Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Cl)cc1Br
Yield: 99.5 %

Procedure:
A rapidly stirred solution of 15.5 grams (0.074 mole) of 2-bromo-4-chlorophenol, 20.0 grams (0.145 mole) of anhydrous powdered potassium carbonate, and 10 mL (0.106 mole) of dimethyl sulfate in 150 mL of acetone was heated at reflux for about 18 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between 100 mL each of water and methylene chloride. The organic layer was removed and washed with an aqueous solution saturated with sodium chloride. The organic layer was then dried with magnesium sulfate and filtered. The filtrate was passed through a short column of silica gel. Elution was accomplished with 500 mL of methylene chloride. The eluate was concentrated under reduced pressure, yielding 16.3 grams of 3-bromo-4-methoxychlorobenzene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>C(Cl)Cl.CCOC(C)=O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Pyrrolidine (20.0 mL, 0.240 mole) was added to a stirred solution of 4-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. under nitrogen. The resultant solution was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with EtOAc (150 mL) before it was washed with half-saturated aqueous NaHCO3 (50 mL). After drying over MgSO4, filtration, and concentration, the oily residue was chromatographed on silica [20% EtOAc in hexanes, then 10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 9.02 g of the benzyl pyrrolidine (94%) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:18]1([NH:24]CCN)C=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCCNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and N-phenylethylenediamine (68 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (51 mg) and a syn-form compound (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=C1Cc2cccc(Cl)c2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2c(Cl)cccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
7-Chloro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:26](N(OC)C)=[O:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][Mg]Br>O1CCCC1>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:16]([C:26](=[O:27])[CH3:32])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloro-N-methoxy-N-methylquinoline-7-carboxamide (312 mg, 0.672 mmol) in tetrahydrofuran (0.9 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (2.9 mL, 4.0 mmol). The reaction was stirred at room temperature overnight, then quenched with sat. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and then concentrated to dryness under reduced pressure to afford the desired product (0.275 g, 98%). LCMS calculated for C22H32ClN2O2Si (M+H)+: m/z=419.2; Found: 419.1.
Reaction SMILES: FC(F)(F)C1C=CC(N2C3C(=CC=CC=3)C([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=N2)=CC=1.C1([N:32]=[C:33]=[O:34])C=CC=CC=1>C1(C)C=CC=CC=1>[N:21]1([C:33]([NH2:32])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]1
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)N1CCCCC1

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 77 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene (60 ml) was added phenyl isocyanate (1.38 ml, 0.013 moles). The reaction temperature rose to 35° C. and the product precipitated from the solution. The product was collected and recrystallized twice from toluene to yield 3.57 g (66%) of N-phenyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p. 190°-192° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:12][N:13]([CH3:14])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C

