Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH2:28][CH2:27][CH2:26][CH:25](Br)[C:24]=1O)=[O:22])[CH3:19]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:18]([O:20][C:21]([CH:23]1[C:24]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]=2[CH2:26][CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: c1ccc(COCCNc2ccccc2)cc1
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of (2-benzyloxy-ethyl)-phenyl-amine (21; prepared according to Example 3(c)) (8.0 g, 26 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4; prepared according to Example 1(d)) (3.2 g, 13 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (30 mL) and dry zinc chloride (10.6 g, 78 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 2 N HCl (100 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (2.5-40% B, 17 CV, 330 g, 100 mL/min) to give 3.49 g (72%) of 9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (25) as an oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 14.2, 20.5, 21.8, 26.5, 38.6, 42.9, 60.4, 68.7, 73.2, 106.4, 108.8, 118.7, 120.7, 127.4, 127.5, 128.3, 136.2, 136.9, 137.8, 175.0.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13](=[O:38])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>C(#N)C.O>[C:26]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:23]([O:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C:13]([CH2:12][NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:39])=[O:2])=[CH:10][CH:9]=2)=[O:38])[CH2:21][CH2:20]1)=[O:37]
Reactant: COC(=O)Cc1ccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)Cc1ccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Yield: 86.1 %

Procedure:
A stirred solution of [4-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionyl}methylamino)phenyl]acetic acid methyl ester (8.00 g, 15.1 mmol) and lithium hydroxide (1.81 g, 75.5 mmol) in acetonitrile (20.0 mL) and water (20.0 mL) was heated at 60° C. for 3 h. The pH of the reaction mixture was adjusted to pH 5 with aqueous hydrochloric acid (1 M) and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM) to give the title compound (6.7 g, 86% yield) as an off-white solid.
Reaction SMILES: [CH3:1][C@@:2]1([C:5](=[O:38])[C@@H:6]([NH:14][C:15](=[O:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][O:3]1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:28][C@@H:26]([CH3:27])[C:25]([NH:24][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:15]([NH:14][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([C@:2]1([CH3:1])[CH2:4][O:3]1)=[O:38])=[O:37])=[O:36]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@]1(C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@]1(C)CO1
Reaction time: 2 h

Procedure:
To tert-butyl ((S)-1-(((S)-1-(((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxo-3-(pyridin-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (315 mg, 0.600 mmol) was added DCM (4 mL) followed by TFA (2 mL). The reaction mixture was allowed to stand for 2 h at which time it was concentrated to provide (S)-2-((S)-2-aminopropanamido)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-3-(pyridin-2-yl)propanamide TFA salt as a yellow oil that was carried forward without further purification. MS (EI) for C25H28F3N4O5, found 425.3 [M-TFA]+.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[C:18]([F:29])[CH:17]=2)[CH2:11]1>C1COCC1>[F:29][C:18]1[CH:17]=[C:16]([N:12]2[CH2:11][C@H:10]([CH2:9][NH:8][C:6]([NH2:5])=[O:7])[O:14][C:13]2=[O:15])[CH:21]=[CH:20][C:19]=1[C:22]1[S:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: NC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Trimethylsilyl isocyanate (0.138 ml, 1.02 mmol) is added to a mixture of 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4] thiadiazin-5-one (0.30 g, 0.925 mmol) in THF (10 ml). The mixture is stirred at room temperature overnight and then is evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.22 g, 65%); 1HNMR (300 MHz, DMSO-d6) δ 3.29-3.36 (m, 2H), 3.59 (s, 2H), 3.78 (dd, J=6.3, 9.1 Hz, 1H), 4.13 (t, J=9.1 Hz, 1H), 4.69-4.77 (m, 1H), 5.58 (s, 1H), 6.31 (t, J=6.0 Hz, 1H), 7.42 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=2.2, 14 Hz, 1H), 7.68 (t, J=8.8 Hz, 1H), 11.6 (s, 1H); mp 235-6; MS (m/z): [M+H]+=368.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.CO.[CH2:21](Cl)Cl>CS(C)=O>[F:18][C:4]([F:17])([F:3])[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]2[CH2:21][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reaction time: 0.05 h
Yield: 10 %

