Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:27].Cl>O1CCOCC1.O>[F:26][C:21]1[CH:20]=[C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:28])=[O:4])=[C:8]2[CH3:27])(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(F)c2)c2ncccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1M Aqueous LiOH (0.52 mL) is added at 0° C. to a stirring solution of [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (200 mg, 0.526 mmol) in 1:1 dioxane/water (4 mL). The reaction mixture is stirred at 0° C. for 15 minutes, then allowed to warm to room temperature. After 2.5 hours, the reaction mixture is neutralised to pH 7 with 1M HCl and the solvent is removed under reduced pressure. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% CH2Cl2 to 5% methanol in CH2Cl2 to afford [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=367.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]2[C:11](=O)[NH:12][C:13](=[O:24])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=[CH:2]1.II.[O:28]1CCOCC1>>[CH:3]1[CH:2]=[N:1][C:9]2[C:4]=1[CH2:5][CH:6]=[C:7]1[C:16]3[C:15]([C:23]4[CH2:22][C:21](=[O:28])[CH:20]=[CH:19][C:18]=4[N:17]=3)=[C:14]3[C:13](=[O:24])[NH:12][CH:11]=[C:10]3[C:8]=21
Reactant: C1COCCO1
Reactant: O=C1NC(=O)C(c2cccc3cc[nH]c23)=C1c1c[nH]c2ccccc12
Agent: II
Product: O=C1C=CC2=C(C1)c1c3c(c4c(c1=N2)=CCC1=CC=NC=41)=CNC3=O

Procedure:
A solution of 3-(1H-indol-7-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (140 mg, 0.428 mmol) and iodine (114 mg, 0.449 mmol) in dioxane (200 mL) was photolyzed with a 450 W Hanovia lamp fitted with pyrex filter for 20 minutes. The mixture was concentrated to ˜20 mL, poured into EtOAc and washed with 10% aq NaHSO3, water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto SiO2. Flash Chromatography (30% EtOAc/hexanes) afforded the title compound as an orange powder which was dried under vacuum at 70° C. for overnight (66 mg, 47%). 1H NMR (400 MHz, DMSO-d6) 12.78 (s, 1H), 12.62 (s, 1H), 11.51 (S, 1H), 8.96 (d, J=8 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 1H), 7.70–7.76 (m, 2H), 7.56 (dd, J=8, 8 Hz, 1H), 7.38 (dd, J=8, 8 Hz, 1H), 6.81 (br s, 1H). MS (electrospray, m/z) 326 (M++1), 324 (M−−1) 324. HRMS 326.0941 (M++1, calcd for C20H12N3O2 326.0930).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=O)[CH3:24])[CH:18]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[CH2:27]([O:31][NH2:32])[CH2:28][CH2:29][CH3:30]>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[N:32][O:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])[CH:18]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1COc1cccc(C(C)=O)c1
Reactant: CCCCON
Agent: Cl
Solvent: CO
Product: CCCCON=C(C)c1cccc(OCc2ccccc2C(=NOC)C(=O)OC)c1
Yield: 71.3 %

