Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[O:36]>>[CH2:38]([O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isobutyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with isobutyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, 6H, J=6.7 Hz), 1.86-2.09 (m, 6H), 3.04-3.16 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.82-3.84 (m, 2H), 4.12-4.16 (m, 2H), 5.02-5.08 (m, 1H), 7.62-7.64 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=474.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([O:10][C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:9]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
Thionyl chloride (50 mL, 680 mmol) was added to 2,4,5-trifluorobenzoic acid (10 g, 57 mmol) and the mixture stirred at 55° C. for 18 hours. After cooling, the excess thionyl chloride was removed in vacuo. The resulting crude oil was azeotroped twice with DCM (30 mL) and toluene (20 mL) and the residue redissolved in DCM (50 mL), then cooled to 0° C. with an ice bath. A mixture of 4-methylphenol (6.4 g, 59 mmol) and triethylamine (10 mL, 71 mmol) in DCM (20 mL) was added over 30 minutes. The reaction was allowed to warm up to room temperature over 1 hour. The crude reaction mixture was partitioned between EtOAc (200 mL) and saturated sodium bicarbonate solution (70 mL). The aqueous layer was separated and extracted with EtOAc (100 mL). The combined organic extracts were combined, washed with saturated sodium bicarbonate solution (70 mL) and water (100 mL), dried over magnesium sulfate and concentrated in vacuo to provide a crude solid, which was purified by silica gel chromatography eluting with 5% EtOAc in heptane to provide the title compound (10.08 g, 66%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>O1CCOCC1>[Br:12][C:13]1[CH:14]=[N:15][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(Nc2ncc(Br)cn2)cc1

Procedure:
2-(4-Aminophenyl)acetic acid (4.56 mmol), 5-bromo-2-chloropyrimidine 4 (3.26 mmol), and p-TSA (0.842 mmol) are heated at reflux in 1,4-dioxane (10 mL) and DMSO (2 mL) for 16 h. The mixture is poured onto water and extracted with EtOAc. Concentration of the organic phase gives 2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.84 (s, 1H), 8.58 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.50 (s, 2H). MS (m/z) (M+1)+: 308.0, 310.0.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.O.NN.[OH-].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 1 h

Procedure:
30 Parts of 1-nitro-anthraquinone-2-carboxylic acid are entered with stirring over the course of 1 hour into a mixture at 70° consisting of 250 parts of water, 10 parts of hydrazine hydrate and 67 parts of aqueous sodium hydroxide solution (30%). The reaction mass is heated to 80° and stirred at 80° over the course of 4 hours. It is subsequently diluted with 250 parts of water and filtered. The precipitate is stirred into 1000 parts of water and acidified with aqueous hydrochloric acid. The precipitate is filtered off, washed with water until the filtrate is colourless and neutral, and then dried. 20 Parts of 1-amino-anthraquinone-2-carboxylic acid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:21])[CH2:12][O:13]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:21])[CH2:12][OH:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OC(=O)CO)cc1
Reaction time: 16 h

Procedure:
4-(2-Benzyloxy-acetoxy)-benzoic acid methyl ester 40 (2 grams, 6.66 mmol) is dissolved in methanol (50 ml) in a pressure vessel, palladium on carbon (50% wet, 5%, 5 grams) added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 16 hours. The catalyst is removed by filtration and distilled off the methanol. The crude 41 can be crystallized from a mixture of chloroform:hexane (1:6) to get the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=[O:26])[CH2:22]2>>[CH3:17][N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)([OH:26])[CH2:22]2
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Product: CN1C2CCC1CC(O)(c1ccc(C(F)(F)F)cc1)C2

Procedure:
The title compound was prepared from 4-bromobenzotrifluoride, n-butyllithium in hexanes (31.2 mL, 2.5M; 77.9 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (5 g, 36 mmol). Yield 6.2 g (60%) as a yellow solid, m.p. 189.2-190.5° C.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C1COCCN1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cn1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of Example C2 (0.145 g, 0.351 mmol), morpholine (0.092 g, 1.052 mmol) and N-methylpyrrolidine (2.99 mg, 0.035 mmol) in dioxane (3 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide (80 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.43 (s, 1H), 9.29 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 3.53 (m, 4H), 3.39 (m, 4H), 1.21 (s, 9H); MS (ESI) m/z: 443.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11]C)[C:7](=[O:16])[O:6][CH2:5]2.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11])[C:7](=[O:16])[O:6][CH2:5]2
Reactant: COc1c(O)c([N+](=O)[O-])c2c(c1[N+](=O)[O-])C(=O)OC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1OCc2c1c([N+](=O)[O-])c(O)c(O)c2[N+](=O)[O-]

