Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=O)=[CH:9]2)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:25])[NH2:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 7-nitro-1H-indole-2-carboxamide (2.50 g), Lawesson's reagent (5.42 g) and tetrahydrofuran (50 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (2.08 g, yield 77%) as yellow crystals. melting point>237° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]1=[O:23])=[O:5])[CH3:2].[OH:24]O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)[NH:15][C:14](=[O:24])[C:13]1=[O:23])=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)CCCCCCn1c(=O)cnc2cc(Br)ccc21
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCn1c(=O)c(=O)[nH]c2cc(Br)ccc21
Temperature: 0 °C

Procedure:
The above ester (3.43 g, 9.0 mmol) was reacted with 30% H2O2 (14.9 ml) in glacial acetic acid (40 ml) at 55° C. for 20h. The mixture was poured onto crushed ice (250 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extract was washed with half saturated sodium hydrogen carbonate solution and water, dried (Na2SO4), evaporated to dryness and stripped with ether. The product was triturated with heptane (20 ml) overnight, the precipitate filtered off, washed with heptane and dried to afford 2.86 g of the title compound. M.p. 187°-190° C. 1H-NMR(DMSO-d6):δ0.80(m, 3H), 1.1(t, 3H), 1.12-1.4(m, 6H) 1.9-2.25(m, 2H), 4.0-4.17(m, 2H), 5.2-5.7(m, 3H), 12.28(s, 1H).
Reaction SMILES: [O:1]1[C:7]23[CH2:8][CH:4]([CH2:5][CH:6]2C=C)[CH2:3][CH:2]13.C1[CH:15]2[CH:16]3[CH:20]=[CH:19][CH:18]([CH:14]2C=C1)[CH2:17]3>>[C:16]12([C:2]34[O:1][C:7]53[CH2:8][CH:4]([CH2:3]4)[CH2:5][CH2:6]5)[CH2:17][CH:18]([CH2:19][CH2:20]1)[CH:14]=[CH:15]2
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC1CC2CC3OC13C2
Product: C1=CC2(C34CC5CCC3(C5)O4)CCC1C2
Temperature: 180 °C
Reaction time: 4 h
Yield: 329.6 %

Procedure:
To a 2-liter stainless steel autoclave reactor was charged 0.99 kg (7.26 mol) 3-epoxy-5-vinyl norbornane and 0.06 kg (0.45 mol) dicyclopentadiene. Stirring was started, and the reactor evacuated of air and padded with 5 psig nitrogen. Heating to 180° C. commenced, and upon achieving 180° C., the reactor was held for 4 hours at this temperature. At the end of this time, the reactor was cooled to ambient temperature and discharged. The major identified components of the charge, as measured by GC area, were: 0.6% dicyclopentadiene, 81.6% 3-epoxy-5-vinyl norbornane, 1.3% epoxyethylepoxy norbornane, 13.6% norbornenyl epoxy norbornane. A total of four reactions were completed and distilled to produce 0.3 kg norbornenyl epoxy norbornane with assay greater than 96% (GC area).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)(=[O:10])[CH3:9]>ClCCl>[NH:15]1[CH2:16][CH2:17][O:18][C@H:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[CH2:14]1
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@@H]1CNCCO1

Procedure:
To a 4:1 solution of dichloromethane and TFA (0.1 M) was added (R)-tert-butyl 2-(acetamidomethyl)morpholine-4-carboxylate. After 1 h the solution was then concentrated in vacuo to give crude (S)—N-(morpholin-2-ylmethyl)acetamide which was used in the next step without further purification. LCMS (m/z) (M+H)=159.0, Rt=0.11 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([CH2:14][NH2:15])[OH:13].[BH4-].[Na+].O>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:15][CH2:14][CH2:12][OH:13])([O-:3])=[O:2]
Reactant: NCCO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(CNCCO)c1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
500 mg of 3-nitrobenzaldehyde and 202 mg of ethanol amine were dissolved in 10 mL of ethanol, followed by stirring at 80° C. To this was added 125 mg of sodium borohydride, followed by stirring for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 594 mg (yield 92%) of a title compound as a yellow solidified product.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:6]=[C:7]([O:10][CH2:11][C@H:12]([OH:28])[CH2:13][NH:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[C:8]=1[F:9].Cl.[CH2:35](O)[CH3:36]>C(OCC)C>[ClH:1].[CH2:35]([O:32][C:31](=[O:33])[CH2:30][CH2:29][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C@H:12]([OH:28])[CH2:13][NH:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:25]2)[C:8]([F:9])=[C:3]([F:2])[CH:4]=1)[CH3:36].[ClH:1]
Reactant: CCO
Reactant: CC(C)(CC1Cc2ccccc2C1)NC[C@@H](O)COc1cc(CCC(=O)O)cc(F)c1F
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)CCc1cc(F)c(F)c(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c1
Temperature: 25 °C

