Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:39]=[CH:38][C:37]([CH:40](OCC)[O:41]CC)=[CH:36][CH:35]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[CH:36][CH:35]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
A mixture of 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (290 mg, 0.48 mmol) in 3N hydrochloric acid (10 mL) was stirred at room temperature overnight. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered to give crude. The crude product was purified by prep-HPLC to give the 4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (20 mg, yield 8%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.83-0.91 (m, 4H), 1.94-2.03 (m, 1H), 3.18-3.23 (m, 1H), 3.46-3.82 (m, 7H), 4.42 (d, J=7.6 Hz, 1 H), 4.87 (d, J=7.4 Hz, 1 H), 7.22-7.41 (m, 7H), 7.52-7.54 (d, J=8.0 Hz, 2H), 7.60 (d, 1H), 9.94 (s, 1H); LC-MS (ESI) m/z: 548 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A suspension of 2.7 g (18.1 mMol) 2,4-dichloropyrimidine, 4.12 g (19.9 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] and 8.45 g (39.8 mMol) K3PO4 in 90 ml NMP is stirred for 22 h at rt. Then the mixture is diluted with 0.5 l CH2Cl2 and 0.9 l of a 5% citric acid solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2) gives the title compound: MS: [M+1]+=320; TLC(CH2Cl2/EtOAc 49:1): Rf=0.42.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](O)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([NH:16][C:14]2[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=2)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to afford the title compound: MS 512 m/z (M+1).
Reaction SMILES: Br[C:2]1C=COC=1C(O)=O.C(O)C.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([OH:26])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([O:26][CH3:2])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(C(=O)O)cc1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1occc1Br
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(OC)c(NC(=O)OC(C)(C)C)c1

Procedure:
A reaction and treatment was conducted in the same manner as in Reference Example 1 except that the 3-bromo-2-furancarboxylic acid and ethanol used in Reference Example 1 were replaced with 3-(tert-butoxycarbonylamino)-4-methoxybenzoic acid (5.00 g) and methanol (0.76 ml), respectively, thereby giving 5.51 g of methyl 3-(tert-butoxycarbonylamino)-4-methoxybenzoate.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:24]([C:23]3[CH:25]=[CH:26][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: CC(C)c1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 4-isopropylaniline as a mixture of cis and trans diastereomers. Light brown solid. MS (m/e): 288.1 [MH+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8](Cl)=[O:9].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(Cl)COc1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of 6.44 g of the product of Step C in 60 ml of chloroform was added at +10° C. to a solution of 10.2 g of N-(tert-butoxycarbonyl)-1,4-diamino-butane in 150 ml of chloroform and after stirring for 2 hours at room temperature, the mixture was evaporated to dryness under reduced pressure. The product was added to water and vacuum filtered to obtain 7.85 g of the desired product melting at 86° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)C.Cl>[Fe].O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Yield: 80.6 %

Procedure:
A mixture of 3-chloro-5-trifluoromethyl-2-(4-nitrophenoxy)pyridine (1.0 g), iron powder (3.2 g), isopropyl alcohol (60 ml), water (6 ml) and dilute hydrochloric acid (0.2 ml of a 2N solution), were heated at the reflux temperature for 12 hours. After cooling and filtering to remove the solid matter, the filtrate was concentrated by evaporation of the volatile portion under reduced pressure. The residual solid was recrystallised from n-hexane to yield 2-(4-aminophenoxy)-3-chloro-5-trifluoromethylpyridine (0.73 g) m.p. 85°-87° C.
Reaction SMILES: [C:1]([C:9]1[NH:13][C:12]([C:14](OC(=O)C)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:9]1[NH:13][C:12]([CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(OC(C)=O)(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Temperature: 40 °C
Reaction time: 24 h
Yield: 49.6 %