Procedure:
5.8 g (0.017 mol) of methyl 2-(3-acetylphenoxymethyl)phenylglyoxylate O-methyloxime and 2.5 g (0.020 mol) of n-butoxyamine hydrochloride in 60 ml of methanol are stirred at room temperature for 24 hours. The mixture is then hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.0 g (71%) of the title compound are obtained as a colorless oil (compound no. 470).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23]([OH:25])=O)=[CH:15][CH:14]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH:41][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[F:12])=[CH:14][CH:15]=3)=[O:25])=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: CCN1CCN(Cc2ccc(N)cn2)CC1
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(F)c(OC)cc(OC)c4F)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (prepared as described in Example 39 but using N-ethyl-piperazine in Step 39.2), and stirring the reaction mixture for 3 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 549.1 [M+H]+; tR=3.22 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1)[CH2:30][CH2:31][OH:32])[CH3:28]
Reactant: CCNCCO
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and 2-ethylamino-ethanol were converted to yield 2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol as yellowish oil, MS: 452 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[OH:16])[N:12]=1.O.[OH-].[Li+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([CH3:30])([CH3:31])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[OH:16])[N:12]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(O)CCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CCC(O)c1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
The resulting propionic acid derivative (80 mg, 0.16 mmol) was dissolved in a mixture of ethanol (2 mL) and water (1 mL). To the solution was then added lithium hydroxide monohydrate (10 mg). The mixture was stirred for 20 hours at room temperature, cooled with ice, neutralized by addition of diluted hydrochloric acid, and subjected to extraction using ethyl acetate. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was removed under reduced pressure, to give 55 mg of the desired compound as pale yellow oil residue (yield 73%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N+]([C:8]1[C:9]([N+]([O-])=O)=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)([O-])=O>C1(C)C=CC=CC=1>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Commercial aromatic nitration processes are generally operated with a mixed acid system comprising sulfuric and nitric acids. A substantial amount of nitric acid is typically lost in an economically and environmentally unsound manner in the spent acid of nitration. For example, conventional dinitrotoluene processes comprise reacting toluene in a first nitration stage to form mononitrotoluene and separating the organic product from the aqueous spent acid phase. The nitric acid in the spent acid phase is usually removed or recovered so that the remaining sulfuric acid can be reconcentrated and recycled. The crude mononitrotoluenes are then nitrated with fresh nitrating acid in a second nitration stage. The dinitrotoluene product is then separated from the aqueous spent acid phase which is recycled to a nitration stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[S:25])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
A solution of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (18 g, 67 mmol) in dry THF was treated with Lawesson's reagent (27 g, 67 mmol) in one portion at room temperature. The mixture was refluxed for 2 h. The title compound was obtained by chromatography on silica gel (PE/EtOAc=30:1 to 10:1). 1H-NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 7.50 (m, 2H), 7.35 (m, 2H), 4.36 (s, 2H), 4.00 (m, 1H), 3.73 (m, 1H), 1.51 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH2:12](N=C=N)[CH3:13].C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][N:3]=1
Reactant: CCN=C=N
Reactant: O=C(O)c1ccc(I)nc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-iodonicotinic acid (23.38 g, 94.20 mmol) in dichloromethane (100 ml) was added a solution of 13-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.86 g, 103.6 mmol) in dichloromethane (250 ml). To this mixture was added ethanol (12.40 g, 269.27 mmol) followed by dimethylaminopyridine (1.15 g, 9.41 mmol). The mixture was heated at 50° C. for 24.5 hours, concentrated in vacuo, and diluted with water (200 ml) then extracted with ethyl ether (550 ml). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to a yellow solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as white needles: mp 48-49° C.; 1H NMR (CDCl3): δ 8.94 (1H, d, J=2.1 Hz), 7.91 (1H, dd, J=2.1, 8.2 Hz), 7.85 (1H, d, J=8.2 Hz), 4.41 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:20][CH:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>CN(C)C=O>[CH3:1][C:2]1[N:3]([C:23](=[O:24])[CH2:22][CH:21]([CH3:26])[CH3:20])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C(=O)OC(C)(C)C
Reactant: CC(C)CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)CC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a solution of tert-butyl 2-methyl-1H-indole-3-carboxylate (300 mg, 1.30 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (103.76 mg, 2.59 mmol, 60%). The mixture was stirred at 0° C. for 30 minutes. Then 3-methylbutanoyl chloride (234.60 mg, 1.95 mmol) was added at 0° C. and the mixture was stirred at room temperature (25° C.) for 2 hours. The mixture was cooled with ice, quenched with water (5 mL), diluted with ethyl acetate (20 mL), washed with brine (20 mL), extracted with ethyl acetate three times (20 mL×3), then dried over sodium sulfate. After concentration, the residue was purified by column on silica gel (0%-5% PE/EA) to afford the title compound (200 mg, yield: 48.89%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[C:45]3[NH:46][NH:47][CH2:48][CH2:49][N:44]3[N:43]=2)=[CH:38][CH:37]=1>CN(C)C=O.O>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[C:45]3[NH:46][N:47]([C:11](=[O:13])[CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH2:48][CH2:49][N:44]3[N:43]=2)=[CH:38][CH:37]=1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccccc12)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of 3-indolylacetic acid (57 mg, 0.325 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (50 mg, 0.325 mmol) and 1-hydroxybenzotriazole (44 mg, 0.325 mmol) in N,N-dimethylformamide (0.6 ml) was stirred for 1 hour at ambient temperature. Then to the mixture was added 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (80 mg, 0.271 mmol) in N,N-dimethylformamide (1 ml). After stirring for 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by crystallization from ethyl acetate to give 7-(4-fluorophenyl)-2-(3-indolylacetyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (87 mg).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[C:12]1C=CC=[CH:17][C:13]=1[C:14](Cl)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:13]([CH3:17])([CH3:14])[CH3:12])=[O:5]
Reactant: O=C(Cl)c1ccccc1I
Reactant: O=C(O)c1ccccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1I
Reaction time: 0.33 h

Procedure:
2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CN(C)C(=O)C.Cl[C:18]([O:20][CH3:21])=[O:19].C(=O)(O)[O-].[Na+]>O>[CH3:21][O:20][C:18]([NH:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: COC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 93 %