Procedure:
To a vigorously stirring mixture of NaH (31.0 mg, 1. 16 mmol) in DMSO (5 mL) at ambient temperature under an argon (g) atmosphere was added (CH3)3S(I)O (248 mg, 1. 12 mmol) in small portions over ca. 1 min. Following complete addition, the reaction was stirred for 20 min. A DMSO (1 mL) solution of 26A (200 mg, 0.870 mmol) was added dropwise over ca. 1 min. The reaction was left to stir for 5 h then quenched with H2O (25 mL) and extracted into EtOAc (3×30 mL). The combined organics were washed with H2O (1×15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (SiO2—12 g; gradient elution: 0.25% MeOH/DCM for 3 min then 0.25-4% MeOH/DCM over 14 min at 25 mL/min) to afford 22.0 mg 26B (10% yield). m/z (ES+) M+1=246.1; HPLC tR=1.09 min. 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.55-7.46 (m, 1H), 3.75 (s, 3H), 2.60 (ddd, J=9.6, 6.1, 4.1 Hz, 1H), 2.00 (ddd, J=8.6, 5.6, 4.1 Hz, 1H), 1.73 (dt, J=9.2, 5.1 Hz, 1H), 1.38 (ddd, J=8.6, 6.4, 5.1 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:11]1([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(NN2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccc(NN2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
A mixture of (4-benzylpiperazin-1-yl)-(4-trifluoromethylphenyl)amine prepared in Reference Example 108 and 10% palladium/carbon (0.53 g) in ethanol (50 ml) was stirred at room temperature under an atmospheric pressure of hydrogen for 6 hours, and then at 60° C. for 10 hours. After the catalyst was removed by filtration through Celite, 10% palladium/carbon (0.53 g) was added to the filtrate, and the mixture was stirred at 60° C. under an atmospheric pressure of hydrogen for 8 hours. After the catalyst was removed by filtration through Celite, the filtrate was concentrated under reduced pressure. The resulting solid was dried in vacuo to afford piperazin-1-yl-(4-trifluoromethylphenyl)amine (1.76 g, yield 90%) as a colorless crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:24](=[O:25])[C:23]5[CH:27]=[CH:28][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=5)=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1ccc(-n2ccc3cc(N)ccc32)cc1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-n3ccc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc43)cc2)cc1

Procedure:
Compound 370 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C32H31N5O2: 518.25; found: 517.95.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[N:12]([OH:24])[C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([Br:23])[CH:14]=2.N.CO>C(#N)C>[NH2:5][C:3]([NH:10][C:11]1[N:12]([OH:24])[C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([Br:23])[CH:14]=2)=[O:4]
Reactant: NC(=O)c1c(N)n(O)c2cc(Br)ccc12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: CC#N
Product: NC(=O)Nc1c(C(N)=O)c2ccc(Br)cc2n1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.5 %

Procedure:
Trichloroacetyl isocyanate (0.10 mL, 0.85 mmol) was added to a solution of 2-amino-6-bromo-1-hydroxyindole-3-carboxamide (Reference compound 2-1, 180 mg, 0.71 mmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 5 hours. 2.0 M Ammonia in methanol solution (4.5 mL, 9.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, 1 N hydrochloric acid (6 mL) and water (25 mL) was added to the residue and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (10 mL), and dried under reduced pressure to give the title compound (90 mg) as a slightly brown solid (yield 42%).
Reaction SMILES: C1(OC([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]#[N:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=O)C=CC=CC=1.[OH-:30].[Na+]>S(=O)(=O)(O)O>[C:16]1([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:12]2[CH2:13][CH2:14][NH:10][CH2:11]2)[C:28]([NH2:29])=[O:30])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(C(=O)Oc2ccccc2)C1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Yield: 65 %