Procedure:
2-Chloro-5-nitropyridine (3.57 g, 22.5 mmol), dimethylamine hydrochloride (5.50 g, 67.5 mmol) and diisopropylethylamine (13.7 mL, 78.7 mmol) were combined in DMSO (15 mL) and the reaction mixture was heated at 80° C. for 4 h. After cooling to RT, water was added and the desired N,N-dimethyl-5-nitropyridin-2-amine was isolated by filtration and used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1.[ClH:38].CCOCC>O1CCOCC1>[ClH:38].[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4ccc(OC(F)F)cc4)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1ccn(-c2ccc(OC(F)F)cc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-(difluoromethoxy)phenyl)-1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (130 mg, 0.25 mmol) was dissolved in dioxane (0.6 ml) and a solution of HCl in dioxane (4M, 0.12 ml, 3.8 mmol) was added. The reaction mixture was stirred overnight at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo to afford (S)-1-(4-(difluoromethoxy)phenyl)-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide hydrochloride (90 mg, 79%) as an off-white solid. MS (ISP): 415.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14](#[N:16])C.ClS(N=C=O)(=O)=O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CCOC(C)=O.C(OCC)(=O)C.CCCCCC.CN(C)C=O>[C:14]([C:9]1[N:8]([NH:7][C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[CH:11][CH:10]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: CC#N
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nn1cccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 2 L, 3-neck RB was fitted w/stir bar, N2 inlet, rubber septum low-temp. thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0° C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temp. below 5° C.); after ˜20 minutes a suspension was observed. After 45 minutes N,N-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temp. below 5° C.) and the reaction mixture became a solution. Stirring @ 0° C. was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninhydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (˜2 L) and stirred with addition of EtOAc (2 L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50% ethyl acetate. The clean, product-containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): δ 7.01 (dd, 1H, J=3.0, 1.6 Hz), 6.82 (dd, 1H, J=4.4, 1.7 Hz), 6.19 (dd, 1H, J=4.2, 2.9 Hz), 4.88 (s, 1H, H2O+NH—), 1.50 (br s, 9H, HN—BOC); MS: LC/MS (+esi), m/z=207.9 [M+H].
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25]([NH:27][C:28]1[NH:32][C:31]([S:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:30][N:29]=1)=[O:26])[CH3:14]>ClCCl>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:27][C:28]1[N:32]=[C:31]([S:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:9])[NH:30][N:29]=1)=[O:26])[CH3:12]
Reactant: CCCCCCCCCCCCCSc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCS(=O)c1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
m-Chloroperbenzoic acid (0.26 g, 1.49 mmol) was added to a cooled (0° C.) solution of the compound of Example 15 in dichloromethane (25 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. The mixture was diluted with CH2Cl2 (100 mL) and washed sequentially with NaHSO3, water, NaHCO3, and brine, dried over Na2SO4, concentrated, and triturated with hexane to give a white solid which was filtered and dried in vacuo to yield 0.42 g; m.p. 178°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+].O1CCCC1.Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1C=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
A 50 mL round-bottom flask was charged with methyl 5-bromo-2-formylbenzoate (1.00 g, 4.11 mmol, 1.00 equiv), lithium hydroxide (2.00 g, 83.5 mmol, 20.0 equiv), tetrahydrofuran (10 mL), and H2O (10 mL). The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride solution (2 mol/L). The solid were collected by filtration to yield 0.700 g (crude) of 5-bromo-2-formylbenzoic acid as a light yellow solid. LCMS (ESI, m/z): 227 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1sc2ccccc2c1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CO)sc2ccccc12
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Add a solution of methyl 3-methylbenzo[b]thiophen-2-carboxylate (5.00 g, 24.2 mmol) in THF (25 mL) dropwise to a 1M solution of lithium aluminum hydride in THF (121 mL, 121 mmol) at 0° C. Stir 1 hour. Add an excess of sodium sulfate decahydrate portionwise (slowly at first), stir for 30 minutes at 0° C., then 2 hours at room temperature. Filter, and wash the cake with THF. Concentrate the combined filtrates to afford the drawn product as a white solid (3.60 g, 83%): 1H NMR (CDCl3) δ 7.81 (m, 1H), 7.68 (m, 1H), 7.35 (m, 2H), 4.92 (d, 2H), 2.40 (s, 3H), 1.77 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:30])[CH2:21][NH:22]C(=O)OC(C)(C)C)[C:15](=[S:31])[NH:14][C:13](=[O:32])[CH:12]=1.[ClH:33]>C(OCC)(=O)C>[ClH:33].[NH2:22][CH2:21][C:20]([NH:19][CH2:18][CH2:17][N:16]1[C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[CH:12][C:13](=[O:32])[NH:14][C:15]1=[S:31])=[O:30]
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCNC(=O)CNC(=O)OC(C)(C)C)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCNC(=O)CN)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate (70 mg, 0.15 mmol) in ethyl acetate (2 mL) was added a solution of HCl in ethyl acetate (2 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure to afford the desired 2-amino-N-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)acetamide hydrochloride as a solid (65 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[C:21]([CH2:26][OH:27])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)Nc2ccc(O)c(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCCN(C)C)c(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
To a solution of 1-[(3,4-dichlorophenyl)methyl]-N-[4-hydroxy-3-(hydroxymethyl)phenyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 26) (0.1 g, 0.245 mmol) in DMF (10 mL), were added potassium carbonate (0.07 g, 2 eq) and (2-chloroethyl)dimethylamine hydrochloride (0.07 g, 2 eq). The reaction was heated at 40° C. for 3 days. After evaporation, the residue was diluted with DCM, washed with water and dried over sodium sulphate. After purification by flash chromatography eluting with DCM/MeOH (90/10) and recrystallisation from methanol, the title compound was obtained as a white solid (18 mg, 16%). HRMS calculated for C22H25Cl2N5O3 (M+H)+ 478.1413, found: 478.1435, Rt: 2.47 min. MP: 163.1° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH3:31])=[O:5])C.[OH-].[Na+].C(OCC)(=O)C>C(O)C.O>[CH3:31][C:7]1[N:8]=[C:9]([NH:11][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Yield: 11.9 %

