Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]CC)=O)=[N:5][C:4]([C:12]([O:14]CC)=O)=[N:3][C:2]=1[C:17]([O:19]CC)=O.[CH3:22][O:23][N:24]1[C:29]([CH3:31])([CH3:30])[CH2:28][CH:27]([NH:32][CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:41][CH3:42])[C:35]([CH3:44])([CH3:43])[CH2:34]2)[CH2:26][C:25]1([CH3:46])[CH3:45]>>[CH3:42][O:41][N:36]1[C:37]([CH3:40])([CH3:39])[CH2:38][CH:33]([N:32]([CH:27]2[CH2:28][C:29]([CH3:31])([CH3:30])[N:24]([O:23][CH3:22])[C:25]([CH3:46])([CH3:45])[CH2:26]2)[C:17]([C:2]2[N:1]=[C:6]([C:7]([N:32]([CH:27]3[CH2:28][C:29]([CH3:31])([CH3:30])[N:24]([O:23][CH3:22])[C:25]([CH3:46])([CH3:45])[CH2:26]3)[CH:33]3[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:41][CH3:42])[C:35]([CH3:44])([CH3:43])[CH2:34]3)=[O:9])[N:5]=[C:4]([C:12]([N:32]([CH:33]3[CH2:34][C:35]([CH3:44])([CH3:43])[N:36]([O:41][CH3:42])[C:37]([CH3:40])([CH3:39])[CH2:38]3)[CH:27]3[CH2:26][C:25]([CH3:46])([CH3:45])[N:24]([O:23][CH3:22])[C:29]([CH3:30])([CH3:31])[CH2:28]3)=[O:14])[N:3]=2)=[O:19])[CH2:34][C:35]1([CH3:44])[CH3:43]
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Reactant: CON1C(C)(C)CC(NC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C
Product: CON1C(C)(C)CC(N(C(=O)c2nc(C(=O)N(C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)nc(C(=O)N(C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)n2)C2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of triethyl 1,3,5-triazine-2,4,6-tricarboxylate and bis(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)amine.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])=O.Cl.[NH2:13][NH:14][C:15]([NH2:17])=[O:16].[OH-].[Na+]>CO.O>[NH2:5][C:4]1[N:14]([C:15](=[O:16])[NH2:17])[N:13]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNC(N)=O
Reactant: N#CC(C=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)n1ncc(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The α-formylphenylacetonitrile obtained above is dissolved in methanol-water (1:1-10:1, 200 ml), and to the solution is added with stirring semicarbazide hydrochloride (9.95 g) under ice cooling. After taking off the ice bath, the mixture is reacted for 12 hours. The reaction mixture is neturalized with 5N sodium hydroxide solution. The mixture is stirred for 20 minutes, and the resulting precipitate is separated by filtration, washed with water and dried to give 3-amino-2-carbamoyl-4-phenylpyrazole (16.82 g). This product is used in the subsequent procedure without further purification.
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:29])([CH3:28])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[S:17]([NH:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[CH3:27])(=[O:19])=[O:18].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:6][Si:7]([CH3:28])([CH3:29])[CH2:8][CH2:9][O:10][CH2:11][C:12]1([CH:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]([S:17]([NH:20][C:21]2[O:25][N:24]=[C:23]([CH3:26])[C:22]=2[CH3:27])(=[O:18])=[O:19])[CH:15]=[CH:14][S:13]1
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)C2C=CSC2(COCC[Si](C)(C)C)C(O)c2ccccc2)c1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
n-BuLi (2.39 M, 177 μl) was slowly added to a solution of (2-trimethylsilylethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (156 mg, 0.38 mmol) in THF at −78° C. under nitrogen. The reaction was stirred at −78° C. for 45 min., then benzaldehyde (45 μl, 0.42 mmol) was added in one lot at −78° C. and the solution was allowed to come to room temperature. Stirring was continued for 1 hr. Purification was achieved by column chromatography using 10% ethyl acetate/hexanes to give 179 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide as a yellow viscous oil (90% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]O.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: COCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOCCOC(=O)CCCCCCCBr
Yield: 78.4 %