Procedure:
A solution of 3.0 g (0.008 mole) of 3-(cyanodiphenylmethyl)-1-pyrrolidinecarboxylic acid phenyl ester in 100 ml of 90% sulfuric acid was stirred at 70° C. for 20 hr. The reaction mixture was cooled, poured over ice and basified by adding, alternately, 50% sodium hydroxide and ice. The mixture was extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized in ethyl acetate. Recrystallization from ethyl acetate-ethanol gave 1.4 g (65%) of title product, molecular ion at 281 by mass spectrometer analysis.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=O)[CH3:18])[N:12]=1)(=O)[CH3:9].C(O)(=O)C>CCO>[CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][N:5]=[C:8]([C:11]1[N:12]=[C:13]([C:17](=[N:5][NH:4][C:3]([N:2]([CH3:7])[CH3:1])=[S:6])[CH3:18])[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: CN(C)C(=S)NN
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=S)N(C)C)c1cccc(C(C)=NNC(=S)N(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 4,4-dimethylthiosemicarbazide (2.70 g, 0.022 mol) and 2,6-diacetylpyridine (1.63 g, 0.10 mol) in 95% EtOH (45 ml) containing glacial acetic acid (0.5 ml) was heated by a steam bath for 1 h and 10 min and allowed to cool to ambient temperature. The yellow precipitate was collected by filtration, washed with 95% EtOH, and subsequently recrystallized from toluene: yield 2.72 g (73%); mp 215° (dec).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.Br[CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH2:29]([O:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Reactant: CC(C)CBr
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCC(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) was coupled under the ester J with 1-bromo-2-methylpropane to afford the title compound. 1H-NMR (CDCl3, 200.15 MHz): δ 7.14 (d, 2H, J=8.6), 6.86–6.82 (m, 6H), 4.11 (q, 4H, J=6.2), 3.98 (dd, 1H, J=7.3, 4.6), 3.66 (d, 2H, J=6.5), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H, J=14.5, 7.3), 2.21 (qn, 2H, J=6.2), 2.11–1.98 (m, 1H), 1.01 (d, 6H, J=6.7).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:18]#[N:19]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1cc(Cl)c(I)c([N+](=O)[O-])c1O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1O
Temperature: 110 °C

Procedure:
A mixture of methyl 5-chloro-2-hydroxy-4-iodo-3-nitrobenzoate (5.00 g, 14.0 mmol) and copper cyanide (1.9 g, 21 mmol) in N,N-dimethylformamide (25 mL) was heated at 110° C. for 2 hours. After cooling to room temperature, the mixture was quenched with 1 N HCl and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was used directly in the next step (3.6 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17]([C:19]1[O:20][C:21]([CH2:24]Cl)=[CH:22][CH:23]=1)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:21]3[O:20][C:19]([C:17]([OH:18])=[O:16])=[CH:23][CH:22]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(O)c1ccc(COc2ccc(-c3ccc(Cl)cc3)cc2)o1

Procedure:
5-(4′-Chloro-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4-chloro-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 72 mg. Mass spectrum (ES) MH+=329.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][N:13]=1)[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1
Yield: 86.2 %

Procedure:
Compound II (22 mg, 0.046 mmol), Pd(PPh3)4 (1.6 mg, 0.0014 mmol), phenylboronic acid (11.2 mg, 0.092 mmol) and potassium carbonate (9.5 mg, 0.07 mmol) were stirred in toluene (2 mL) at 90° C. in a sealed tube for 20 h. Then the reaction mixture was filtrated through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 70:30) to furnish 16 mg of III in mixture with the starting material.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18](NC(N)=S)[CH:19]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[C:16]([NH:1][C:2]2[S:3][C:4]3[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[N:6]=2)[CH:15]=1
Reactant: COc1ccc(Cl)cc1NC(N)=S
Reactant: Nc1nc2c(s1)C(=O)CCCC2
Product: COc1ccc(Cl)cc1Nc1nc2c(s1)C(=O)CCCC2
Yield: 26 %

