Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH:33](O)=[O:34]>CN(C=O)C>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][CH:33]=[O:34])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CNCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of C-(3-chloro-pyrazin-2-yl)-methylamine bis-hydrochloride (6.0 g, 0.027 mol) in DMF (50 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.9 g, 0.041 mol), diisopropyl ethylamine (24.2 mL, 0.139 mol), hydrate (400.0 mg, 0.003 mol) and formic acid (1.57 mL, 0.041 mol). The reaction was left to stir at rt for 16 h under an atmosphere of nitrogen. The solvent was then removed under reduced pressure and the residue was purified by chromatography (5% DCM in hexane. 1H NMR (400 MHz, CD3OD) δ ppm 4.72 (s, 2H), 8.26 (s, 1H), 8.39 (d, J=1.77 Hz, 1H), 8.57 (d, J=2.53 Hz, 1H). MS (ES+): m/z 172.11, 174.09 [MH+]; HPLC: tR=1.57 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C(N(CC)CC)C>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:9]=1
Reactant: C#CCCCC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: CCCCC#CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The following were stirred at ambient temperature for about 2 hours 30 minutes, 49 ml of 1-hexyne, 75 ml of triethylamine, 40 mg of cuprous iodide, 40 mg of bis triphenylphosphine palladium dichloride and 9 g of parabromobenzoyl chloride.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:12][CH:13]=1)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.5 ml (32.3 mmol) of TMP are initially introduced at −15° C. in 20 ml of diethyl ether, and 20.0 ml (31.8 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min, a solution of 10.0 g (30.4 mmol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene in 80 ml of diethyl ether is added. When the addition is complete, the batch is warmed to RT and stirred for 90 min. The solution is cooled to −70° C., and 10.0 ml (0.16 mol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=95:5). The further purification is carried out by recrystallisation from n-heptane. 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 121° C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](C)=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.N1CCCCC1.C(C1C=C2C(=CC=1)C(=[O:44])CCC2)(C)(C)C.C=O>C(O)C.Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8](=[CH:7][CH:6]=1)[C:9](=[O:44])[CH:10]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)CCCC2=O
Reactant: CC1=C(CN2CCCCC2)CCc2cc(C(C)(C)C)ccc21
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2=O
Yield: 83 %

Procedure:
This Example illustrates the preparation of 7-tert-butyl-4-methyl-3-piperidinomethyl,1,2-dihydronaphthalene (Compound number 3 of Table I). Piperidine hydrochloride (12.6 g 0.103 mol), 6-tert-butyl-1,2,3,4-tetrahydronaphthalen-1-one (80.0 g, 0.04 mol) and paraformaldehyde (2.64 g, 0.088 mol) were refluxed in ethanol (200 ml) with concentrated hydrochloric acid (1 ml) as a catalyst for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml); the ethereal extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 6-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (10.0 g 83% yield) melting at 47°-9°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33].[CH:34](=O)[CH2:35][CH3:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][N:28]([CH2:34][CH2:35][CH3:36])[CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33]
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1
Reactant: CCC=O
Product: CCCN1CCC(N(CC)Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)CC1

Procedure:
Intermediate 85 was coupled with propionaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 508. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.5-7.4 (m, 3H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.1 (d, 2H), 2.7 (q, 2H), 2.6 (m, 3H), 2.3 (m, 4H), 1.7-1.6 (m, 4H), 1.5-1.4 (m, 2H), 0.94 (t, 3H), 0.80 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[S:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)s1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
0.18 g (0.04 equivalent) of Pd(PPh3)4 and then 1.2 g (0.0084 mol) of 5-chloro-2-thiopheneboronic acid are added to a solution of 1.4 g (0.0038 mol) of ethyl 2-[(4-bromophenyl)oxy]-4-cyclohex-1-en-1-ylbutanoate in 20 ml of dimethoxyethane. 4.2 ml of 2M sodium carbonate solution are added at room temperature. The reaction mixture is stirred overnight and then refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The extract is washed with 1N sodium hydroxide and then with saturated aqueous NaCl solution and finally dried over Na2SO4. After concentrating, the black oil obtained is purified by flash chromatography (95/5 heptane/ethyl acetate). 1.1 g of a thick oil are obtained.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18](Cl)=[O:19].Cl.Cl.[NH2:23][C:24]1[CH:56]=[CH:55][C:27]([O:28][C:29]2[CH:30]=[CH:31][C:32]3[N:36]=[C:35]([CH2:37][O:38][C:39]4[CH:52]=[CH:51][C:42]([CH2:43][CH:44]5[S:48][C:47](=[O:49])[NH:46][C:45]5=[O:50])=[CH:41][CH:40]=4)[N:34]([CH3:53])[C:33]=3[CH:54]=2)=[CH:26][CH:25]=1>CN(C)C=O>[O:49]=[C:47]1[NH:46][C:45](=[O:50])[CH:44]([CH2:43][C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:37][C:35]3[N:34]([CH3:53])[C:33]4[CH:54]=[C:29]([O:28][C:27]5[CH:55]=[CH:56][C:24]([NH:23][C:18]([C:9]6[CH:10]=[CH:11][C:12]7[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=7)[CH:8]=6)=[O:19])=[CH:25][CH:26]=5)[CH:30]=[CH:31][C:32]=4[N:36]=3)=[CH:52][CH:51]=2)[S:48]1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccc5ccccc5c4)cc3)cc21
Yield: 73.4 %

