Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C2NC=C(C(OCC)=O)C=2)=CC=1.FC1C=CC(S(Cl)(=O)=O)=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:40]2[C:44]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[CH:43][C:42]([C:53](OCC)=[O:54])=[CH:41]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([N:40]2[C:44]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[CH:43][C:42]([CH:53]=[O:54])=[CH:41]2)(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Agent: CCOC(=O)c1c[nH]c(-c2ccc(OC)cc2)c1
Agent: O=S(=O)(Cl)c1ccc(F)cc1
Product: COc1ccc(-c2cc(C=O)cn2S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
Using ethyl 5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate and 4-fluorobenzenesulfonyl chloride, a procedure as in Reference Example 4 was performed to synthesize ethyl 1-[(4-fluorophenyl)sulfonyl]-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate, and procedures as in Reference Examples 5 and 6 were sequentially performed to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@H:15]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:15]2[O:16][C@H:17]([CH2:20][OH:21])[C@@H:18]([OH:19])[C@H:14]2[F:13])=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1nc(N)nc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
2-Amino-6-methoxypurine (0.8 g, 4.8 mmoles) which may be prepared according to R. W. Balsiger and J. A. Montgomery (J. Org. Chem. 20:1573, 1960) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (2,400 I.U.) and purine nucleoside phosphorylase (3,900 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 6, the reaction was diluted to 100 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 10, the reaction was diluted to 200 ml with 5 mm potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 16, 2,640 I.U. of thymidine phosphorylase and 4,360 I.U. of purine nucleoside phosphorylase were added. On day 24, the reaction was filtered and the filtrate was evaporated. The residue was suspended in methanol. The suspension was filtered and the filtrate evaporated. The residue was dissolved in water and applied to a 2.5×7 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing the column with water, the product was eluted with methanol/water (9/1). After the solvent was removed under vacuum, the residue was dissolved in water and lyophilized to obtain title compound which analyzed as a 0.5 hydrate.
Reaction SMILES: [CH2:1]=[O:2].[Cl-].[Mg+2].[Cl-].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[OH:14].Cl>C(#N)C.C(N(CC)CC)C>[Cl:6][C:7]1[C:8]([OH:14])=[C:9]([C:10]([CH3:13])=[CH:11][CH:12]=1)[CH:1]=[O:2]
Reactant: C=O
Reactant: Cc1ccc(Cl)c(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)c(O)c1C=O
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Paraformaldehyde (4.73 g, 163 mmol), magnesium chloride (7.76 g, 81.7 mmol) and triethylamine (14.2 ml, 102 mmol were added to a solution of 2-chloro-5-methylphenol (5.80 g, 40.8 mmol) in acetonitrile (100 ml) and the mixture was vigorously stirred at 90° C. for 10 hours. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. After the organic layer was successively washed with 1N hydrochloric acid, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane/ethyl acetate=3/1) to give crude 3-chloro-2-hydroxy-6-methylbenzaldehyde. According to a method similar to Example (28-3) and Example (28-4), from the crude compound obtained in the above, tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-chloro-6-methylbenzoate was obtained (1.82 g, three-step total yield: 13%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:22]([C:8]1[CH:9]=[C:10]([S:13]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:15])=[O:14])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:24]=[CH:25][C:2]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:40][NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])[CH:46]=2)=[CH:3][C:4]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)NCc1cccc(B(O)O)c1
Reactant: Cn1nccc1-c1cc(Br)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Temperature: 120 °C
Yield: 60.9 %

Procedure:
In a 5 mL microwave vial 4-[4-bromo-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzene sulfonamide (Patent WO 2010079443, 500 mg, 0.97 mmol) was dissolved in 1,4-dioxane (3 mL) under nitrogen. (3-{[(Tert-butoxycarbonyl)amino]methyl}phenyl)boronic acid (362 mg, 1.44 mmol), bis(triphenylphosphine) palladium (II) dichloride (68 mg, 0.1 mmol), sodium carbonate (204 mg, 1.92 mmol) and water (0.5 mL) were added and the reaction vessel sealed and heated to 120° C. for 45 minutes in the microwave. The reaction mixture was partitioned between ethyl acetate (20 mL) and 0.2M aqueous HCl (20 mL). The organic layer was separated, filtered then concentrated in vacuo. The residue was purified by silica gel column chromatography (ISCO™, 12 g silica, 99:1 DCM:Acetic acid to 90:10:1 DCM:MeOH:Acetic acid gradient) to afford the title compound (380 mg, 61%) as a pale orange solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:24][CH:25]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Product: CS(=O)(=O)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 54.5 %

