Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([NH:14][C:15]([NH2:17])=[NH:16])(=[O:13])[CH3:12]>CN(C=O)C.CCOC(C)=O>[C:5]1([C:3]2[N:16]=[C:15]([NH:14][C:11](=[O:13])[CH3:12])[NH:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.0 g (10 mmol) of 2-bromoacetophenone in DMF (30 mL) was added 3.0 g (29 mmol) 1-acetylguanidine in one portion, the reaction mixture was stirred at rt for 2 days. The reaction mixture was diluted with EtOAc (250 mL) and washed with saturated NH4Cl aq. solution (50 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by a flash column chromatography eluting with EtOAc to give N-(4-phenyl-1H-imidazol-2-yl)-acetamide. (0.5 g, 24%). LCMS: 203 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](N)=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].CC1C(C(O)=O)=C(C(F)(F)F)C=C(C)N=1>>[CH3:20][S:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:8]1([C:6]([NH:5][C@H:4]([C:3]([OH:29])=[O:2])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:18])=[O:19]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: Cc1cc(C(F)(F)F)c(C(=O)O)c(C)n1
Product: CS(=O)(=O)CCCCC1(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCCC1

Procedure:
4-[(2,6-Dimethyl-4-trifluoromethyl-3-pyridinyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-L-phenylalanine was prepared from 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester and 2,6-dimethyl-4-trifluoromethyl-3-pyridine carboxylic acid using the general procedure described in example 364.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].CI.[C:52](OCC)(=O)C>CN(C)C=O.O>[CH3:1][C:2]1([CH3:47])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:7]=[C:6]([C:19]3[N:20]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH3:52])[C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2c(-c3cc4ccc(NC(=O)OCc5ccccc5)cc4n3COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=O)OCc1ccccc1)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Under an argon atmosphere, to a solution of benzyl (2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate (3 g, 4.6 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (219 mg, 5.5 mmol) under ice-cooling, and the mixture was stirred for 10 min. Then, to the reaction mixture was added methyl iodide (0.6 ml, 6.9 mmol), and the mixture was further stirred for 3 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.2 g, yield 69%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][NH2:10].[CH2:11]([N:13]1[C:18](S(C)=O)=[C:17]([C:22]#[N:23])[C:16](=[O:24])[N:15]2[N:25]=[CH:26][CH:27]=[C:14]12)[CH3:12]>C(O)C>[NH2:23][C:22]1[N:9]([CH3:8])[N:10]=[C:18]2[C:17]=1[C:16](=[O:24])[N:15]1[N:25]=[CH:26][CH:27]=[C:14]1[N:13]2[CH2:11][CH3:12]
Reactant: CNN
Reactant: CCn1c(S(C)=O)c(C#N)c(=O)n2nccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1c2nn(C)c(N)c2c(=O)n2nccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
Triethylamine (1.44 g) and methylhydrazine (1.44 g) were added to a solution of 3.25 g of 4-ethyl-5-methanesulfinyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile in 60 ml of ethanol. The mixture was stirred at room temperature for 10 minutes and then stirred at 100° C. for 20 minutes. The reaction mixture was ice-cooled and the crystals precipitated were collected by filtration and sequentially washed with ethanol, methanol and diethyl ether to provide 1.2 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+]>COCCOC.C(O)C.O1CCCC1>[CH3:1][N:2]([CH3:18])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:8][CH2:7][CH:6]([C:29]#[N:30])[CH2:5][CH2:4]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cccc(C2(N(C)C)CCC(=O)CC2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1cccc(C2(N(C)C)CCC(C#N)CC2)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexanone (2.47 g, 10 mmol) and tosylmethyl isocyanide (2.54 g, 13 mmol) in anhydrous 1,2-dimethoxyethane (40 ml) and anhydrous ethanol (2 ml) was cooled to −30° C. A solution of potassium tert-butylate (2.70 g, 24 mmol) in anhydrous tetrahydrofuran (20 ml) was then added dropwise such that the internal temperature did not rise above 5° C. The mixture was stirred at 0° C. for 1 h, at room temperature for 24 h and then under reflux for 5 h. The reaction mixture was cooled to room temperature and filtered. The residue on the filter was washed with 1,2-dimethoxyethane. The filtrate was concentrated i. vac., the residue was taken up in diethyl ether and the solution was washed with water (3×20 ml) and saturated sodium chloride solution (20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (1.76 g) was purified by flash chromatography with ethyl acetate and then ethyl acetate/methanol (9:1→8:2).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[N:11][C:6]2[O:7][CH2:8][CH2:9][NH:10][C:5]=2[CH:4]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20].C(N(CC)CC)C.O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([N:10]2[CH2:9][CH2:8][O:7][C:6]3[N:11]=[CH:12][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][C:5]2=3)=[O:20])[CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26]
Reactant: FC(F)(F)c1cnc2c(c1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C(F)(F)F)cc32)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