Procedure:
A reaction was conducted by a similar procedure to that described in Example 52 using triethylamine (0.32 ml), 2-naphthoyl chloride (153 mg), 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and anhydrous N,N-dimethylformamide (8 ml). The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate and water. The precipitate was isolated by filtration to afford the title compound (337 mg, white powder, mp 221-223° C.).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(OCC)(=O)C>[CH:10]1[C:11]2[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 150 °C

Procedure:
To a 500 ml three-neck round bottom flask was added 25 g. carbazole, 218 g. dimethyl formamide, 45.5 g. potassium carbonate and 43 g. 6-chloro-1-hexanol. The reaction mixture was heated at 150° C. for 6 hours, and cooled to room temperature. 500 g. ethyl acetate was added, washed with 250 g water, then 250 g water with 50 g concentrated HCl, then 250 g. saturated brine. The solvent was removed on a rotary evaporator to yield 58 g of a brown semi-solid. The crude product was purified using a silica gel flash chromatography column with dichloromethane as the elutant. The concentrated product fractions yielded 33.3 g. of a white solid product; ˜90% pure by gas chromatography.
Reaction SMILES: [C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11]O)=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:50].CC#N>C1COCC1>[C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11][Br:50])=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
To a solution of the product of Step D (0.53 g, 1.38 mMol) in dry THF (10 mL) were added Ph3P (0.49 g, 2.06 mMol), CBr4 (0.69 g, 2.06 mMol) and CH3CN (2 mL), and the mixture was stirred at room temperature for 14 h. At the end of this period, the reaction mixture was concentrated in vacuo to provide an oil, which was then purified by flash chromatography on silica-gel using ethyl acetate-hexane (1:9) to provide the titled product as a thick colorless oil (0.57 g).
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1([S:9][S:10][CH:11]2[CH2:13][CH2:12]2)[CH2:8][CH2:7]1.Br[CH2:15][C@@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1.[Cl-].[NH4+]>C1COCC1>[CH3:21][C:18]1([CH3:22])[O:17][C@H:16]([CH2:15][C:6]2([S:9][S:10][C:11]3([CH2:15][C@@H:16]4[CH2:20][O:19][C:3]([CH3:4])([CH3:2])[O:17]4)[CH2:13][CH2:12]3)[CH2:8][CH2:7]2)[CH2:20][O:19]1
Reactant: C1CC1SSC1CC1
Reactant: CC1(C)OC[C@@H](CBr)O1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CC2(SSC3(C[C@@H]4COC(C)(C)O4)CC3)CC2)O1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
n-Butyl lithium (1.7 M in hexane, 1.2 eq) is added dropwise over 1 hour to a solution of 1,2-dicyclopropyldisulfane (1 eq) in THF (1.5 mL/mmol), at −20° C. (S)-4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (1.1 eq) is then added at −78° C. and stirring at −78° C. continued for an additional 4 hours. Saturated aqueous ammonium chloride solution is added and the mixture is extracted with ethyl acetate (3×). The combined organic extracts are dried (Na2SO4) and purified by flash chromatography (ethyl acetate in hexane eluant).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.ClCCl>[CH2:20]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
(2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.65 g, 10.80 mmol) was dissolved in dimethylformamide (75 ml) and cooled in an ice bath. Sodium hydride (60% in hexanes, 0.57 g, 23.75 mmol) was added and stirred for 10 min. To this solution, benzyl bromide (1.39 ml, 11.69 mmol) dissolved in dichloromethane (9 ml) was dropwise added and the reaction mixture was overnight stirred at room temperature. The solvent was evaporated under reduced pressure and the residue redissolved in ethyl acetate. This organic phase was washed with water, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 3.93 g (77% yield) of the final product were obtained, pure enough to perform the next synthetic step.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10]([Br:21])=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10]([Br:21])=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 70 °C
Yield: 123.6 %