Procedure:
To a suspension of the propionic acid of Example 2 (2 g) in ethanol (20 mL) was added 2M HCl in diethyl ether (2 mL). The mixture was heated to reflux for 3 h. After cooling to RT, the resulting solution was concentrated to a yellow oil and dried under vacuum. The contents of the flask solidified to give the title compound as an HCl salt (2 g): 1H NMR (dmso-d6): δ 9.05 (m, 1H); 8.62 (m, 1H); 7.18 (m, 2H); 7.11 (m, 2H); 6.98 (app. d, J=7.1 Hz, 1H); 6.91 (m, 1H); 6.0 (br s, 1H); 4.27 (m, 1H); 4.14 (d, J=5.2 Hz, 2H); 4.06 (q, J=7.1 Hz, 2H); 3.18 (m, 1H); 3.09 (m, 2H); 2.98 (m, 1H); 2.82 (t, J=7.5 Hz, 2H); 2.61 (m, 5H); 1.97 (d, J=5.4 Hz, 2H); 1.39 (s, 6H); 1.17 (t, J=7.1 Hz, 3H): LCMS (m/z) M+H=476.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[C@@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
Heat a mixture of (3S,4S)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.035 mol, 7.5 g), 5-bromo-2-fluoronitrobenzene (0.038 mol, 8.48 g) and triethyl amine (0.073 mol, 7.44 g) in ethyl acetate (250 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (16.16 g, crude).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23](=[O:25])[O:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.ClCCl>O1CCCC1>[O:25]=[C:23]1[O:22][N:21]=[C:20]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH:13]=[O:12])[NH:24]1
Reactant: O=c1[nH]c(-c2cccc(CO)c2)no1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Yield: 71.9 %