Procedure:
A mixture of 10 g of 3-nitroaniline and 100 ml of N,N-dimethylacetamide was stirred under ice cooling and 8.2 g of methyl chloroformate was added dropwise to the mixture. After stirring the mixture for 30 minutes, 300 ml of water was added to the reaction mixture and then the reaction mixture was neutralized by the addition of sodium bicarbonate to deposit crystals, which were recovered by filtration, washed with water, and dried. The amount of the product was 13.1 g (yield: 93%).
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][C:7]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)([C:12]#[N:13])[CH2:8][CH2:9][C:10]\1=O)C.[CH2:29]([N:33]=[C:34]([NH2:36])[NH2:35])[C:30]([OH:32])=[O:31].[OH-].[Na+]>CO>[C:12]([C:7]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)[CH2:8][CH2:9][C:10]2[N:36]=[C:34]([NH:33][CH2:29][C:30]([OH:32])=[O:31])[N:35]=[CH:4][C:5]=2[CH2:6]1)#[N:13]
Reactant: COc1ccc(C2(C#N)CCC(=O)/C(=C/N(C)C)C2)c2c1oc1ccccc12
Reactant: NC(N)=NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc(NCC(=O)O)ncc3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in example 6 (100 mg, 0.267 mmol), guanidine acetic acid and sodium hydroxide (54 mg, 1 mol) in 10 ml of methanol was stirred at 60-70° C. for 8 hrs. Methanol was evaporated under vacuum and the reaction mass was diluted with 10 ml of water. The aqueous layer was washed with ether, acidified with 0.1 N HCl to pH 2 and extracted with ethyl acetate. The organic layer was washed with water followed by brine, and concentrated under vacuum. The crude product was crystallized form hexane to give 60 mg (52.45% yields) of a yellow colored solid.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14](N)[S:15][C:11]=2[CH:10]=1.[ClH:19]>CC#N.[Cu](Cl)Cl>[Cl:19][C:14]1[S:15][C:11]2[CH:10]=[C:9]([CH3:8])[CH:18]=[CH:17][C:12]=2[N:13]=1
Reactant: Cl
Reactant: Cc1ccc2nc(N)sc2c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
t-Butyl nitrite (3.25 mL, 27.4 mmol) was added to a suspension of copper (II) chloride (2.95 g, 22.0 mmol) in CH3CN (31 mL). 6-Methyl-2-aminobenzothiazole (3.0 g, 18 mmol) was added portionwise over ˜30 min., and the reaction mixture was stirred at rt overnight. The reaction mixture was poured into 20% aqueous HCl (100 mL) and was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 10% EtOAc in Hexanes gradient), yielding 2.50 g (74%) of the title compound as a yellowish oil that solidified on standing. LC-MS: RT=9.71 min., [M+H]+=184.0.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:16])[N:7]([CH2:8][CH2:9][OH:10])[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]12.Cl[CH2:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:19]([CH2:18][O:10][CH2:9][CH2:8][N:7]1[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]2[C:3]1=[O:16])=[O:26])[CH3:25]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a slurry of sodium hydride (57% dispersion in oil, 66.1 g; 1.57M), in tetrahydrofuran (500 ml) cooled to 0° under nitrogen was added B 2-phthalimidoethanol (150 g; 0.785M) followed by ethyl 4-chloroacetoacetate (129 g; 0.785M) in tetrahydrofuran (250 ml) over 1 hour. The mixture was stirred at room temperature overnight then poured into a mixture of 1M hydrochloric acid (800 ml) and ethyl acetate (750 ml). The organic phase was separated and the solvent was evaporated at reduced pressure. The residue separated into two layers and the upper layer of mineral oil was removed to leave the title compound (243 g) as a crude product which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[NH:9][C:8]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[N:7][N:6]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:39])([CH3:40])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:8]2[NH:9][C:5]([CH2:4][C:3]([OH:41])=[O:2])=[N:6][N:7]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1nnc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2nnc(CC(=O)O)[nH]2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
A mixture of rac-(5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazol-3-yl)-acetic acid methyl ester (20 mg, 0.033 mmol) was dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield rac-(5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazol-3-yl)-acetic acid (6.7 mg, 34%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H26Cl2F2N6O3+H [(M+H)+]: 591.1485. found: 591.1483.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 85.5 %

Procedure:
A slurry of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene (15.1 g, 46.8 mmol) in absolute ethanol (500 mL) and methanol (200 mL) was purged with nitrogen, treated with 10% palladium on carbon (1.2 g, 50% water by wt.) and placed on a Parr Hydrogenator under 43 psi of hydrogen gas. The catalyst was removed by filtration. Solvent removal under reduced pressure gave a solid after drying. Purification by flash silica gel chromatography using a step gradient of 50 to 85% ethyl acetate in hexane gave 11.7 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxybenzenamine, NMR (CDCl3, TMS) δ1.45 (s, 9), 1.7 (m, 2), 1.86 (m, 2), 3.25 (m, 2), 3.68 (m, 2), 4.25 (m, 1), 6.63 (m, 2), 6.76 (m, 2).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1)[CH3:23]
Reactant: Cc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1
Reactant: CCOc1ccc(S)cc1
Product: CCOc1ccc(Sc2cc(N3CCN(C)CC3)nc(-c3ccc(C)cc3)n2)cc1

Procedure:
In a similar manner, the above prepared 4-chloro-6-(4-methyl-1-piperazinyl)-2-(4-tolyl)-pyrimidine is reacted with p-ethoxythiophenol to afford 4-(4-ethoxyphenylthio)-6-(4-methyl-1-piperazinyl)-2-(4-tolyl)-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1cccnc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cccnc1
Yield: 101.2 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) in DMF (100 mL) with triethylamine (8.53 mL, 61.2 mmol) and 3-aminomethylpyridine (4.16 mL, 40.8 mmol). After the precipitate was isolated by filtration, it was dried for three hours in a vacuum oven at 60° C. to provide 13.0 g of 2-chloro-3-nitro-N-(pyridin-3-ylmethyl)quinolin-4-amine as a yellow solid.