Procedure:
5-Hydroxy-6-methoxy-4,7-dinitro-3H-isobenzofuran-1-one (210 mg) was dissolved in ethyl acetate (2.5 ml) followed by addition of aluminum chloride (132 mg) in nitrogen atmosphere. Pyridine (265 μl, 3.28 mmol) was added dropwise. The resulting mixture was heated to reflux for 2 hours, and then quenched with water (0.5 ml) and conc. HCl (0.5 ml) at 75° C. Ethyl acetate (15 ml) was added and phases were separated. The aqueous layer was extracted once with ethyl acetate (15 ml). The combined organic layers were dried over anhydrous Na2SO4. The product was filtrated, evaporated to dryness and recrystallized from heptane-toluene-ethyl acetate.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc2ccccc12

Procedure:
Following General Procedure B′ and using 1-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 69°-73° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:25])=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:25])[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1-c1cc(OC)ccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1cc(CCl)ccc1-c1cc(OC)ccc1F
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a stirred solution of 5.3 (0.8800 g, 2.891 mmol) in DCM (15 mL) at 23° C. was added thionyl chloride (0.4218 mL, 5.783 mmol). The reaction mixture was then stirred overnight. The reaction was concentrated and then purified by combiflash (0 to 10% EtOAc/Hexanes) to provide 5.4 (0.7980 g, 85.50% yield).
Reaction SMILES: [CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2csc(C3CCC3)n2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(/C=C/c2csc(C3CCC3)n2)c1
Temperature: 0 °C
Yield: 111.7 %

Procedure:
A mixture of 0.3 g of (E)-2-cyclobutyl-4-[2-(3-nitrophenyl)ethenyl]thiazole, 0.9 g of tin(II) chloride dihydrate and 50 ml of ethyl alcohol was heated to reflux for 16 hr. The mixture was then diluted with ice water and an excess of 3N sodium hydroxide. This mixture was extracted with methylene chloride and the combined extracts were washed with water followed with brine and then dried (MgSO4). Condensation in vacuo yielded 0.3 g of (E)-3-[2-[2-Cyclobutyl-4-thiazolyl]ethenyl]phenylamine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[NH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:46]([O:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][NH:39][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole made as described in Preparation 1 (20.9 g, 40 mmol), N-(2-aminoethyl)(t-butoxy) carboxamide (15 g, 90 mmol), and potassium carbonate (15.5 g, 110 mmol) in THF (75 mL) was stirred for 48 hours at room temperature. The mixture was concentrated and extracted with 1M aqueous KOH (20 mL) and EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Silica gel chromatography (EtOAc:hexanes) gave intermediate (7a) as a white solid (12.7 g).
Reaction SMILES: [NH2:1][CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]([CH3:15])[C:3]1=[O:16].[C:17]([O:21][C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])([CH3:20])([CH3:19])[CH3:18].O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O.ClCCl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:27](=[O:28])[NH:1][CH:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]([CH3:15])[C:3]1=[O:16])[CH3:26])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1C=CC(c2ccccc2)=CC(N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C=C(c2ccccc2)C=CN(C)C1=O
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 96.7 %

Procedure:
3-Amino-1-methyl-5-phenyl-1,3-dihydro-azepin-2-one (330 g, 1.54 mol) is combined with dichloromethane (3 L), N-(tert-butoxycarbonyl)-L-alanine (291.4 g, 1.54 mol), and hydroxybenzotriazole hydrate (259.5 g, 1.617 mol). The solution is cooled to about 10° C. To this solution is added diisopropylethylamine (335.4 mL, 1.925 mol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (310.1 g, 1.617 mol) and the contents are allowed to gradually warm to room temperature. After 3.5 hours, the reaction contents are poured into water (1000 mL) and the layers are allowed to separate. The organic layer is further washed with water (1000 mL), 0.1 N HCl (1000 mL), saturated NaHCO3 solution (1000 mL) and finally saturated aqueous sodium chloride solution. The dichloromethane layer is dried over Na2SO4, filtered, and concentrated via rotary evaporation to provide the title compound (about 574 g, 97%) as a tan foam. The material is of sufficient purity to use directly in the next step.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[N:36]O)[NH2:35]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[N:36]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:26][N:35]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1ccccc1Cl
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3Cl)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 34.8 mg (0.266 mmol) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 34.8 mg (27% of theory).
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[CH2:12]Br>CO>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH2:12][NH:1][C:4]2=[O:3]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: N
Solvent: CO
Product: O=C1NCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL microwave tube 3-bromo-2-bromomethyl-benzoic acid methyl ester is dissolved in methanol (15 mL) and mixed with 7.0M methanolic ammonia (6.3 mL) and 17.0M aqueous ammonia (7.3 mL). The microwave tube is sealed and the mixture is stirred overnight at room temperature. The precipitate formed is filtered out and washed with cold water, then dried under vacuum to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O>[N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 757.6 %