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.120 g) and methanesulfonyl chloride (0.030 ml) were treated as in Example 36 to give the title compound (0.078 g) as a pale yel low oil (yield: 54.5%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH3:29])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH3:29])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:12][N:13]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (300 mg) and ethyl 4-bromobutyrate (85%1) are dissolved in N,N-dimethylformamide (1 ml) and thereto is added potassium carbonate (82 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3% 17:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (296 mg). MS (m/z): 721 [M+H]+
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:46](=[O:47])[C@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[NH:44][C:42](=[O:43])[O:41][CH3:40]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
A solution of the product of Example 1H (0.18 g, 0.33 mmol) in THF (3.3 mL) was treated with the product of Example 1F (0.11 g, 0.60 mmol), DEPBT (0.15 g, 0.50 mmol), and N,N-diisopropylethylamine (0.29 mL, 1.66 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0%-75% ethyl acetate in chloroform to give the title product (0.19 g, 81% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.75 (s, 9 H), 0.78 (s, 9 H), 1.28 (m, 2 H), 1.55 (m, 1 H), 2.70 (m, 4 H), 3.55 (d, J=11.77 Hz, 6 H), 3.85 (m, 3 H), 4.15 (m, 1 H), 4.80 (d, J=5.15 Hz, 1 H), 6.75 (d, J=9.19 Hz, 1 H), 6.86 (d, J=9.56 Hz, 1 H), 7.13 (m, 5 H), 7.22 (d, J=8.46 Hz, 2 H), 7.32 (m, 1 H), 7.52 (d, *8.82 Hz, 1 H), 7.88 (m, 5 H), 8.64 (d, j=4.41 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)#[N:8].[Cl:25][C:26]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)=[CH:30][N:29]=[C:28]([N:39]2[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]2)[N:27]=1.Cl>O.COCCOC.CO.O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:25].[CH3:45][C@H:43]1[O:42][C@@H:41]([CH3:46])[CH2:40][N:39]([C:28]2[N:29]=[C:30]([C:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=3[C:7]#[N:8])[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=3)=[CH:26][N:27]=2)[CH2:44]1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Reactant: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2Cl)ccn1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2-c2cc(F)ccc2C#N)ccn1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
Sodium carbonate (166 mg, 1.568 mmol) in water (2 mL), bis(triphenylphosphine) palladium(II) chloride (11.01 mg, 0.016 mmol) and 2-cyano-5-fluorophenylboronic acid pinacol ester (155 mg, 0.627 mmol) were added to a solution of cis-4-[4-chloro-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]-2,6-dimethylmorpholine (100 mg, 0.314 mmol) in 1,2-dimethoxyethane (3 mL). The reaction mixture was heated to 100° C. for 2 hour. The reaction mixture diluted with water (5 mL) and extracted with DCM (5 mL×2). The organic extracts were combined, dried (MgSO4), filtered and the solvent was removed. The resulting residues were then purified by MDAP and fractions containing desired product were combined and evaporated to give a solid. The solid was then dissolved in methanol (2 mL) and 4M HCl in dioxane (1 mL) was added. The solvent was removed to give the title compound (50 mg). LC/MS [M+H]+=404. 1H NMR (400 MHz, d6-DMSO): δ 8.82 (1H, s), 8.56 (1H, d), 8.10-8.05 (1H, m), 7.77-7.79 (1H, m), 7.56-7.62 (1H, m), 7.45-7.39 (2H, m), 4.70-4.66 (1H, m), 3.63-3.57 (2H, m), 2.76-2.68 (2H, m), 2.64 (3H, s), 1.18 (6H, d).
Reaction SMILES: [C:1]([O:5][SiH:6]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:17]([Si:19]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])[O:20][CH:21]([CH3:23])[CH3:22])=[CH2:18]>C1(C)C(C)=CC=CC=1>[C:8]([O:7][Si:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=[CH:17][Si:19]([O:20][CH:21]([CH3:23])[CH3:22])([O:24][CH:25]([CH3:27])[CH3:26])[O:28][CH:29]([CH3:31])[CH3:30])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O[SiH](OC(C)(C)C)OC(C)(C)C
Reactant: C=C[Si](OC(C)C)(OC(C)C)OC(C)C
Solvent: Cc1ccccc1C
Product: CC(C)O[Si](C=C[Si](OC(C)(C)C)(OC(C)(C)C)OC(C)(C)C)(OC(C)C)OC(C)C
Temperature: 225 °C

Procedure:
Into a 45 cc Parr bomb was added 2.5 g (0.010 mol) tritertbutoxysilane, 4.7 g (0.020 mol) vinyltriisopropoxysilane, 1.0 g xylene and 2000 ppm Ru3CO12 (29 mg) as a catalyst. The reaction was heated to 225° C. for 3 hours in a fluidized sand bath. A single product, 1-tritertbutoxysilyl-2-triisopropoxysilylethylene was formed.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:24]1[NH:27][C:26](=[O:28])[CH2:25]1)(=O)C.[Cl:29][CH2:30][C:31](=[O:42])[C:32](=[N+:40]=[N-:41])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCl>[C:36]([O:35][C:33]([C:32](=[N+:40]=[N-:41])[C:31](=[O:42])[CH:30]([CH:24]1[NH:27][C:26](=[O:28])[CH2:25]1)[Cl:29])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CCl