Procedure:
A mixture of 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid ethyl ester (500 mg, 1.17 mmol) in ethanol (10 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (3.51 mL, 3.51 mmol). The resulting mixture was heated to 50° C. for 18 h. At this time, the reaction was treated with an additional amount of a 1N aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol). This mixture was heated at 50° C. for an additional 8 days. At this time, the reaction was diluted with water (100 mL), acidified to pH=5, and treated with ethyl acetate. The resulting white solid was collected by filtration and dried in vacuo. The filtrate was extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid (55.7 mg, 11.9%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ9.09 (broad s, 1H), 7.22 (m, 15 H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:12]#[N:13])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][CH3:8].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:12]#[N:13])([CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][CH3:8])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CCCC(C(C)C)C(C#N)C(=O)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(C)C)C(C#N)(CC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-cyano-3-isopropyl-hexanoic acid methyl ester (1.9 g, 9.6 mmol) in 10 mL of THF is added to a slurry of NaH (washed with hexane, 0.23 g, 9.6 mmol) in 20 mL of THF which is cooled in an ice water bath under argon. The solution is stirred for 10 minutes, and t-butyl bromoacetate (2.1 g, 10.6 mmol) is added. The solution is warmed to room temperature. After 12 hours, the reaction is quenched by addition of 50 mL of saturated KH2PO4 and the THF is evaporated. The organic products are extracted into Et2O (3×50 mL), and the combined organic layers are dried over MgSO4. The solvent is evaporated, and the remaining oil is chromatographed under medium pressure over silica gel in 25% hexane/CH2Cl2. Yield of 2-cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester=1.3 g (42%) as an oil.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH3:45])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=2[CH2:23]1)[CH3:2]
Reactant: COCCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCCOC)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 20.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-(3-methoxypropyl)-N-methylacetamide (9.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=O.[OH-].[Na+]>C(O)C.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[C:6]([F:12])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 67 %

Procedure:
To a stirred solution of 155 g (0.83 mole) of 4-chloro-2-fluoroacetanilide in 400 ml of ethanol was added dropwise a solution of 72.0 g (1.8 moles) of sodium hydroxide in 100 ml of water. Upon completion of addition the reaction mixture was heated under reflux for three hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether. The combined extracts were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 81.0 g of 4-chloro-2-fluoroaniline; b.p. 83-85/12 mm. The reaction was repeated several times.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10].[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]([F:9])=[CH:5][C:4]=1[Cl:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 89 %

Procedure:
To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54 mol) in conc. H2SO4 (50 mL) was slowly added a mixture comprised of cone. H2SO4 (40 mL) and fuming HNO3 (40.8 mL, 0.89 mol). The resultant mixture was stirred for 30 min at 0° C. The reaction mixture was poured into ice water and the precipitated solid was collected by filtation and washed with water to give 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J=7.2 Hz, 1H), 8.12 (d, J=10.8 Hz, 1H), 3.89 (s, 3H); MS (ESI) m/z: 250.1 (MAI).