Procedure:
8-Bromooctanoic acid (22.3 g), 2-(2-methoxyethoxy)-ethanol (14.08 g) and p-toluenesulphonic acid (0.1 g) were added to toluene (250 ml) and the resulting solution heated at reflux temperature for 16 hours. Ethyl acetate (500 ml) was then added and the solution washed with aqueous K2CO3 solution and water, dried and evaporated. The residual oil was distilled to give 2-(2-methoxyethoxy)-ethyl 8-bromooctanoate (25.5 g), 77%) as a colourless oil, b.p. 126°-128° C./0.08 mm Hg.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[CH:21][N:22]5[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=3)=[CH:9][C:8]=2[C:34]([F:37])([F:36])[F:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:39]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[CH:21][N:22]5[CH2:27][CH2:28][C:29]([O-:31])=[O:30])[N:14]=3)=[CH:9][C:8]=2[C:34]([F:35])([F:36])[F:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:39]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(C5CCCCC5)c(C(F)(F)F)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCn1ccc2c(-c3noc(-c4ccc(C5CCCCC5)c(C(F)(F)F)c4)n3)cccc21
Temperature: 40 °C
Yield: 67.6 %

Procedure:
Ethyl 3-(4-{5-[4-cyclohexyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanoate (D69) (63 mg, 0.123 mmol) was dissolved in ethanol (8 ml) and sodium hydroxide (2M, 0.5 ml, 1.000 mmol) was added. The reaction was heated at 40° C. for 18 h. LCMS showed complete conversion to product. The reaction mixture was concentrated in vacuo and the white solid filtered off and washed with water. On filtration, much compound redissolved and passed through, so solid and filtrate were combined and separated between dichloromethane (10 mL) and 2M HCl (3 mL). The aqueous phase was extracted with further dichloromethane (10 mL). The organic phases were isolated by phase separator, combined and the solvent removed in vacuo. The solid was then dissolved in acetonitrile and water with addition of an equimolar amount of sodium hydroxide (2M, 53 μL) before the solution was freeze-dried to give the title compound (42 mg) as a white solid. δH (methanol-d4, 400 MHz): 8.48 (1H, d), 8.43 (1H, dd), 7.98 (1H, dd), 7.86 (1H, d), 7.73 (1H, d), 7.46 (1H, d), 7.32 (1H, app. t), 7.15 (1H, dd), 4.52 (2H, t), 3.04 (1H, t), 2.69 (2H, t), 2.0-1.8 (5H, m), 1.63 (2H, dd), 1.53-1.37 (3H, m). MS (ES) C26H24F3N3O3 requires 483; found 482 (M−H+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:51][CH2:52][CH3:53])[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[CH3:2]>CO.Cl>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:51][CH2:52][CH3:53])[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[CH3:2]
Reactant: CCCOC(=O)c1c(CC)nc(CCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCOC(=O)c1c(CC)nc(CCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 39.8 %

Procedure:
0.96 g of propyl 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate was dissolved in 22 mL of methanol and then 4.8 g silica gel and 6 drops of 6N HCl were added. The gel was filtered away after 3 days and the resulting silica was washed with CH2Cl2 and then ethyl acetate. The combined organic solutions were evaporated and the residue was chromatographed with a gradient of 0 to 5% methanol in chloroform to provide 0.25 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Temperature: 60 °C
Yield: 78.1 %

Procedure:
A solution of methyl 4-bromo-2-(isopropylsulfonyl)benzoate (Intermediate 242; 516 mg; 1.61 mmol) in THF (10 ml) was treated with a 5 N solution of NaOH in water (4 mL) and the reaction mixture was heated at 60° C. for 1 day. The reaction mixture was acidified with aqueous HCl and the reaction mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated to dryness affording the title compound as a pale yellow solid (386 mg; 78%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH2:8].C(O)(=O)C.[N:13]#[C:14][NH2:15].C([O-])(=O)C>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH:8][C:14]([NH2:15])=[NH:13]
Reactant: COCCOCCN
Reactant: N#CN
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COCCOCCNC(=N)N
Temperature: 90 °C
Yield: 28.4 %