Reactant: CC(=O)OC1CC(=O)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)C(Cl)C1CC(=O)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
1.8 ml (13.0 mmol - 2.6 equivalents) of triethylamine and then 2.3 ml (12.0 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate were added to a solution, which had been cooled to 0° C., of 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.42 g (6.5 mmol) of tert.-butyl 4-chloro-2-diazo-3-oxobutanoate in 45 ml of anhydrous dichloromethane. The cooling bath was removed and the mixture was stirred at room temperature for 5 h, then 0.3 ml (1.5 mmol - 0.3 equivalent) of trimethylsilyl trifluoromethanesulphonate was added and the mixture was stirred at room temperature for 1 h. To work up, it was poured into a mixture of cold saturated NaHCO3 solution and ethyl acetate, extraction with ethyl acetate was carried out, and the organic extracts were washed with saturated NaCl solution and dried over MgSO4. After evaporation of the solvent in vacuo and chromatography on 40 g of silica gel (toluene:ethyl acetate 1:1), 426 mg (30%) of the title compound were obtained as a mixture of diastereomers (10:1), Rf: 0.35 (toluene:ethyl acetate 1:1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(C(=O)Cl)cc2)cn1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
The 4-(4-methylimidazol-1-yl)benzoyl chloride (0.99 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.64 g) and diisopropylethylamine (0.60 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of hydrous sodium magnesium silicate, and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.52 g) was obtained as a solid, m.p. 140-145° C.; MS, m/z: 369 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8]2.[NH2:17][NH2:18]>CO>[Cl:15][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:4][C:3]([NH:17][NH2:18])=[O:2])[CH:6]=2)[N:11]=1
Reactant: NN
Reactant: COC(=O)Cc1ccc2nc(Cl)ccc2c1
Solvent: CO
Product: NNC(=O)Cc1ccc2nc(Cl)ccc2c1

Procedure:
(2-Chloro-quinolin-6-yl)-acetic acid methyl ester (0.160 g, 0.679 mmol), hydrazine (0.218 g, 6.79 mmol) and methanol (3 mL) were stirred at room temperature. The reaction was evaporated to give (2-chloro-quinolin-6-yl)-acetic acid hydrazide. This compound was not purified and was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (m, 1H), 8.43 (d, 1H, J=9.2 Hz), 7.91 (m, 2H), 7.75 (m, 1H), 7.58 (m, 1H), 4.30 (bs, 2H), 3.57 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[C:23](=[O:25])=[O:24]>C1COCC1.CCOCC.CCOC(C)=O>[OH:11][C:9]([CH3:12])([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=1
Reactant: O=C=O
Reactant: CC(C)(O)Cc1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
1-(4-bromophenyl)-2-methyl-propan-2-ol (2.77 g, 12.1 mmol) was dissolved in dry THF (30 mL) and the solution was cooled to −78° C. Tert-butyllithium in pentane (15 mL of 1.7 M, 25.4 mmol) was added dropwise over 10 minutes and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was added via cannula to crushed solid CO2 (53.2 g, 1.21 mol) in Et2O under a flow of nitrogen gas. The reaction mixture was allowed to warm to room temperature, diluted with EtOAc and washed with water. The aqueous phase was acidified (pH 2) with 1N HCl solution and the aqueous layer was extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(2-hydroxy-2-methyl-propyl)benzoic acid (620 mg, 26%) as a white solid. ESI-MS m/z calc. 194.0. found 195.3 (M+1)+; Retention time: 0.93 minutes (3 min run).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:5]([CH3:13])([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:23])=[O:3])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Sc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C)(Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated, diluted with 1:1 hexane:diethyl ether and extracted with H2O. The water layer was cooled with ice and acidified to pH 3. The acid was then extracted with chloroform and the organic layer was dried over MgSO4, filtered and concentrated to afford of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid. Yield 580 mg, 16%; MS: 303.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13]>C1COCC1.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of 5.82 g (30 mmol) of 2,4-dichloro-5-nitropyrimidine (N. Whittaker, J. Chem. Soc., 1951:1565–1570) in 100 mL THF at −78° C. is added dropwise over 5 minutes a solution of 3.87 g (60 mmol) of 70% aqueous ethylamine in 20 mL of 2-propanol. After being stirred at −78° C. for 15 minutes, the reaction mixture is allowed to warm to room temperature, and the solvent is removed under vacuum. The residue is worked up in EtOAc and chromatographed on silica, eluting with hexane/EtOAc (92:8), to give 4.90 g (81%) of the title compound: mp (hexane) 64–66° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:25][N:24]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:43]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:43])[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=4)=[CH:25][N:24]=3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.