Procedure:
To a solution of diethyl (5-benzoylpyrrol-2-yl)-acetoxymethanedicarboxylate (142 mg, 0.367 mmol) and triethylsilane (102 mg, 0.440 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (84 mg, 0.734 mmol). The reaction mixture was stirred at 40° C. for 24 hours. Additional triethyl silane (51 mg, 0.220 mmol) and trifluoroacetic acid (84 mg, 0.734 mmol) was added. The reaction mixture was stirred at 40° C. for an additional 24 hours. The mixture was cooled to room temperature, washed with cold 10% aqueous sodium hydroxide and saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with hexane/ethyl acetate (87:13) to provide 60 mg (50%) of diethyl (5-benzoylpyrrol-2-yl)methane-dicarboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Br)=[N:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1.[CH3:22][NH:23][CH3:24]>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][N:23]([CH3:24])[CH3:22])=[N:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1
Reactant: Cn1nc(-c2cccc(Cl)c2)nc1-c1ccccc1CBr
Reactant: CNC
Solvent: c1ccccc1
Product: CN(C)Cc1ccccc1-c1nc(-c2cccc(Cl)c2)nn1C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 4. g. of 1-methyl-3-(3-chlorophenyl)-5-(2-bromomethylphenyl)-1,2,4-triazole in 50 ml. of anhydrous benzene, 8.8 ml. of a benzene solution containing 20% of dimethylamine are added maintaining the temperature of about 5°-10° C. The mixture was maintained under stirring for 16 hours and then washed with 10% sodium hydroxide and with an aqueous solution of sodium chloride. The organic solution is dried over sodium sulfate and then evaporated. The crude product is purified by distillation at 175° C./0.07 mm Hg. Yield 86%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:7][O:8][C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)=[O:4].S(=O)(=O)(O)O>>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]=2[C:3]1=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(-c2cc3onc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
A mixture of 26.1 g. (0.0815 mole) of N-methyl-5-(4-methylphenacyl)-3-phenyl-4-isoxazole carboxamide and 261 ml. of 2M sulfuric acid is refluxed for 24 hours. The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and then recrystallized from ethanol to give 5-methyl-3-phenyl-6-(p-tolyl)-isoxazolo [4,5-c]pyridin-4(5H)-one; m.p. 155° to 156° C.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[N:22]=[N:21]2)[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[N:22]=[N:21]2)[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(CCn1nnc2ccccc2c1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CCn1nnc2ccccc2c1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 45.1 %

Procedure:
To a solution of the compound (100 mg) obtained from step 3 above in dichloromethane (2 ml) at 0° C. was added trifluoroacetic acid (8 ml) and stirred the reaction mixture for about 2-3 hours and then at room temperature for 3 hours. The solvent and excess reagents were evaporated under reduced pressure and the residue thus obtained was purified by preparative thin layer chromatography (eluant-ethyl acetate) to furnish the title compound (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]12[O:19][CH2:18][CH2:17][C@H:16]1[CH2:15][S:14][C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:12]2>CO.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]23[O:19][CH2:18][CH2:17][C@H:16]2[CH2:15][S:14][C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:12]3)[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)OCC[C@H]2CS1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To a solution of (±)-tert-butyl (4aR,7aR)-7a-(2-fluoro-5-nitrophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (31 mg, 0.078 mmol) in methanol (3.9 mL) was added 10% Pd/C (17 mg), and the reaction mixture was stirred at rt under a hydrogen atmosphere for 2 h. The reaction mixture was filtered through a pad of Celite and concentrated directly to give the title compound as a colorless oil (30 mg, 99%). 1H NMR (500 MHz, CDCl3) δ 6.87 (2H, m), 6.63 (1H, m), 4.17 (1H, m), 4.09 (1H, m), 3.35 (1H, m), 3.05 (1H, m), 2.89 (1H, m), 2.35 (1H, m), 2.23 (1H, m), and 1.51 (9H, m). MS (M+H)+: 368.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([Cl:32])[CH:26]=1>>[Cl:32][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]4[CH3:21])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:29][C:28]=1[OH:31]
Reactant: CC1CCCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: C[C@H]1CCCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1

Procedure:
Intermediate 108 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H), 8.24 (s, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.44 (t, 1H), 7.15 (s, 1H), 7.08 (d, 1H), 6.93 (d, 1H), 6.84 (d, 1H), 5.37 (t, 1H), 4.36 (d, 1H), 3.75 (d, 1H), 3.66 (m, 2H), 2.93 (m, 2H), 2.80 (t, 2H), 2.42 (s, 1H), 1.75 (m, 5H), 1.38 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH:33]1([Zn+])[CH2:35][CH2:34]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:33]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:31])([F:30])[F:29])[CH2:35][CH2:34]1
Reactant: [Zn+]C1CC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CC4)c(C(F)(F)F)c3)cc21
Temperature: 90 °C