Procedure:
5.96 g (50.0 mmol) of 2-(2-methoxyethoxy)ethylamine and 3.00 g (50.0 mmol) of acetic acid were placed in a 30 ml two neck flask. While heating the flask in a 90° C. oil bath, 3.10 g (73.7 mmol) of cyanamide was added. After 5 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 3.15 g of the title compound (wax-like, 14.2 mmol, 28.5% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH2:15].C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: C=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 2,4-dinitrofluorobenzene (6.38 g, 34 mmol), 4-vinylphenol (4.32 g, 36 mmol), 4.97 g K2CO3 and 2-3 crystals of BHT inhibitor was dissolved in 75 ml NMP and stirred at 40° C. under nitrogen for 4 hr. The reaction mixture was poured into a separatory funnel containing 150 ml water and extracted 3×100 mls with ethyl acetate. The combined organics were washed with 100 ml 10% KOH, and brine, dried with anhydrous MgSO4 and concentrated. The residue was recrystallized from 70% ethyl acetate in hexane yielding 9.5 g product.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][S:48](Cl)(=[O:50])=[O:49].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:42][CH:41]=2)=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.258 g, 0.43 mmol) in tetrahydrofuran (4.5 mL) was added methanesulfonyl chloride (0.05 mL, 0.64 mmol) and triethylamine (0.30 mL, 2.14 mmol). The final crude product was purified by preparative HPLC (10–100% acetonitrile to H2O, 20 min.) (0.042 g, 28% yield): 1H NMR (CD3OD) δ 7.93 (dd, 1H), 8.54 (br s, 1H), 8.29 (dd, 1H), 8.20 (m, 2H), 7.87 (dd, 1H), 7.62 (m, 2H), 3.23 (s, 3H); ES-MS (m/z) 355 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:4].[BH4-].[Na+].CC(O)=O>CO>[OH:4][CH2:3][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:18])([F:19])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH3:1]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C=O)cc2OC1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)CO)cc2OC1C(F)(F)F
Reaction time: 0.42 h

Procedure:
To a solution of ethyl 7-(1,1-dimethyl-2-oxoethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (6.90 g, 20.2 mmoles) in 200 mL of MeOH stirring in an ice bath, was added portionwise NaBH4 (763 mg, 20.2 mmoles) as a solid. After 25 min, HOAc was cautiously added, and the solution concentrated. The residue was partitioned between DCM and water, and the organic extract dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using a gradient of 0-10% EtOAc—DCM as eluent gave the title compound, 5.4 g, as a very pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)/[C:11](=[N:30]/[NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)C2=O
Reactant: NNC(=O)c1ccccc1
Product: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1-benzyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. 1H NMR (CDCl3): δ 3.77 (s, 3H), 4.94 (s, 2H), 6.35 9d, 1H), 6.62 (dd, 1H), 7.29-7.36 (m, 4H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.01 (d, 2H), 13.95 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH3:11])[C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[N:26]=[C:27]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:28]([CH3:34])=[N:29]2)=[O:23]>CN(C=O)C.C(Cl)Cl>[C:36]([NH:35][C:27]1[C:28]([CH3:34])=[N:29][C:30]2[C:25]([N:26]=1)=[C:24]([C:22](=[O:23])[CH2:21][CH:5]([C:4](=[O:10])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH3:11])[C:6]([O:8][CH3:9])=[O:7])[CH:33]=[CH:32][CH:31]=2)([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)(OC)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 4,4-dimethoxy-3-oxovalerate (Sigma Aldrich, 0.127 ml, 0.744 mmol), K2CO3 (EMD Biosciences, 0.135 ml, 2.231 mmol), 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (0.25 g, 0.744 mmol) in DMF (2.97 mL) was stirred at RT for 2 d. Reaction mixture was diluted with DCM and washed with alternating water and brine washes (2×) to remove DMF. The organic layer was concentrated and advanced to the next step. m/z (ESI, +ve) 446.1 (M+H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22]([NH:24][CH:25]([C:32]#[N:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.[NH2:41][OH:42]>C(O)C>[NH2:33]/[C:32](=[N:41]\[OH:42])/[C@H:25]([NH:24][C:22]([CH:18]1[N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:9][CH:10]=2)(=[O:15])=[O:16])[CH2:21][CH2:20][S:19]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#CC(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N/C(=N\O)[C@H](NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (92 μl, 0.66 mmol) was slowly added to a suspension of product Ic, e.g., 3-(biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-1,3-thiazolidine-2-carboxamide, and hydroxylamine.hydrochloride (46 mg, 0.66 mmol) in ethanol (5 mL), under stirring. The reaction mixture was heated under reflux for 16 h, and then cooled to RT. The solvents were removed and the resulting solid was suspended in water and extracted with three portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording intermediate Id, e.g., N-[(1R,2Z)-2-amino-2-(hydroxyimino)-1-phenylethyl]-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (272 mg, quantitative yield) which was directly used in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][CH2:29]S(C1C=CC=CC=1)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:29][CH2:28][CH2:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]=4[CH3:17])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 31 %