Procedure:
Following the procedure described for 26z by condensing 5-chloro-2-methoxyphenylthiourea gave 30z (light brown solid; 26% for two steps). 1H NMR (600 MHz, DMSO-d6): δ 7.81 (d, J=2.4 Hz, 1H), 7.75 (dd, J=9 Hz, 2.4 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 3.83 (s, 3H), 2.84-2.75 (m, 2H), 2.58-2.52 (m, 1H), 2.33-2.28 (m, 1H), 1.90-1.74 (m, 4H). 13C NMR (150 MHz, DMSO-d6): δ 194.4, 169.8, 154.5, 148.9, 134.1, 130.2, 125.7, 122.6, 121.7, 116.3, 57.6, 42.9, 30.5, 24.4, 21.5.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>CC1C=CC=CC=1C>[CH2:23]([O:22][C:21]([NH:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:25])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1N
Solvent: Cc1ccccc1C
Product: CCOC(=O)Nc1cc(OCc2ccccc2)ccc1C(=O)OCC
Reaction time: 6 h
Yield: 71 %

Procedure:
To a stirred mixture of 7 parts of ethyl 2-amino-4-(phenylmethoxy)benzoate and 45 parts of dimethylbenzene were added dropwise 3.25 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 6 hours at reflux temperature. The reaction mixture was cooled and the solvent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 6.1 parts (71%) of ethyl 2-[(ethoxycarbonyl)-amino]-4-(phenylmethoxy)benzoate (15).
Reaction SMILES: [CH:1]([C:4]([CH3:18])([N:7]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:20]>>[CH:1]([C:4]([CH3:18])([N:7]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17])[C:5]([NH2:6])=[O:20])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(C#N)N1C(=O)c2cccnc2C1=O
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2cccnc2C1=O
Temperature: 0 °C

Procedure:
To 330 mL concentrated sulfuric acid is added portion wise with thorough stirring 298 g of finely divided 5,7-dihydro-alpha-isopropyl-alpha-methyl-5,7-dioxo-6H-pyrrolo[3,4-b]pyridine-6-acetonitrile so that the temperature did not go about 72° C. After the addition the temperature is adjusted to 60°-65° C. and maintained there for 11/2 hours. The mixture is cooled, quenched with ice and finally diluted to approximately 4 liters. After adding 454 g sodium acetate and cooling at 0° C. for 2 hours the mixture is filtered, the solids collected and washed twice with 500 mL water containing sodium acetate followed by water to remove all the sulfuric acid. The solid is dried to give 289 g of product, mp 176°-178° C. Material made in a similar way and analytically pure had mp 188°-190° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)N1CCN(c2nc3cc(C(=O)O)ccc3s2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2nc3cc(C(=O)N4CCCC4)ccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carboxylic acid (530 mg, 1.75 mmol), pyrrolidine (149 mg, 2.10 mmol) and DIEA in THF (7.3 mL) was stirred for 30 min at rt. Then PyBOP was added and the reaction mixture was stirred at rt overnight. The mixture was concentrated and the residue was neutralized with an aqueous solution of Na2CO3 to pH 7. Then the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified with preparative HPLC to give 490 mg (78%) of (2-(4-isopropylpiperazin-1-yl)benzothiazol-5-yl)(pyrrolidin-1-yl)methanone as a trifluoroacetate salt.
Reaction SMILES: O[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:31])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:31][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Oc2ccc(CO)cc2)nc1)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc(CCl)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (3.06 g, 7.9 mmol) in dichloromethane (90 mL) was added thionyl chloride (1.7 mL, 23.3 mmol), and the resulting solution was stirred for 4 hours at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.95 g of the title compound.