Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1I.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=1)#[CH:10]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[C:10]#[C:9][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=1
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: Brc1cc(I)c(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C#Cc2cc(Br)sc2Br)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of 2,5-dibromo-3-iodothiophene (3.52 grams, 9.57 mmol) and 1-ethynyl-4-pentylbenzene (1.65 grams, 9.57 mmol) in triethylamine (50 milliliters) were added dichlorobis(triphenylphosphine)palladium (II) (0.28 gram, 0.4 mmol) and copper(I) iodide (38 milligrams, 0.2 mmol) at 0° C. under argon. The resulting reaction mixture was stirred at 0° C. for 6 hours and at room temperature for 20 hours under argon. After evaporation of the solvent, the product obtained was purified by column chromatography on a silica gel using hexane as eluent. 2,5-Dibromo-3-(4-pentylphenyl)ethynylthiophene was obtained as a colorless liquid was. Yield: 3 grams (73 percent).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][N:7]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)[CH2:3][OH:4].C1([O:25][C:26](=O)[NH:27][C:28]2[N:29]([CH3:36])[N:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)C=CC=CC=1>CS(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:9]2[CH2:10][N:7]([CH2:6][CH2:5][C@H:2]([NH:1][C:26]([NH:27][C:28]3[N:29]([CH3:36])[N:30]=[C:31]([CH:33]4[CH2:34][CH2:35]4)[CH:32]=3)=[O:25])[CH2:3][OH:4])[CH2:8]2)=[CH:17][CH:16]=1
Reactant: Cn1nc(C2CC2)cc1NC(=O)Oc1ccccc1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: CS(C)=O
Product: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.158 g, 0.58 mmol) and (5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (0.150 g, 0.58 mmol) in DMSO (3 ml) is stirred at ambient temperature for 6 hours, then partitioned between water and ethylacetate. The organic phase is washed again with water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 10:90 methanol/dichloromethane) to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea. [M+H] 434.33.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH2:16][C:17]([NH2:19])=[O:18].O>CN(C=O)C>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: NC(=O)CI
Reactant: COC(=O)c1cc(O)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(N)=O)ccc1N
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a suspension of NaH (299 mg, 7.48 mmol) in DMF (20 ml) at 0° under argon atmosphere was added methyl 2-amino-5-hydroxybenzoate (1.25 g, 7.48 mmol) and 2-iodoacetamide (1.38 g, 7.48 mmol). The mixture was stirred at 0° for 1 hr and at r.t overnight. At 0° water was given to the reaction mixture. The product was extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a methylenchloride gradient to obtain the title compound (1.03 g, 64%) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([CH3:21])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:13]2[CH:14]=[C:15]([CH3:21])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Reactant: C=Cc1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/c2cccc(Cl)c2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-methylquinazolin-4-ol (29 mg) in DMF (2 mL) was added 3-chlorostyrene (0.020 mL), followed by palladium acetate (4.0 mg), tri-o-tolylphosphine (9.0 mg) and N,N-diisopropylethylamine (0.20 mL). The resulting mixture was heated at 120° C. for 24 h, then was cooled to room temperature. The supernatant was concentrated in vacuo to a dark semi-solid which was triturated with 50% (v/v) methanol/dichloromethane (4 mL) and diethyl ether (ca. 0.1 mL) to afford the title compound as a tan solid (20 mg). 1H NMR (300 MHz, DMSO-d6): δ11.0 (s, 1H), 9.06 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, J=16.7 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.69 (dd, J=1,8, 1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.59 (dd, J=8.0, 1.8 Hz, 1H), 7.43 (dd, J=8.9, 8.0 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 7.37 (d, J=16.7 Hz, 1H), 7.35 (m, 1H), 2.43 (s, 3H). HPLC (Method B) 11.7 min. MS (APCI+): m/z 456, 458.