Procedure:
A stirred mixture, under nitrogen, of 27.0 g of 3-(4-piperidyl-6-chloro-1,2-benzisoxazole, 31.3 g of 2-methyl-3-(3-phenylsulfonylpropyl)indole and 27.6 g of anhydrous potassium carbonate in 500 ml of methyl ethyl ketone was heated under reflux for 6 hrs. The mixture was cooled and treated with 150 ml of water. The organic phase was separated, extracted with water and concentrated to an oily residue. The residue was dissolved in 50 ml of ethyl acetate and absorbed on a chromatography column containing 300 g of silica gel packed in ethyl acetate. Elution with ethyl acetate, followed by concentration of the eluent and trituration with ether, provided 12.1 g (31% yield) of product. Recrystallization from a small volume of toluene afforded the anlytical sample, mp 108°-110°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(-n2ccnc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(-n2ccnc2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 10ml of ethanol was dissolved 0.342 g of 3-amino-4,5-diethoxycarbonyl-6-(imidazol-1-yl)-2-phenylpyridine, and 0.5 ml of hydrazine monohydrate was added to the solution. The mixture was heated under reflux for 7 hours. After the reaction mixture was concentrated, the residue was acidified with acetic acid. The resulting precipitate was collected with. filtration and washed with water, followed by reprecipitation from DMF/H2O, to give 0.2 g of the title compound as yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH2:11](O)[CH2:12][OH:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][CH:6]1[C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: OCCO
Reactant: N#Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccc(C2OCCO2)c1
Yield: 100 %

Procedure:
A mixture of 3-cyanobenzaldehyde (9.81 g), ethylene glycol (9.31 g), p-toluenesulfonic acid monohydrate (0.07 g) and toluene (200 ml) was heated under reflux for 15 hrs., while removing generated water with a Dean-Stark trap. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-(1,3-dioxolan-2-yl)benzonitrile (13.1 g, yield 100%) as a colorless oil. NMR (CDCl3) δ: 4.01–4.17 (4H, m), 5.83 (1H, s), 4.50 (1H, t, J=7.6 Hz), 7.63–7.74 (2H, m), 7.80 (1H, t, J=1.6 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:26]1[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: N[C@H](CCO)c1ccc(C(F)(F)F)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (200 mg, 0.70 mmol) and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (180 mg, 0.82 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.7 mL, 4 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3C(F)(F)F)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 2-(trifluoromethyl)phenylboronic acid (190 mg, 1.0 mmol) to afford after chromatographic purification the title compound (175 mg, 79%). 1H NMR (CDCl3, 300 MHz) δ7.69 (d, 1H, J=7.7 Hz), 7.50 (dd, 1H, J=7.3, 7.7 Hz), 7.40 (dd, 1H, J=7.7, 7.3 Hz), 7.31 (d, 1H, J=7.3 Hz), 6.89 (s, 1H), 6.85 (s, 1H), 3.82-4.30 (m, 2H), 3.66-3.71 (m, 1H), 2.88-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS-ApCI: 445 [M+H+].