Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([O:11][C:12](=[O:19])[CH:13]([CH:17]=O)[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:17]=1)=[O:19])[CH3:10]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C=O)C(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C

Procedure:
Similar to Example 1, equimolar amounts of 2-pyridylhydrazine and 2-formyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was determined to be the named product (m.p. 49° C.-50° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CN(C)C1C=CN=CC=1.CC(O)=O>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C[C@@H]1CCCC[C@H]1O
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl-D-alanine (2.5 mmol. 0.556 g) and trans-2-methylcyclohexanol (3 equivalents, 1 mL) were dissolved in 7 mL THF at room temperature, followed by the addition of 70 mg 4-dimethylaminopyridine. DCC (2.5 mmol, 0.515 g) was then introduced with stirring. The solution turned cloudy immediately and was stirred at room temperature overnight. The reaction mixture was stirred for another 15 min after several drops of HOAc were added to it. Dicyclohexylurea (DCU) was filtered off and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate. The EtOAc solution was filtered, washed with 0.5N HCl (2×), brine (2×), 5% NaHCO3 (2×) and finally brine (2×). The organic phase, after being dried over anhydrous Na2SO4, showed one UV-positive tlc spot. A second spot, which could only be detected by phosphomolybdic acid (PMA)--Ce(SO4)2 spray, was identified as the unreacted alcohol by tlc comparison with authentic material. The ethyl acetate solution was evaporated to dryness and dried under high vacuum, giving a clear oil weighing 0.965 g. The crude material was chromatographed on a Merck Si--60 size C prepacked column by gradient elution with toluene to toluene:ethyl acetate (9:1). After evaporation, 0.629 g (72.0%) of clear, colorless oil was recovered: nmr (CDCl3, ppm), 0.85-2.05 (13H, m, aliphatic H of cyclohexanol), 0.9 (3H, d, J=6 Hz, CH3) 1.3 (3H, d, J=7 Hz, obscured by other aliphatic protons, β--CH3 of Ala), 4.3 (2H, m, CH--O-- and α--H), 5 (2H, s, ArCH2 --), 5.25 (1H, broad s, amide H), 7.15 (5H, s, ArH5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:22]([C:3]2[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]3[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:12][O:13][C:14]=3[CH3:15])=[CH:7][C:2]=2[CH3:1])=[O:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)NC1CC1
Yield: 54 %

Procedure:
As described for example 44, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol) was converted, using cyclopropylamine instead of 4-amino-tetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 122 mg, 54%) which was obtained as a white solid. MS: m/e=365.3 [M+H]−.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OC(C)(C)C)[C:16]3=[O:28])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)[C:16]1=[O:28]
Reactant: CCc1cnc(N2CCC(N3CC[C@H](NC(=O)OC(C)(C)C)C3=O)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Yield: 100 %

Procedure:
A solution of (S)-tert-butyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (1 g, 2.6 mmol) in 50% TFA/CH2Cl2 (10 mL) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and washed with 1N NaOH (100 mL) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.75 g, 2.6 mmol, 100%)
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4([C:28]#[N:29])[CH2:27][CH2:26]4)[CH:20]=3)[CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:26][CH2:27]5)[CH:20]=4)[CH:16]=3)[CH:32]=[CH:33][C:6]=2[N:5]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Potassium thiocyanate (7.00 g, 72 mmol) was suspended in acetic acid (120 mL) and the mixture was stirred at room temperature for 10 min. To the obtained solution was added a solution of N-[5-(4-aminophenoxy)-2-methylphenyl]-3-(1-cyanocyclopropyl)benzamide (6.90 g, 18 mmol) in acetic acid (120 mL), and the mixture was further stirred at room temperature for 30 min. To the obtained solution was added dropwise slowly a solution of bromine (3.60 g, 22.5 mmol) in acetic acid (80 mL) and, after the completion of the dropwise addition, the mixture was further stirred at room temperature for 12 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (400 mL), washed with 5% aqueous sodium hydrogencarbonate solution (200 mL×2) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (6.27 g, 79%) as a pale-yellow amorphous substance.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28](O)=[O:29]>>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:29]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc2ccccc2c1
Product: O=C(Cc1ccc2ccccc2c1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-napthylacetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.44 (ddd, J=8.0, 1.4, 0.6 Hz, 1H), 8.12-8.16 (m, 1H), 8.01-8.09 (m, 2H), 7.87-7.97 (m, 4H), 7.48-7.59 (m, 3H), 3.91 (s, 2H); MS (ESI−) M/Z 396 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)([F:28])[F:27])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[Cl:35][C:31]1[CH:30]=[C:29]([C:26]([F:27])([F:28])[CH2:25][O:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:36])[CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3cccc(Cl)c3)c2)Cc2ccccc2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCC(F)(F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
20 mg of the compound of step 3 were dissolved in 5 ml of a mixture of THF and water (9:1), and 1.9 mg (77.5 μmol) of lithium hydroxide were added. After stirring at room temperature for 3 d, the mixture was acidified with 1 M hydrochloric acid and evaporated. The residue was purified by silica gel chromatography (DCM/methanol 95:5) and RP HPLC (water/ACN gradient) to give 8 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[C:20](O)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:6][CH:7]=1)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)O
Reactant: O=C1O[C@H](c2ccccc2)CN1c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Oc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Yield: 52 %