Procedure:
Step 2 A mixture of 7-(azidomethyl)-4-bromo-9H-carbazole-1-carboxamide (350 mg, 0.814 mmol), triphenylphosphine (427 mg, 1.627 mmol), and water (18 μL, 0.976 mmol) in THF (10 mL) was heated at 70° C. for 3.5 h. The mixture was cooled to rt and partitioned between EtOAc and 1 M hydrochloric acid. The pH of the aqueous phase was raised to 8-9 with sodium hydroxide pellets, and then was extracted with EtOAc. The organic phase was dried and concentrated to provide crude 7-(aminomethyl)-4-bromo-9H-carbazole-1-carboxamide as a yellow glassy foam (320 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 11.61 (1H, br.), 8.47-8.55 (1H, m), 8.19 (1H, br. s.), 7.81-7.84 (1H, m), 7.76 (1H, s), 7.63-7.66 (1H, m), 7.53-7.59 (2H, m), 7.41 (1H, d, J=8.1 Hz), 7.27 (1H, dd, J=8.4, 1.3 Hz), 3.90 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[C:20](=[O:21])[N:5]2[N:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[C:8]([CH3:10])=[CH:9][C:4]2=[N:3]1.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:7]2[C:8]([CH3:10])=[CH:9][C:4]3[N:5]([C:20](=[O:21])[N:2]([CH3:1])[N:3]=3)[N:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: Cc1cc2nn(C)c(=O)n2nc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2nn(C)c(=O)n2nc1-c1cccc(N)c1

Procedure:
A mixture of 5.0 g of 2,7-dimethyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one, 50 ml. of trifluoroacetic acid and a catalytic amount of 10% palladium on carbon are shaken in a Parr bottle under 40 lb. pressure of hydrogen for 2 hours and then filtered. The filtrate is concentrated in vacuo to an oil which is dissolved in 50 ml. of water and adjusted to pH 4.7 with 5N sodium hydroxide. The resulting solid is collected by filtration and air dried, giving 3.6 g. of the desired product as a green solid, m.p. 192°-195° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.Cl.[F:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[F:25][CH:26]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:27]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: FC1CCNC1
Agent: Cl
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCC(F)C2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and 3-fluoro-pyrrolidine hydrochloride (226 mg, 1.2 equiv.) (prepared by the method of Giardina, G et al, Synlett (1995), (1), 55–7) are converted to the named compound as a slightly brownish yellow solid (258 mg, 45%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][C@H:36]1[C@H:41]2[CH2:42][C@H:38]([CH:39]=[CH:40]2)[C@H:37]1[C:43]([NH2:45])=[O:44]>>[NH2:45][C:43]([C@@H:37]1[C@@H:38]2[CH2:42][C@@H:41]([CH:40]=[CH:39]2)[C@@H:36]1[NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18])=[O:44]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NC(=O)[C@H]1[C@@H](N)[C@@H]2C=C[C@H]1C2
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2[C@H](C(N)=O)[C@H]3C=C[C@@H]2C3)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 55% purity by HPLC. MS(ESI+): m/z=487.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cu][C:15]#[N:16]>CN(C)C=O.O.Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:10])[CH3:9]
Reactant: N#C[Cu]
Reactant: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(C#N)c([N+](=O)[O-])c1
Yield: 77.5 %

Procedure:
The product of Example 91A (0.581 g, 2.380 mmol) and copper (I) cyanide (0.426 g, 4.760 mmol) in N,N-dimethylformamide (5 mL) under a nitrogen atmosphere were heated in 160° oil bath for 1.5 hour. The reaction was cooled, treated with a solution of iron (III) chloride hexahydrate (2.48 g) in water (3.72 mL) and concentrated hydrochloric acid (0.62 mL), and then heated at 65° for 20 minutes. The cooled reaction mixture was extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed sequentially with 1N aqueous HCl (25 mL), 3N aqueous sodium hydroxide (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 20:80 ethyl acetate/hexanes afforded the title compound as a yellow liquid (0.351 g, 1.845 mmol, 58%). 1H NMR (300 MHz, CHLOROFORM-D) □ppm 1.33 (d, J=6.99 Hz, 6 H) 2.82-3.47 (m, 1 H) 7.66 (dd, J=7.91, 1.29 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1 H) 8.18 (d, J=1.47 Hz, 1 H); MS (DCI) m/z 208 (M+NH4)+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:21]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[S:24][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Yield: 90 %

Procedure:
The title compound was prepared from 4-anisoyl chloride and 2-(4-methoxyphenyl)benzo[b]thiophene (Part A) as a tan solid in 90% yield following recrystallization from THF-hexanes.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[NH2:6][C:7]1([C:18]([OH:20])=[O:19])[CH2:12][CH2:11][C:10]([O:16][CH3:17])([CH2:13][O:14][CH3:15])[CH2:9][CH2:8]1.[CH3:21]O>>[NH2:6][C:7]1([C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11][C:10]([O:16][CH3:17])([CH2:13][O:14][CH3:15])[CH2:9][CH2:8]1
Reactant: CO
Reactant: COCC1(OC)CCC(N)(C(=O)O)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COCC1(OC)CCC(N)(C(=O)OC)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
At 0° C., 4.1 ml (55.60 mmol) of thionyl chloride were added dropwise to 4.70 g of the compound from Example 20A in 50 ml of methanol. The mixture was stirred at 0° C. for 0.5 hours and at 40° C. overnight. After cooling, the mixture was concentrated, the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted repeatedly with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 392 mg (61% of theory from Example 16A) of the title compound as a diastereomer mixture which was reacted without further purification.