Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O.[CH3:12][N:13](C)C=O>Cl>[C:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: N#Cc1ccc(C=O)c(F)c1
Temperature: 150 °C

Procedure:
A stirred mixture of 4-bromo-2-fluorobenzaldehyde (39 g, 192 mmol) and cuprous cyanide (18.9 g, 211 mmol) in dimethylformamide (100 ml) was heated to 150° C. for 12 hours under nitrogen atmosphere. The dark solution was cooled and a solution of ferric chloride (34 g, 211 mmol) in hydrochloric acid (2M, 100 ml) was added, followed by water (100 ml). Solid crystallised from the mixture and was filtered, washed with water and dried at 40° C. in vacuo. Recrystallisation from cyclohexane (500 ml) gave 4-cyano-2-fluorobenzaldehyde (m.p. 79° C.) as yellow needles.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@@:12]1([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C@H:14]([CH3:15])[O:13]1.C([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][CH2:27]1)(=O)C>CO.C(O)C>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]([OH:13])([C@H:14]([S:25][C@@H:26]1[CH2:27][O:28][C@@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][CH2:31]1)[CH3:15])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CC(=O)S[C@H]1CO[C@H](c2ccccc2)OC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1cccc(F)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1cccc(F)c1F

Procedure:
0.29 ml (1.4 mmol) of a 4.9 M solution of sodium methoxide in methanol were added to a solution of 1.77 g (7.1 mmol) of (2R,3S)-2-(2,3-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Step 7(iv) above] and 2.20 g (9.2 mmol) of trans-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 20 ml of ethanol. The resulting mixture was then heated under reflux for 7 hours. After cooling the reaction mixture, it was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to afford 3.65 g of the crude title compound. An aliquot (0.28 g) of the crude residue was purified by chromatography on a silica gel (15 g) column using a 2:5 mixture of ethyl acetate and hexane as eluent to afford 0.21 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8])[NH:5][CH:6]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[NH:9][CH2:10][CH:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]2[CH:6]=1
Reactant: CCOC(=O)/C=C/CNC(=O)c1cc(Br)c[nH]1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC1CNC(=O)c2cc(Br)cn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(E)-Ethyl 4-(4-bromo-1H-pyrrole-2-carboxamido)but-2-enoate (2.35 g, 7.80 mmol) was treated with ACN (30 mL) and DBU (0.27 mL, 1.80 mmol) and stirred at RT for 2 h. The mixture was then concentrated in vacuo. Chromatographic purification of the residue (silica gel, 30-50% EtOAc in hexanes) afforded ethyl 2-(7-bromo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (1.24 g, 4.12 mmol, 52.8% yield) as a colorless viscous oil which crystallized to a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 6.93 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.8 Hz), 5.87 (1H, br. s.), 4.65 (1H, tt, J=6.8, 3.4 Hz), 4.11-4.24 (2H, m), 3.92 (1H, dd, J=12.8, 4.0 Hz), 3.46-3.54 (1H, m), 2.74-2.90 (2H, m), 1.26 (3H, t, J=7.1 Hz). m/z (ESI, +ve ion) 301.0/303.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]=[CH:10][C:11]([CH3:20])=[CH:12][CH:13]=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[CH3:22][C:23]1([CH3:52])[CH2:28][O:27][CH:26]([C:29]([CH3:51])=[CH:30][CH2:31][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:25][CH2:24]1.[O-]CC.[Na+]>ClCCl.[Cl-].[Na+].O>[CH3:22][C:23]1([CH3:52])[CH2:24][O:25][CH:26]([C:29]([CH3:51])=[CH:30][CH:31]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=[CH:9][CH:8]=[C:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:27][CH2:28]1
Reactant: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=O
Reactant: CC(=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C1OCC(C)(C)CO1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C1OCC(C)(C)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.7 g (50 mmol) of the product from step b) were dissolved in 125 ml of dichloromethane. 25.7 g (55 mmol) of 3-(5,5-dimethyl-1,3-dioxan-2-yl)but-2-enyltriphenylphosphonium chloride were added. At 0° C., 20.4 g of a 20% strength ethanolic solution of sodium ethoxide (60 mmol) were added over the course of 1 hour. The mixture was stirred at 0° C. for 1 hour and then 50 ml of semiconcentrated brine were added. The organic phase was separated off, washed once with 50 ml of semiconcentrated brine, dried over sodium sulfate and concentrated in a rotary evaporator at 20° C. down to 20 mbar. The residue (38.2 g) was purified by flash chromatography on silica gel (eluent: cyclohexane/methyl t-butyl ether 4:1). 19.9 g (93.4% of theory) of the title compound were obtained. For characterization, the product was dissolved by heating in 100 ml of ethyl acetate. 50 ml of diisopropyl ether were added to the hot solution and, after cooling to 0° C., the mixture was stirred for 1 hour. The crystals which formed were filtered off, washed with cold ethyl acetate/diisopropyl ether mixture (2:1 vol./vol.) and dried in a stream of nitrogen. Yield: 8.9 g of red crystals. Melting point 157.5 to 158° C. E11 (CHCl3): 2495 (423 nm), 2243 (448 nm).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H].ClCCl>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, to a solution of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (400 mg, 996 μmol) in ethyl acetate (20 mL) was added Palladium/charcoal activated (10% Pd) (80.0 mg) at room temperature. The atmosphere in the reaction flask was replaced with hydrogen gas and the mixture was stirred at room temperature for 3 hours. After replacing the atmosphere of the reaction system again with argon, to the mixture was added dichloromethane (15 mL) and stirred at room temperature for an hour. The catalyst was removed by filtration. After concentration under reduced pressure, the residue was purified by column chromatography (silica gel 40 g, n-hexane/ethyl acetate=2/1) to give Compound 7r (403 mg, 994 μmol, 99.8%) as a brown oily substance. Rf=0.48 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.93 (s, 9H), 2.92 (t, 3H, J=8.0 Hz), 3.05 (t, 3H, J=8.0 Hz), 6.25 (s, 2H), 6.81-6.90 (AA′BB′, 2H), 7.10-7.18 (m, 1H), 7.18-7.35 (m, 4H), 7.75-7.85 (AA′BB′, 2H), 8.27 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), 18.0, 25.6 (3C), 31.7, 34.0, 120.0 (2C), 125.7, 126.1 (2C), 128.2 (2C), 128.5 (2C), 130.9, 135.6, 138.5, 140.1, 141.9, 152.3, 154.6; IR (KBr, cm−1) 507, 635, 677, 698, 750, 781, 841, 914, 1009, 1103, 1146, 1167, 1213, 1254, 1389, 1420, 1454, 1512, 1605, 2857, 2928, 2955, 3061, 3318.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][N:8]([CH2:7][C:6]([OH:41])=[O:5])[CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1