Procedure:
0.50 g (1.96 mM) of (5R)-3-(4-hydroxyphenyl)-5-phenyl-2-oxazolidinone synthesized in Example 2, 0.26 g of hexanoic acid and 20 ml of methylene chloride were placed in 50 ml-round bottomed flask, followed by stirring to form a solution. To the solution, 0.43 g (2.08 mM) of N,N'-dicyclohexylcarbodiimide and 0.10 g of 4-dimethylaminopyridine were added in succession, followed by stirring for 8 hours at room temperature. The precipitated N,N'-dicyclohexylurea was filtered out and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=20/1) and recrystallized from methanol to obtain 0.36 g of (5R)-3-(4-hexanoyloxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 52.0%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH2:13][CH2:14][C:15]([CH2:21][CH:22]=[CH2:23])([CH2:18][CH:19]=[CH2:20])[C:16](=[O:17])[C:5]=12>C(O)C>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH2:13][CH2:14][C:15]([CH2:18][CH:19]=[CH2:20])([CH2:21][CH:22]=[CH2:23])[CH:16]([OH:17])[C:5]=12
Reactant: C=CCC1(CC=C)CCn2c(c(C)c3ccccc32)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCC1(CC=C)CCn2c(c(C)c3ccccc32)C1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Sodium borohydride (10.53 g, 270 mmol) was added portionwise upon cooling to a solution of 6,7,8,9-tetrahydro-10-methyl-8,8-bis(2-propenyl)pyrido[1,2-a]indol-9-one (12.8 g, 45.8 mmol), in ethanol (350 mL) at 25° C. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo to near-dryness, and the residue partitioned between water (300 mL) and ether (300 mL). The separated organic layer was washed with brine (100 mL), dried over MgSO4, filtered and evaporated to afford 12.63 g (98%) of the title compound as a light amber oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: O=CC1CCOCC1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCOCC3)CC3CC3)c(SC)nn12
Reaction time: 1 h
Yield: 55.2 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (78 mg) [CAS No. 50675-18-8] and sodium triacetoxyborohydride (87 mg) were added, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (70 mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N+:13]([C:4]1[C:5]([NH2:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([F:28])([F:27])[F:16])[CH:3]=1)([O-:15])=[O:14]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])cc(-c2ccccc2C(F)(F)F)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (10.0 g, 35.2 mmol, as prepared in the previous step), 2-trifluoromethylphenylboronic acid (8.70 g, 45.8 mmol), and (dppf)PdCl2 DCM (1.44 g, 1.76 mmol) were placed in a 500 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser. The flask was evacuated and backflushed with Ar. DME (150 mL) and 2M aq Na2 CO3 (50.0 mL, 100 mmol) were added via cannula. The mixture was stirred at 90° C. for 18 h. The mixture was cooled to RT, diluted with EtOAc (100 mL), then washed with water (100 mL) and brine (100 mL). The combined aqueous layers were extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified on an 80-g pre-packed SiO2 column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 11.3 g (92%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.35 (d, J=2.0 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.75 (br. s., 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:6]([N:19]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:20]=[O:21])=[C:5]2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Li]CCCC.[CH3:41][C:42]([CH3:44])=[O:43].[NH4+].[Cl-]>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:42]([OH:43])([CH3:44])[CH3:41])=[CH:10][CH:9]=3)[C:5]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:6]2[N:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[O:21])=[CH:13][CH:14]=1
Reactant: CC(C)=O
Reactant: O=CN(c1cccnc1)c1c(OCc2ccccc2)c2cc(Br)ccc2n1Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)c(OCc1ccccc1)c(N(C=O)c1cccnc1)n2Cc1ccc(F)cc1
Temperature: -100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 201 mg of {5-Bromo-1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide in 10 mL of THF at −100° C. was added 0.5 mL of n-BuLi (1.6 M in hexanes) and the mixture was stirred at −100° C. for 30 min. To this cold solution, 190 μL of acetone was added and the reaction mixture was allowed to warm to room temperature. At this time, aqueous NH4Cl was added, the product was extracted with ethyl acetate and the organic phase was washed with brine and dried over anhydrous Na2SO4. Flash chromatography (100% hexane to hexane/ethyl acetate 1:2) and swish with CH2Cl2/hexane yielded 61 mg of the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.S(Cl)([Cl:16])(=O)=O.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:16][C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cl)CCCNC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of ethyl 2-oxopiperidine-3-carboxylate (30 g) in THF (300 mL) was added dropwise sulfuryl chloride (14.2 mL) at 0° C.-5° C., and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (300 mL) at 0° C., and the mixture was stirred at room temperature for 30 min and extracted with ethyl acetate (300 mL×3). The extract was washed with saturated brine (300 mL), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1, 60 mL×2) to give the title compound (32.7 g). MS (ESI+): [M+H]+ 206.1.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=N)OCC)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:18]#[N:19]>CO>[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]2[N:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:22]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[N:14]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(NC2CCCCC2)c(N)c1
Reactant: CCOC(=N)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of ethyl 4-hydroxybenzimidate hydrochloride (5, 1.26 g, 6.7 mmol) and compound 4 (1.5 g, 5.0 mmol) in methanol (10 mL) was refluxed overnight under a nitrogen atmosphere. The reaction mixture was cooled to rt, filtered, and washed with methanol to afford 6 as a pinkish brown solid (1.26 g, 68%). ESI-MS m/e 372.1 (M+1).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:3]1=2.[O-:13][C:14]#[N:15].[K+]>O>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH:12][C:14]([NH2:15])=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][C:3]1=2
Reactant: NC1CCCCc2sccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCCCc2sccc21
Reaction time: 1 h