Procedure:
To a solution of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (200.5 mg, 0.444 mmol) in tetrahydrofuran (1 mL) was added 0.5 M cyclopropylzinc(II) bromide solution in tetrahydrofuran (8.87 mL, 4.44 mmol) and bis(tri-t-butylphosphine)palladium (46.3 mg, 0.089 mmol) at room temperature. The mixture was heated at 90° C. for 63 h. The mixture was then quenched with 1 N aqueous HCl solution and filtered through Celite®. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine solution to remove excess HCl and concentrated under reduced pressure. The residue was purified by HPLC. The combined fractions were triturated with saturated aqueous sodium bicarbonate solution to basic solution and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and acidified to pH 4. The organic layer was washed with water until the aqueous layer was neutral. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound as a light brown solid (36.6 mg). LCMS m/z=430.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.74-0.88 (m, 2H), 0.98-1.07 (m, 2H), 2.02-2.12 (m, 2H), 2.34 (dd, J=15.98, 9.03 Hz, 1H), 2.59-2.76 (m, 4H), 3.39-3.52 (m, 1H), 5.10 (s, 2H), 6.69 (dd, J=8.72, 2.53 Hz, 1H), 6.91 (d, J=2.40 Hz, 1H), 7.10-7.26 (m, 2H), 7.61 (d, J=8.34 Hz, 1H), 7.72 (d, J=1.14 Hz, 1H), 10.45 (s, 1H), 12.20 (bs, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]([Cl:36])=[O:35]>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:34]([CH:30]5[CH2:31][CH2:32][CH2:33][O:29]5)=[O:35])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: O=C(Cl)C1CCCO1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCCO4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 32.5 mg (0.24 mmol) of tetrahydrofuran-2-carbonyl chloride are reacted together by general method F. 40.9 mg (68.1% of theory) of the title compound are obtained.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:14]=[N-:15]
Reactant: Nc1ccc(I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(I)cc1
Reaction time: 1 h

Procedure:
6 g of p-iodoaniline was dispersed in a solution comprising 25 cc of water and 7.5 cc of 36% hydrochloric acid and cooled with ice. 2.1 g of sodium nitrite was dissolved in 13 ml of water and the resulting solution was added dropwise slowly to the dispersion to effect the diazotization reaction. A solution of 2.5 g of sodium azide in 18 ml of water was added dropwise thereto and, after stirring for one hour, the mixture was subjected to extraction with benzene. After the dehydration with sodium sulfate, benzene was evaporated to obtain p-azidoiodobenzene.
Reaction SMILES: Br[CH:2]([C:14]([C:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1)=[O:15])[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].C(#N)C.C[O-].[Na+].[C:31]([OH:39])(=[S:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(=O)C>[C:31]([S:38][CH:2]([C:14]([C:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1)=[O:15])[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(c1csc2ccccc12)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1csc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
As for Example 21, 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (0.01 mole) in 25 ml. of acetonitrile is added to a mixture of 0.01 mole of sodium methoxide and 0.015 mole of thiobenzoic acid in 25 ml. of acetonitrile. The mixture is stirred at room temperature for 16 hours, one ml. of acetic acid is added and the solvent is evaporated in vacuo. The residue is partitioned between dichloromehane and water containing acetic acid. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is removed in vacuo to give the product of the Example as a yellow glass.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:36])[CH2:30]/[CH:31]=[CH:32]/[C:33](O)=[O:34]>>[CH3:28][N:29]([CH3:36])[CH2:30]/[CH:31]=[CH:32]/[C:33]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH:20]=1)=[O:34]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: CN(C)C/C=C/C(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 35 %

Procedure:
(E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-4-(dimethylamino)but-2-enoic acid using Method E (35% yield). HPLC: 99%, RT=3.399 min. MS: m/z=466 [M+H]+, RT=3.37 min. 1H-NMR (DMSO-d6) δ 10.52 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H), 8.04 (s, 1H), 7.74 (d, 1H), 7.48 (t, 1H), 7.43-7.38 (m, 3H), 7.29-7.26 (d, 2H), 7.17-7.12 (m, 3H), 7.05-6.99 (m, 3H), 6.74 (m, 1H), 6.48 (d, 1H), 3.94 (d, 2H), 2.79 (s, 6H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][C:29]([F:32])([F:31])[F:30])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][C:29]([F:31])([F:30])[F:32])=[C:21]([CH:26]=1)[CH2:20][NH:19][C:12]1[N:11]=[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:7][CH2:6]2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=1
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3cc(Cl)ccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(NCc2cc(Cl)ccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-N2-[5-chloro-2-(trifluoromethoxy)benzyl]-5-nitropyrimidine-2,4-diamine (51 mg, 0.1 mmol) in DMF (0.5 mL) was added 1,4-dibromobutane (36 μL, 0.3 mmol) and DIPEA (104 μL, 0.6 mmol). The reaction mixture was stirred at 50° C. for 24 h and then 72 h at room temperature. The reaction mixture was then partitioned between EtOAc (20 mL) and saturated NaHCO3 (less than 1 mL). The organic phase was washed with water (2×2 mL) and dried over Na2SO4. The resulting residue was purified by preparative HPLC to afford 13 mg (25%) of the title compound as a yellow oily solid, m/z 529.3 [M+1]+
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:20](=[O:23])[CH2:21][CH3:22])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2nc(CC)no2)s1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and propionyl chloride.