Procedure:
Add PCC (5.22 g, 24.2 mmol) to a solution of 3-(3-hydroxymethyl-phenyl)-4H-[1,2,4]oxadiazol-5-one (3.10 g, 16.1 mmol) in tetrahydrofuran:dichloromethane (125 mL:125 mL) and stir. After 4 hours concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product as a white solid (2.20 g, 72%): 1H NMR (DMSO-d6) δ 7.83 (t, 1H), 8.10-8.17 (m, 2H), 8.35 (m, 1H), 10.09 (s, 1H), 13.15 (bs, 1H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][C:26]([CH3:29])=[N:27][N:28]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:29][C:26]1[S:25][C:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13]/[CH:2]=[C:3]3\[C:4](=[O:12])[NH:5][C:6]4[C:11]\3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[N:28][N:27]=1
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Reactant: O=C1Nc2ccccc2C1=CO
Product: Cc1nnc(NS(=O)(=O)c2ccc(N/C=C3\C(=O)Nc4ccccc43)cc2)s1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and 4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide. 1H NMR (DMSO) 13.90 (bs, 1H); 10.84 (d, 1H); 10.58 (s, 1H); 8.62 (d, 1H); 7.81 (d, 2H); 7.60 (d, 1H); 7.55 (d, 2H); 7.12 (m, 1H); 6.95 (m, 1H); 7.84 (d, 1H); 2.48 (s, 3H). Electrospray MS 414 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]([OH:28])=O)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:47]([NH:50][NH2:51])(=[O:49])[CH3:48]>C1COCC1>[C:47]([NH:50][NH:51][C:26](=[O:28])[CH2:25][C:21]1[C:22](=[O:24])[N:23]=[C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:29]([F:30])([F:32])[F:31])[CH:4]=3)=[CH:10][CH:11]=2)[NH:19][CH:20]=1)(=[O:49])[CH3:48]
Reactant: O=C(O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Reactant: CC(=O)NN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(=O)NNC(=O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
To a solution of (2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-4-oxo-1,4-dihydro-5-pyrimidinyl)acetic acid (91 mg, 0.194 mmol) in THF (2 mL) was added EDC (149 mg, 0.776 mmol) and HOBT (89 mg, 0.582 mmol). The mixture was stirred at room temperature for 15 min and acetohydrazide (21.57 mg, 0.291 mmol) was added. The mixture was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (28 mg, 0.053 mmol, 27.5% yield). LCMS: rt=3.04 min, [M+H+]=525
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:19](OC(Cl)(Cl)Cl)=[O:20]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[N:4]=[C:19]=[O:20]
Reactant: Nc1ccc(OCc2ccc(Cl)cc2)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 5.0 grams (0.02 mole) of 2-fluoro-4-(4-chlorophenylmethoxy)aniline in 150 mL of toluene was stirred and a solution of 3.4 mL (0.02 mole) of trichloromethyl chloroformate in 20 mL of toluene was added slowly. Upon completion of addition, the reaction mixture was stirred at 25° C. for one hour. After this time the reaction mixture was warmed to reflux, where it was stirred for about 18 hours. The reaction mixture was then concentrated under reduced pressure, yielding 5.5 grams of 2-fluoro-4-(4-chlorophenylmethoxy)phenyl isocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:13][C:7]1([CH3:12])[C:6]2[CH:14]=[C:2]([O:1][S:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=3[Cl:22])(=[O:32])=[O:31])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[O:8]1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-hydroxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.00 g, 5.17 mmol), prepared according to the procedure in example 69, in methylene chloride (25 mL) at 0° C. was added triethylamine (0.9 mL, 6.45 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (1.27 g, 5.17 mmol) was added. The solution was stirred for one hour, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Trituration with ether gave (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate as a white solid (1.55 g, 75%). 1H NMR (DMSO-d6): δ 10.37 (s, 1H), 8.13 (dd, J=8.2, 1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.5 Hz, 1H), 7.60 (t, J=8.05 Hz, 1H), 7.02 (dd, J=8.7, 2.6 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 1.48 (s, 6H). MS (ESI) m/z 400/402/404 ([M−H]−); Anal. calcd for C16H13Cl2NO5S: C, 47.78; H, 3.26 N, 3.48. Found: C, 47.14; H, 3.46; N, 3.49.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.CN(C)CCN(C)C.[Li]CCCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([CH2:11][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[OH:38])[S:8][C:6]=2[N:7]=1
Reactant: Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: O=Cc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a solution of 5-chloro-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (1.33 g, 4.91 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.74 mL, 5.40 mmol) in anhydrous THF (50 mL) was added a solution of n-BuLi (2.5 M in hexanes, 2.4 mL, 6.0 mmol) dropwise at −78° C. The reaction mixture was stirred for 15 min, then a solution of benzaldehyde (0.65 mL, 6.29 mmol) in anhydrous THF (5 mL) was added rapidly. The mixture was stirred at −78° C. for 15 min, then allowed to warm to RT and partitioned between EtOAc and H2O. The organic layer was isolated, washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (1.20 g, 66%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][CH:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>>[CH3:30][CH:31]([S:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:35])=[O:34])[CH3:32]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CC(C)S(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(Propane-2-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and propane-2-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[OH:27])[OH:18])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:34](Br)[CH:35]=[CH2:36].C(OCC)(=O)C>O1CCCC1>[CH2:36]([O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH:17]([OH:18])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14]1)[CH:35]=[CH2:34]
Reactant: COc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(O)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)ccc1C(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
53 mg (2.2 mmol) of sodium hydride was suspended in 5 ml of tetrahydrofuran. To the resultant suspension was added a solution which had been prepared by dissolving 837 mg (2 mmol) of 2-(4-diphenylmethylpiperazinyl)-1-(2-hydroxy-4-methoxyphenyl)ethanol in 5 ml of tetrahydrofuran under ice-cooled conditions. Thereafter, 2 ml of a tetrahydrofuran solution of 266 mg (2.2 mmol) of allylbromide was added and heated with refluxing for 4 hours. After being cooled to room temperature, the resultant mixture was added with 50 ml of ethyl acetate. The mixture was then washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed, and the residue was subjected to thin-layer chromatography to give 419 mg of 1-(2-allyloxy-4-methoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol as a colorless oily substance (yield: 46%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([O-])(=O)C.[Na+].C([BH3-])#[N:30].[Na+]>CO>[CH2:8]([CH:9]([NH2:30])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC(CCc1ccccc1)CCc1ccccc1