In a 5 ml flask, 7-trifluoromethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (27 mg, 0.23 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (65 mg, 0.20 mmol) were dissolved in dichloromethane (0.6 ml), and then triethylamine (0.55 ml, 0.33 mmol) was added thereto dropwise at 0□. After stirring for 4 hours at room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:100. The fractions containing the product were collected and evaporated to obtain white solid (64 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:12]1[CH:13]=[CH:14][C:15](=[O:18])[CH2:16][CH2:17]1)=[O:5]
Reactant: O=C1C=CNCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=CN(C(=O)c2c(Cl)cccc2Br)CC1
Reaction time: 0.5 h
Yield: 399.9 %

Procedure:
A solution of 2-bromo-6-chlorobenzoic acid chloride (0.5 mmol) in dichloromethane (5 ml) was added dropwise to a solution of 2,3-dihydro-4-pyridinone (5.1 mmol, 495 mg) and triethylamine (1.2 ml) in dichloromethane (20 ml). After stirring for 30 minutes, the solution was diluted with water, separated, the aqueous extract further extracted with dichloromethane, the combined organic extracts combined and washed with brine, dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 30% ethyl acetate in hexane to yield the title compound as a pale yellow oil (629 mg). MS (+CI) m/z 316 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH:22]([CH3:24])[CH3:23])=[CH:6][CH:7]=[C:8]([CH3:21])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:20])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:19])[CH2:17][Cl:18])C.[H-].C([Al+]C(C)C)(C)C.O>C1(C)C=CC=CC=1>[Cl:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14][CH2:13][C:12]([CH3:20])=[CH:11][CH2:10][CH2:9][C:8]([CH3:21])=[CH:7][CH:6]=[C:5]([CH:22]([CH3:23])[CH3:24])[CH2:4][OH:3]
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=CCCC(C)=CCCC(C)=CC=C(CO)C(C)C)CCl
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
14-Chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8, 12-tetradecatetraenoic acid ethyl ester (670 mg, 1.81 mmol) is dissolved in dry toluene (200 ml) under argon atmosphere and to the solution is gradually added a 1 M solution of diisopropylaluminum hydride in toluene (4 ml) while cooling and stirring on ethanol-dry ice bath. After 30 minutes, disappearance of the starting compound is confirmed. To the mixture is added water (1.5 ml), and after removing the bath, the mixture is thoroughly stirred. To the mixture is added a drying agent (anhydrous magnesium sulfate) and the mixture is further stirred. The mixture is filtered and concentrated and the resulting residue is chromatographed (n-hexane/ethyl acetate =12:1) on silica gel column to give the desired alcohol, 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraene-1-ol (492 mg, 79%) from the desired fraction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[N:17]=[C:13]3[NH:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:5][CH:4]=1)#[N:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])[N:17]=[C:13]3[N:12]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([C:36]([F:47])([F:46])[F:35])[CH:42]=3)[C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
Ethyl 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4,7-dihydro[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (50 mg, 0.11 mmol), 3-(trifluoromethyl)phenylboronic acid (63 mg, 0.33 mmol, 3 eq.), anhydrous copper(II) acetate (60 mg, 0.33 mmol, 3 eq.) and molecular sieve (50 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (2.5 ml), pyridine (71 μl, 0.88 mmol) and triethylamine (46 μl, 0.33 mmol, 3 eq.) were added. After 12 h of stirring, more 3-(trifluoromethyl)phenylboronic acid (21 mg, 0.11 mmol, 1 eq.), anhydrous copper(II) acetate (20 mg, 0.11 mmol, 1 eq.) and pyridine (36 μl, 0.44 mmol) were added. After a further 24 h of stirring, the mixture was filtered through kieselguhr, the residue was washed with dichloromethane and methanol and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23.3 mg, 35% of theory).
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:9](=[CH2:11])=[N-:10].C(O)(=O)C>C(OCC)C>[N+:9](=[CH:11][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N-:10]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)CC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl acetyl chloride (1.136 grams) in dry ethyl ether (10 mL) was slowly added to a 0° C. diethyl ether (20 mL) solution of freshly generated diazomethane (from 20 grams Diazald). After stirring for 30 minutes, the reaction was warmed to ambient temperature for another 30 minutes. Acetic acid (2 mL) was added and the reaction partitioned between methyl tert-butyl ether and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Concentration afforded an oil containing the title compound which was immediately used with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([C@@H:36]([OH:38])[CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:38][C@@H:36]([CH3:37])[C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:23])[CH2:34][OH:35]
Reactant: C[C@H](O)[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (102 mg, 0.23 mmol), (2R,3S)-2-aminobutane-1,3-diol (34 mg, 0.32 mmol), and HATU (97 mg, 0.25 mmol). Then added acetonitrile (6 mL) followed by N,N-diisopropylethylamine (0.25 mL, 1.43 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-100% EtOAc) to afford 100 mg (82%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2S)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a white solid. MS: [M+Na]+=551.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)#[N:2].O.[NH2:20][NH2:21]>CCO>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)[nH]n2)CC1