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[N:10]1([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C:35](=[O:45])[C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([OH:44])[CH:37]=5)[CH2:29][CH2:28]4)[CH:24]=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:10]1([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[C:25]([N:27]4[CH2:28][CH2:29][CH:30]([CH2:33][NH:34][C:35](=[O:45])[C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH2:6][C:5]6[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=6)[CH:37]=5)[CH2:31][CH2:32]4)[CH:24]=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: COc1cc(O)cc(C(=O)NCC2CCN(c3ccnc(-c4cccc(-n5cccn5)c4)n3)CC2)c1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccc(F)cc2)cc(C(=O)NCC2CCN(c3ccnc(-c4cccc(-n5cccn5)c4)n3)CC2)c1
Temperature: 40 °C
Yield: 65.2 %

Procedure:
4-Fluorobenzyl chloride (15 μl, 0.12 mmol) was added to a solution of N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-hydroxy-5-methoxybenzamide (Example 13, 55 mg, 0.11 mmol) and cesium carbonate (80 mg, 0.24 mmol) in DMF (1 ml). The reaction mixture was heated to 40° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics were filtered through a hydrophobic frit and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography, eluting with iso-hexane and increasing amounts of ethyl acetate to give the title compound N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-(4-fluorobenzoxy)-5-methoxybenzamide as a white solid (42.5 mg). 1H NMR (CDCl3): δ 8.64 (1H, t, J=1.88 Hz), 8.34-8.29 (2H, m), 8.06 (1H, d, J=2.48 Hz), 7.86 (1H, ddd, J=8.02, 2.33, 1.07 Hz), 7.74 (1H, d, J=1.74 Hz), 7.54 (1H, t, J=7.90 Hz), 7.43-7.37 (2H, m), 7.11-7.05 (2H, m), 6.96 (1H, t, J=1.75 Hz), 6.91 (1H, t, J=1.74 Hz), 6.65 (1H, t, J=2.25 Hz), 6.49-6.44 (2H, m), 6.21 (1H, t, J=6.08 Hz), 5.04 (2H, s), 4.60 (2H, s), 3.82 (3H, s), 3.39 (2H, t, J=6.43 Hz), 3.01-2.92 (2H, m), 2.04-1.88 (3H, m), 1.33 (2H, qd, J=12.28, 4.12 Hz).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:34])(=[O:33])[N:19]=3)=[C:14]([OH:35])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:36][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:39].[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([N:28]([CH3:40])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:33])(=[O:34])[N:19]=3)=[C:14]([OH:35])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:36][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:39]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(N(C)S(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
N-{3-[(1R,2S,7R,8S)-3-(4-Fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 15, 92 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (44 mg, 0.32 mmol) and iodomethane (0.011 mL, 0.18 mmol) were added sequentially. The reaction was stirred at 25° C. for 18 h. The reaction was quenched via the addition of 1.0 M aqueous hydrochloric acid solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (91 mg, 0.15 mmol, 96%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.18-2.85 (9H, m), 2.90 (3H, s), 2.97 (3H, s), 3.38 (3H, s), 3.45-3.47 (1H, m), 5.17-5.21 (2H, m), 6.96-7.08 (3H, m), 7.72-8.02 (3H, m). LC-MS (ESI) calcd for C27H29FN4O6S2 588.67, found 589.2 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][CH2:15][CH3:16])=O)[CH2:8][CH2:7]1)[CH3:2].[BH4-].[Na+].C(O)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:14][CH2:15][CH3:16])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCNC(=O)[C@H]1CC[C@H](CC(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred suspension of ethyl{trans-4-[(ethylamino)carbonyl]cyclohexyl}acetate (Step A; 740 mg; 3.07 mmol) and sodium borohydride (558 mg; 14.74 mmol) in THF (6 mL) was heated at reflux. Acetic acid (845 mL) was added dropwise over 1 h and the resultant mixture was heated at reflux for 2 h more. The reaction was cooled in an ice bath and carefully quenched with H2O (1.5 mL). 