Procedure:
A solution of 2 g (9,6 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 40 ml 50% fluoroborio acid was added 100 ml water, filtered and then ice-cooled. A solution of 0,68 g (9,9 mmol) sodium nitrite in 20 ml water was added, and after stirring at 0° C. for 15 min. 0,68 g (1,0 mmol) sodium azide dissolved in 20 ml water was added. Stirring was continued at 25° C. for 2 h. The precipitate was filtered off and washed with water to give 1,8 g (80%) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. IR (KBr): 2100 cm-1 (N3). NMR (DMSO-d6): 11.7 (2H, broad s), 7.03 (lH,s), 6.93 (lH,s).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:20]2[C:15](=[C:16]([N+:21]([O-])=O)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(NCc1ccccc1)c1cccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c(C(=O)NCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
5% Palladium on carbon (14 mg) was added to a suspension of N-benzyl-5-nitronaphthalene-1-carboxamide (128.0 mg, 0.418 mmol) in methanol (2.5 ml). The mixture was stirred at room temperature for 2 hours, under hydrogen atmosphere. After the palladium on carbon was filtered off, the filtrate was concentrated. The residue was solidified by a mixture of isopropyl ether: ethyl acetate (1:1), and the resulting solid was washed with isopropyl ether and dried to give the title compound as a light yellow solid (102 mg, 88.7%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:46])([F:45])[CH2:40][CH2:41][CH2:42][CH2:43]Br>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:43][CH2:42][CH2:41][CH2:40][C:39]([F:46])([F:45])[F:38])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: FC(F)(F)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCC(F)(F)F)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of acetonitrile is mixed with 101 mg (0.73 mmol) of potassium carbonate and 149 mg (0.73 mmol) of 1,1,1-trifluoro-5-bromopentane [CAS Reg. No. 54932-74-00] and stirred under reflux for 12 h. After conversion is complete, the salts are filtered off and the mother liquor is evaporated. 205 mg (0.28 mmol, 79% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([CH2:3][N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=O.[F:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].CC(C)=O>CO.CCOCC>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:1][CH2:3][N:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[C:5](=[O:14])[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cccc(C(=O)N(CC=O)c2ccccc2OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CO
Product: COc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)c1
Reaction time: 0.75 h
Yield: 46.1 %

Procedure:
N-Formylmethyl-3-methoxy-N-(2-methoxyphenyl)-benzamide (141 mg, 0.473 mmol), and 4-(4-fluorobenzoyl)piperidine (125 mg, 0.60 mmol) were dissolved in methanol (4.5 ml) to which was subsequently added molecular sieve 4A (300 mg) at room temperature. After 1 hour of stirring at the same temperature, sodium cyanoborohydride (12 mg, 0.191 mmol) was added to the above mixture, followed by 45 minutes of stirring and subsequent addition of acetone (2 ml). The reaction solution was diluted with ether (15 ml) and filtered through cerite, and the solvent was removed by evaporation. The thus obtained colorless oily residue was dissolved in ether (7 ml), mixed with saturated hydrogen chloride/ether solution (7 ml) and stirred for 5 minutes. After removing the ether layer, the reaction solution was mixed with water (7 ml) and potassium carbonate (1.5 g) and extracted with ether and dried on potassium carbonate, and then the solvent was removed by evaporation. Thereafter, the resulting colorless oily residue was purified by subjecting it to a silica gel column chromatography (ether:hexane=3:2) to obtain 107 mg (46.1%) of the title compound in the form of light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](N=C(N(C)C)N(C)C)([CH3:30])([CH3:29])[CH3:28].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:28][CH:27]([CH3:30])[CH3:29])[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-methylpyridin-2-yl)benzenesulfonamide (187 mg, 0.5 mmol) in acetonitrile (5 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.261 mL, 1.250 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.190 mL, 1.750 mmol) added. The reaction was then heated by microwaves to 160° C., for 25 minutes. After cooling, dicholormethane (5 mL) was added to the mixture and the organic phase washed with water (5 mL) then separated using a hydrophobic frit. The solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (ammonium carbonate modifier) to give the title product (8.5 mg). LCMS (3 min, High pH) Rt 1.88 min, m/z (ES+) 430 (M+H).