Procedure:
A solution of {4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-acetic acid tert-butyl ester (250 mg, 0.44 mmol), DCM (5 mL), and TFA (5 mL) is stirred at rt for 1 h. The solution is concentrated in vacuo and separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 512.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.41 (s, 1H), 8.33 (d, J=9.1 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J=3.5 Hz, 1H), 7.89 (s, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.38-7.47 (m, 2H), 7.12 (dd, J=9.0, 2.4 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 4.08 (s, 2H), 3.56 (s, 2H), 3.26 (t, J=6.1 Hz, 2H), 3.07 (t, J=5.7 Hz, 2H).
Reaction SMILES: CC([O-])=O.[K+].Cl[CH2:7][C:8](=[O:24])[CH:9]([N:15]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCO.CCOC(C)=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[CH:7]=[C:8]([OH:24])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:15]1
Reactant: CCOC(=O)C(N=Nc1ccccc1F)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2F)cc1O
Temperature: 25 °C
Yield: 102.9 %

Procedure:
KOAc (1.14 g) was added portionwise to a solution of ethyl 4-chloro-2-(2-fluoro-phenylazo)-3-oxobutanoate (2.75 g) in EtOH (30 mL), and the mixture was refluxed for 1 hour. After being cooled to room temperature, the mixture was diluted with EtOAc and washed with H2O (twice) and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 2.47 g of the title compound. KOAc means potassium acetate.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]([C:3]2[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: O=Cc1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Mg]
Agent: c1cc[nH+]cc1
Product: COc1cc(C(=O)c2ccc(Br)cc2)cc(OC)c1OC

Procedure:
First, magnesium was added to 1-bromo-3,4,5-trimethoxybenzene as a starting material, as shown in Reaction 6, and then 4-bromobenzaldehyde was added thereto to obtain a compound. Thus obtained compound was oxidized using PDC to obtain a Compound 21 derivative [(4-bromophenyl)(3,4,5-trimethoxyphenyl)methanone]. Using thus obtained compound as a starting material aminothiazole was introduced in the same manner as in the synthesis of Compound 516 to obtain Compound 571 in a form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: c1ccncc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole), pyridine (158 mg, 2 mmoles) in dimethylsulfoxide (DMSO) (1 ml) was stirred for 1 hour at room temperature. To the mixture was added ethyl acetate (20 ml) to precipitate a solid (620 mg), which was added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture was stirred for 30 minutes at 40° C. and concentrated to dryness. The residue was dissolved in H2O (40 ml) and some insolubles were removed. The aqueous solution was charged on a column of reverse phase (PrepPAK-500/C18, 100 ml) eluting with H2O (300 ml) and 5% aqueous CH3OH (800 ml), and the eluate was monitored by uv (254 nm) and HPLC. The fractions (5% aqueous CH3OH) containing the desired product were combined, concentrated to a small volume and lyophilized to yield 40 mg (8%) of the title compound (I-1B), melting at >200° C. (dec.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](N3CCOCC3)[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C[OH:50]>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([OH:50])[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: CO
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(CBr)N2CCOCC2)C1SC(=O)OCC1CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidine-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate (300 mg) in a mixture of methanol (22 ml) and methylene chloride (3.5 ml), and the mixture is stirred at room temperature under nitrogen atmosphere after addition of 10% hydrochloric acid (4ml). After 2 hours, the reaction mixture is poured into ice water, and is extracted with chloroform. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl 4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-α-(2-bromo-1-hydroxyethylidene)azetidine-1-acetate (252 mg). Foam. Yield: 92.8%. IR: νmaxCHCl3 3426, 1781, 1710, 1690, 1601 cm-1. NMR: δCDCl3 0.23-1.33m5H, 3.84-4.36m4H, 4.55s2H, 5.10-5.32m3H, 5.88(5Hz)1H, 6.83-8.33m9H, 12.0s1H.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)cc2)n1