Procedure:
To a solution of 1,5-Diphenylpentan-3-one (5.26 g, 22.1 mmol), ammonium acetate (8.52 g, 110.5 mmol) and sodium acetate (9.06 g, 110.5 mmol) in methanol (80 mL) was added a solution of sodium cyanoborohydride (1.67 g, 26.52 mmol) in methanol (20 mL) and the reaction heated to reflux. After stirring at reflux for 30 min, the reaction was cooled and concentrated to dryness. The residue was partioned between methylene chloride and 2N sodium hydroxide. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 2-5% methanol/methylene chloride) provided N-(1-phenethyl-3-phenyl-propyl)amine. To a solution of the above amine (2.1 g, 8.82 mmol) in ethanol (50 mL), was added 2-imidazole-carboxaldehyde (813 mg, 8.47 mmol) and the reaction heated to 50° C. After stirring for 2 hr, the resulting homogeneous solution was treated with sodium borohydride (400 mg, 10.58 mmol) and allowed to stir overnight. The reaction was concentrated to dryness and the residue was partioned between methylene chloride and 2N sodium hydroxide. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 5% methanol/methylene chloride) provided compound 22.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4]([Cl:31])=[O:5]
Reactant: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)Cl)C(C)(C)C)c2C1
Reaction time: 2 h

Procedure:
To a solution (S)-3,3-dimethyl-2-(7-methyl-3-phenyl-5,6,7,8-tetrahydroimidazo [1,5-a]pyrazine-1-carboxamido)butanoic acid (Compound 281) (0.11 g. 0.30 mmol) in DCM was added oxalyl chloride (0.08 g, 0.60 mmol) followed by a catalytic amount of DMF. The resulting mixture was stirred for 2 h and the solvent was evaporated, toluene (2 mL) was added and the mixture was concentrated again. The resulting product (Intermediate 23A) was dried under vacuum and then used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25](F)=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1)[CH3:2].[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:12])([F:11])[F:13])[C:14]([F:15])([F:17])[F:16])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1)[CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 84.5 %

Procedure:
N-[2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-fluoro-3-nitrobenzamide (1.5 g, see WO 2005/073165) and 1H-1,2,4-triazole (0.24 g) were dissolved in N,N-dimethylformamide (15 ml). To the solution, potassium carbonate (0.88 g) was added and the mixture was stirred under heating at 70° C. for 3 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography to obtain N-[2ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-3-nitro-4-(1H-1,2,4-triazol-1-yl)benzamide (1.4 g, yield 80%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(OCC)C.O>[CH2:1]([O:8][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (19.7 g, 182.3 mmol) was slowly added to a suspension of sodium hydride (15.9 g 55% in mineral oil, 364.5 mmol) in anhydrous diethyl ether (116 mL) and the resulting mixture was stirred at room temperature for 1 hour. It was then diluted with some diethyl ether to ensure good stirring. Ethyl 4-chloro-3-oxobutanoate (12.3 mL, 91.1 mmol) was then slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was cooled with an ice bath and then diluted with cold water and diethyl ether pH was adjusted to 4 with 5 N HCl and it was extracted three times with diethyl ether containing some ethyl acetate. The combined organic phases were dried over Na2SO4 and it was concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step.