: CCOC(CCP(C)(=O)[O-])OCC
Reactant: CCOP(C)OCC
Agent: C=CC=O
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: CCOC(CCP(C)(=O)OCC)OCC
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Into a 100 ml. red flask was introduced 12.5 g. of acrolein, and 15 mg. of hydroquinone and 45 ml. of anhydrous ethyl alcohol were added thereto. The resulting mixture was stirred at -10° C. in a stream of nitrogen and then 13.6 g. of diethyl methylphosphonite was added dropwise thereto over 20 minutes. After stirring further for 30 minutes at the same temperature, the mixture was stirred for 2 hours at 0° C. and subsequently for 4 hours at room temperature, followed by further reaction at 70° C. for 12 hours. After the reaction mixture thus obtained was concentrated by evaporation of the ethanol under reduced pressure, the residue was subjected to distillation under reduced pressure to give a fraction boiling at 85° to 91° C./0.17 mmHg. and thus was obtained 12.2 g. of a light-yellow oil of ethyl, 3,3-diethoxypropylmethylphosphinate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].NC1C=C(C=CC=1N)C(N)=O.[Cl:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1.C1(C2(C3C=CC(C=O)=CC=3)OCCO2)C=CC=CC=1.N>CO>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([C:35]3[NH:8][C:7]4[CH:6]=[CH:5][C:4]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:3][C:2]=4[N:1]=3)=[CH:33][CH:32]=2)=[O:30])=[CH:39][CH:40]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Reactant: O=Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: N
Agent: NC(=O)c1ccc(N)c(N)c1
Agent: O=Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Solvent: CO
Product: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccc(Cl)cc4)cc3)nc2c1

Procedure:
The title compound was prepared as described in Example 1 substituting 3,4-diamino-benzenesulfonamide for 3,4-diamino-benzamide and 4-(4-chloro-benzoyl)-benzaldehyde for 4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde in Step C (reaction mixture was heated to 60° C.). TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2): Rf=0.32. HPLC (Method A): Rt=8.03. MS (ESI+): mass calculated for C20H14ClN3O3S, 411.0; m/z found, 412.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 13.48 (br s, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.16 (br s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.76 (br s, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.73 (br s, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.25 (br s, 2H).