1.5NNaOH (10 mL) was added and the reaction was extracted with EtOAc (3×50 mL). The combined extracts were washed with H2O and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was redissolved in EtOH (4 mL) and 4N HCl(EtOAc) (0.9 mL) was added dropwise. The reaction stirred at room temperature for 14 h. The reaction was diluted with EtOAc (30 mL) and washed successively with 2N NaOH, H2O, and brine (15 mL each). The aqueous layers were re-extracted with EtOAc (2×25 mL) and the extracts were washed with brine (15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford ethyl{trans-4-[(ethylamino)methyl]cyclohexyl}acetate as a yellow oil. LCMS=228.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 4.14 (q, J=7.1 Hz, 2 H), 2.66 (q, J=7.2 Hz, 2 H), 2.47 (d, J=6.9 Hz, 2 H), 2.19 (d, J=6.8 Hz, 2 H), 1.83-1.78 (m, 4 H), 1.59-1.52 (m, 2H), 1.44-1.36 (m, 2 H), 1.27 (t, J=7.1 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H), 1.03-0.97 (m, 2 H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[CH:9]([S:12][CH3:13])[C:8](=[N:14][C:15]2[CH:20]=[CH:19]N=CC=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([N:5]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[C:8]([NH:14][CH2:15][C:20]2[CH:19]=[CH:10][N:5]=[CH:1][CH:2]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSC1C(=O)N(C(C)(C)C)N=CC1=Nc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1c(NCc2ccncc2)cnn(C(C)(C)C)c1=O
Reaction time: 0.33 h

Procedure:
Into 7 ml of an absolute methanol solution of 0.91 g of 2-tert-butyl-4-methylthio-5-(4-pyridylimino)pyridazin-3-(2H)-one, 0.07 g of sodium borohydride was added in a few times under cooling with ice. The mixture was stirred for 20 minutes. Methanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed twice with water and dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to column chromatography. Using an eluent (n-hexane:ethyl acetate=1:9), 0.58 g of the desired product (Compound No. 7) having a melting point of 107° to 110° C. was obtained.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Fc1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
A solution of 4.41 g (18.2 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihyrochloride (Preparation 1), 3.78 g (28.5 mmol) of 2-chloro-5-fluoropyrimidine (B. Baasner, E. Klauke J. Fluroine Chem., 1989, 45, 417-430), and 9.07 g (85.6 mmol) of sodium carbonate in 180 mL of water were heated at 95° C. for 16 h. The mixture was cooled to room temperature, extracted with chloroform (2×), dried (magnesium sulfate), filtered and evaporated. Purification by flash chromatography on silica gel using 95:5 chloroform:methanol gave 5.56 g (81%) of title compound. mp 148-149.5° C. 13C NMR (CDCl3): δ26.8, 29.0, 39.1, 44.2, 49.7, 54.8, 58.7, 60.8, 66.2, 145.0, 145.3, 149.9, 153.2, 158.7. Anal calcd for C13H19FN4O: C, 58.63; H, 7.19; N, 21.04; found: C, 58.36; H, 7.18; N, 20.87.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[CH:20]=[CH:19][C:11]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)=[O:7])(O)=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].CC(C)=O>ClC1C=CC=CC=1Cl>[CH:15]1[C:14]2[C:10]3[CH:9]=[C:8]4[C:20]([C:1](=[O:2])[C:4]5[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=5[C:6]4=[O:7])=[CH:19][C:11]=3[S:12][C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc2sc3ccccc3c2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)c2cc3c(cc21)sc1ccccc13
Temperature: 140 °C
Yield: 16.1 %

Procedure:
To a mixture of 2-(o-carboxybenzoyl)dibenzothiophene (35.6 g, 107 mmol) and phosphorus pentachloride (33.5 g, 161 mmol) in anhydrous 1,2-dichlorobenzene (430 cm3) is added aluminum chloride (21.4 g, 161 mmol). The mixture is then heated at 140° C. for 17 hours. The reaction mixture cooled to 23° C. and the solvent removed under vacuum to give a black solid. Acetone (500 cm3) is added and the mixture filtered to give a green/yellow solid which is dried under vacuum. To the solid is added dichloromethane (1000 cm3) and the mixture heated. The hot mixture is passed through a very short plug of silica (dichloromethane) to give anthra[2,3-b]benzo[d]thiophene-7,12-dione as a yellow solid (5.43 g, 16%). MS m/z 314 (M+). 1H NMR (300 MHz, CDCl3) 9.04 (s, 1H), 8.73 (s, 1H), 8.31-8.41 (m, 3H), 7.86-7.93 (m, 1H), 7.78-7.85 (m, 2H), 7.50-7.61 (m, 2H); 13C NMR (75 MHz, CDCl3) 183.1, 182.8, 145.3, 141.3, 139.9, 134.7, 134.2, 134.1, 133.9, 133.8, 131.1, 129.9, 128.8, 127.4, 125.5, 123.2, 123.1, 122.4, 120.8.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][O:43][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(C)CO