Procedure:
A mixture of 50 grams of 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride in 100 ml. of water is stirred at about 15° C. and a solution of 23.1 grams of potassium cyanate in 100 ml. of water is added dropwise. After completion of the addition, the mixture is warmed slowly to 70°-75° C. and held there for one hour. The mixture is cooled and the white solid is collected by filtration and washed with water. The solid is air-dried, pulverized, and washed with acetonitrile. Upon drying, this crude product is treated with hot acetone whereby there is obtained 5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea, m.p. 217° C. dec.
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:20](=[O:22])=[O:21].C1(C)C=CC=CC=1>CCOCC>[OH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:20]([OH:22])=[O:21])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: Cc1sc2cc(CCO)ccc2c1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1sc2cc(CCO)ccc2c1C(=O)O

Procedure:
Successive treatment of 3-bromo-6-(2-hydroxyethyl)-2-methylbenzo[b]thiophene with n-butyl lithium in ether followed by carbon dioxide according to the method of Example 11(ii) gave 6-(2-hydroxyethyl)-2-methylbenzo[b]thiophene-3-carboxylic acid, m.p. 166°-169° C. (from toluene).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][O:1][C:2]2[CH:3]=[C:4]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=S(=O)(Oc1ccc(Cc2ccccc2)c(O)c1)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)ccc2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 294 mg (0.787 mmol) of 2-chlorobenzenesulfonic acid 3-hydroxy-4-benzylphenyl ester, as prepared in the preceding step, in tetrahydrofuran (5 mL) containing 236 μL (1.10 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol, as prepared in step f of Example 1, 300 μL (2.72 mmol) of N-methylmorpholine, and 309 mg (1.18 mmol) of triphenylphosphine was added 185 μL (1.18 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at ambient temperature for 1 h, quenched with saturated NaHCO3, and extracted into ether. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (ethyl acetate/hexane (1:2)) gave 382 mg of the title compound as a colorless foam. 1H-NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=1.5, 8 Hz), 7.55-7.64 (m, 2H), 7.35-7.40 (m, 1H), 7.08-7.26 (m, 5H), 6.93 (d, 2H, J=8 Hz), 6.65 (d, 2 Hz), 6.53 (dd, 1H, J=2, 8 Hz), 3.87 (s, 2H), 3.67 (d, 2H, 6 Hz), 2.69 (t, 2H, J=13 Hz), and 1.47 (s, 9H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C30H34ClNO6S: 594.2 (M+Na). Found: 594.0, 472.0 (M - (tert-butoxycarbonyl)+H).
Reaction SMILES: Cl.[CH2:2]1[CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[CH2:5][CH2:4][CH:3]1[NH:16][C:17]([NH:19]C(=O)C1C=CC=CC=1)=[O:18]>[OH-].[Na+]>[CH2:2]1[CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[CH2:5][CH2:4][CH:3]1[NH:16][C:17]([NH2:19])=[O:18]
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN2CCc3ccccc3C2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCN2CCc3ccccc3C2C1
Yield: 73.8 %

Procedure:
1-(1,3,4,6,7,11b-Hexahydro-2H-benzo[a]quinolizin-2-yl)-3-benzoylurea hydrochloride (0.98 g) was refluxed in 2N sodium hydroxide solution (50 ml) for 4 hours. The solution was filtered and the residue washed with water, then ethanol, and finally ether before drying to give the title compound (0.46 g) melting point 235° C. C14H19N3O requires: C, 68.54%; H, 7.81%; N, 17.13%. Found: C, 68.53%; H, 7.79%; N, 17.33%.