Procedure:
Example 26 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27) using DMF as the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.N=CO[CH2:34][NH:35][C:36](=[O:39])[O:37][CH3:38].C(O)(=O)C>ClC(Cl)Cl>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=[C:34]3[NH:35][C:36](=[O:39])[O:37][CH3:38])[CH2:17][CH2:16]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)NCOC=N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 60 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl)carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is stirred in water. The latter is decanted and the residue is taken up again in water. The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding methyl [1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-yl]carbamate; mp. 137.8° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N+]([O-])=O)=[CH:4][C:3]=1[C:21]1[O:22][CH2:23][CH2:24][CH2:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1>CN1CCCC1=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([S:40][C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)=[CH:4][C:3]=1[C:21]1[O:22][CH2:23][CH2:24][CH2:25][N:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Nc1c(C2=NCCCO2)cc([N+](=O)[O-])c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1c(C2=NCCCO2)cc(Sc2ccc(Cl)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 51.4 %

Procedure:
14 g of 1-amino-2-(5,6-dihydro-4H-1,3-oxazin-2-yl)-4-nitroanthraquinone, 5.4 g of potassium carbonate, 100 cc of N-methylpyrrolidone and 5.9 g of 4-chlorothiophenol are reacted as in Example 2. The reaction mixture is worked up as described in that example to give 9.2 g of 1-amino-2-(5,6-dihydro-4H-1,3-oxazin-2-yl)-4-(4-chlorophenylmercapto)-anthraquinone, corresponding to a yield of 51% of theory.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].CI.[C:15]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:15][O:12][C:3]1[C:2]([I:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(O)c1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OC)c1I

Procedure:
Methylation of the phenolic --OH group in (12) with MeI-K2CO3 in refluxing acetone proceed smoothly to give 2,4-dimethoxy-3-iodobenzaldehyde (13), m.p. 103.3° C. [1H-NMR: (90 MHz, CDCl3, δ): 3.90 (overlapping s, 2×3H, C2 and C4-OCH3), 6.62 and 7.78 (pair of doublets. Jab=8Hz, C5-H and C6-H), 10.12 (s, 1H, HC=O).]
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 148D (0.108 g, 0.17 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[N:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([F:13])[CH:15]=1)[N:8]=[CH:7]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1ccc(F)c2[nH]ncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)c2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Yield: 25.9 %

Procedure:
7-Fluoro-4-(methyloxy)-1H-indazole (D26) (500 mg, 3.01 mmol), the {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (1.48 g, 6.02 mmol), copper (II) acetate (820 mg, 4.51 mmol), powdered molecular sieves (550 mg) and pyridine (0.49 mL, 6.02 mmol) in DCM (15 mL) were stirred at room temperature in the presence of air. After 4 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM (3×) and the combined organics were washed with brine and dried over MgSO4. The crude (1.71 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc (0 to 20%) in hexane to afford 286 mg of title compound (D27).
Reaction SMILES: [CH:1]1([C:4]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])([CH3:11])[CH2:5][C:6](OCC)=[O:7])[CH2:3][CH2:2]1.CO.[NH3:21]>>[C:15]([S:13]([NH:12][C:4]([CH:1]1[CH2:3][CH2:2]1)([CH3:11])[CH2:5][C:6]([NH2:21])=[O:7])=[O:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: N
Reactant: CCOC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Solvent: CO
Product: CC(CC(N)=O)(NS(=O)C(C)(C)C)C1CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of ethyl 3-cyclopropyl-3-(1,1-dimethylethylsulfinamido)butanoate (1.16 g, 4.21 mmol) in ammonia 7N in methanol (20 ml, 140 mmol) in a microwave sealed tube was stirred at 45° C. overnight. The volatiles were removed in vacuo and the residue was directly purified by flash chromatography on silica eluting with a gradient of dichloromethane/methanol to yield the title compound (155 mg, 15%); MS (ESI, m/z): 247.2 (M+H+).