Agent: [Li]CCCC
Product: CC(C)(C)COc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and neopentyl alcohol by the procedure described in Reference Examples 6 and 7 to afford 2-(2,2-dimethylpropyloxy)-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=514 (M++1); Rt4.48 min. 1H-NMR400 MHz (CDCl3): δ 1.20-1.30 (s, 9H), 3.88 (s, 2H), 7.15-7.28 (m, 7H), 7.40-7.43 (m, 1H), 7.58-7.61 (m, 1H), 8.52-8.56 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.[K+].[Br-]>O1CCCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH:6]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(Cl)cc1

Procedure:
The operation is carried out in a fashion similar to that described in Example 2, but starting from 1.12 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate and 1.3 cm3 of para-chlorophenyl isocyanate in 50 cm3 of tetrahydrofuran. After treatment, 1.2 g of tert-butyl (2RS,5SR)-1-{2-[3-(4-chlorophenyl)ureido]acetyl}-5-phenylprolinate are obtained in the form of an amorphous solid [proton NMR (250 MHz, DMSO D6, δ in ppm), 1.50 (s, 9H, (CH3)3); 1.85 (m, 2H, CH2); 2.2 and 2.4 (2m, 2H, CH2); 3.25 and 3.85 (ABX, 2H, CH2N); 4.30 (dd, 1H, CHN); 5.20 (dd, 1H, CHN); 6.3 (t, 1H exchangeable, NH); 7.2 to 7.6 (m, 9H, aromatic); 9 (s, 1H exchangeable, NH)], [infrared spectrum (KBr), characteristic bands in cm-1 3370, 3065, 3030, 2980, 2930, 287, 1735, 1595, 1490, 1450, 1545, 1365, 1150, 830, 760, 700].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].[CH3:25][NH2:26]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:19])([CH2:20][NH:26][CH3:25])[C:21]([F:24])([F:22])[F:23])=[O:15]
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Temperature: 21 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (750 mg, 2.18 mmol) in anhydrous tetrahydrofuran (10 ml) was added methylamine (2M in tetrahydrofuran, 4 ml, 8 mmol) and stirred at 21° C. for 15 hours. It was evaporated to give a foam which was triturated with diethyl ether (ca. 5 ml). The resulting solid was filtered off and washed with a little diethyl ether and then petroleum ether)(40-60° to give the title compound (465 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[C:13]([NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Product: COC(=O)c1ccnc(NC(=O)C(C)(C)C)c1

Procedure:
The title compound is prepared in quantitative yield (1.25 g, colorless syrup) from methyl 2-aminoisonicotinate hydrochloride (1.00 g, 5.30 mmol) and pivaloyl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:7]=[CH:6][C:5](=[O:8])[O:4]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:18]([O:1][CH2:2][C@@H:3]1[CH:7]=[CH:6][C:5](=[O:8])[O:4]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1C=C[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 2.25 g of (25)-2-(hydroxymethyl)-2H-furan-5-one (compound 40b, 2.11 g, 16.0 mmol) and imidazole (1.63 g, 24.0 mmol) in DCM was added tert-butyl(chloro)diphenylsilane (5.2 mL, 20.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was washed with brine. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1N hydrochloric acid, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 4.6 g of (25)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-2H-furan-5-one (compound 40c) as a white solid. MS obsd. (ESI+) [(M+H)+]: 353.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)cc1N1CCCCC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (3.0 g), piperidine (2.93 ml) and potassium carbonate (5.11 g) in N,N-dimethylformamide (30 ml) was stirred at 100° C. for 12 hours. The mixture was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 4-bromo-2-(1-piperidinyl)benzaldehyde (3.5 g).