Temperature: 80 °C

Procedure:
A 5 mL conical reaction vial was charged with tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate (348 mg, 1.379 mmol), hydrazine monohydrate (329.4 μL, 6.896 mmol) and EtOH (4 mL). The reaction vessel was sealed and heated to 80° C. for 20 hours. The volatiles were removed to afford tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate as a foam (367 mg. 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above prepared 5-methoxy-benzofuran-2-carboxylic acid ethyl ester (8.10 g, 36.8 mmol) was dissolved in 250 mL of CH2Cl2, cooled to 0° C., and treated with BBr3 (73.6 mL of 1M solution in CH2Cl2, 2 eq.). After 2 h, the reaction mixture was carefully poured onto crashed ice, twofold extracted with CH2Cl2, washed with brine, dried over magnesium sulfate, and evaporated to dryness. Ensuing flash chromatography (SiO2, hexane/AcOEt=8/2) delivered then 5.63 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[C:4](=O)[CH2:3]1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[CH:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:3]1
Reactant: C1CCNC1
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CC(N2CCCC2)c2sccc2O1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
A solution of 5,6-dihydro-5,5-dimethylthieno[3,2-b]pyran-7-one (1.0 g, 5,5 mmol), pyrrolidine (2.3 ml, 27.4 mmol) sodium cyanoborohydride (0.345 g, 5,5 mmol) and 1N aqueous hydrochloric acid (5,5 ml, 5,5 mmol) in methanol (15 ml)-was stirred at rt for 1 day. Additional sodium cyanoborohydride (0.345 g, 5,5 mmol) was added and the solution was stirred an additional 1 day; additional sodium cyanoborohydride (1.0 g, 15.9 mmol) was added again and the mixture stirred 5 additional days. The mixture was poured into water (100 ml) and extracted with dichloromethane. The dichloromethane solution was washed with water and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using 2% methanol in dichloromethane as the eluant to give the product 0.70 g (54%) as a yellow solid; mp 49°-50° C.; IR(KBr): 2971, 1560 and 1394 cm-1 ; MS:m/z 238 (MH+); H NMR-(CDCl3): δ 1.27(s,3H), 1.45(s3H), 1.80(m,4H), 1.91(m,2H), 2.76(m,4H), 4.09(m,1H), 6.57(d,J=5.4 Hz,1H), and 7.04(d,J=5.4 Hz,1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([OH:11])[CH2:2]1.Cl[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>[NH4+].[Cl-]>[OH:11][C@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([C:13]([O:15][CH3:16])=[O:14])[CH2:2]1
Reactant: O[C@@H]1CNc2ccccc2C1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COC(=O)N1C[C@@H](O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.8 %

Procedure:
To a stirred solution of tetrahydroquinolin-3-ol 10 (200 mg, 1.34 mmol) and methyl chloroformate (1 mL, 13 mmol) in CH2Cl2H2O (4:1), was added K2CO3 (1.8 g, 13 mmol) at 0° C. and the reaction mixture was further allowed to stir for 6 h at 25° C. Progress of reaction was monitored by TLC and after completion of reaction, a saturated solution of NH4Cl (20 mL) was added. The organic layer was separated; the aqueous layer was extracted with CH2Cl2 (2×50 mL). Combined organic layers were washed with brine (2×25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude products. Chromatographic purification of crude product with petroleum etherethyl acetate (6:4 v/v) as eluent gave 11 (291 mg) as oily liquid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N2CCSCC2)nc1
Yield: 98 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using thiomorpholine instead of isopropylamine, to the title compound (125 mg, 98%), which was obtained as a white solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=S)[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:31][OH:32])[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=S)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=NO)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-chromene-4-thione (222.0 mg, 0.38 mmol) in 4.0 mL of pyridine was added 80.0 mg (1.15 mmol) of hydroxylamine hydrochloride. The solution was stirred at 110° C. for 2 h. The solvent was removed under vacuum and the residue was treated with ice. The resulting slurry was filtered. The filter cake was washed with H2O purified by prep HPLC to afford 71.4 mg (35.5% yield) of desired product, I-26, as a yellow syrup (TFA salt). 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s br, 1H), 9.99 (s, 1H), 7.88 (d, 2H), 7.79 (d, 1H), 7.08 (d, 2H), 7.02 (d, 1H), 6.99 (s, 1H), 6.88(dd, 1H), 4.16(t, 2H), 4.02(d, 2H), 3.84 (s, 3H), 3.67(t, 2H), 3.52(d, 2H), 3.31(t, 2H), 3.12(m, 2H), 2.17 (m, 2H) ppm. LC/MS: 411.2 (M+H), HPLC/Method A (Rt 4.03 min, 98.0% purity).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1N.N(OCCC(C)C)=O.[ClH:23]>C(#N)C.[Cu](Cl)Cl>[Cl:23][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl
Reactant: Cc1cccc(-c2ccccc2)c1N
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1cccc(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
During a five minute period a solution of 3-methyl-[1,1'-biphenyl]-2-amine (5.8 g, 0.0316 mole) in 15 ml of dry acetonitrile was added to a stirred mixture of anhydrous copper (II) chloride (7.5 g, 0.038 mole) and isoamyl nitrite (5.55 g, 0.0474 mole) in 100 ml of anhydrous acetonitrile. The reaction mixture was stirred at room temperature for two hours, 65° for two hours, then room temperature for two days. The mixture was diluted with 600 ml of 2 N aqueous hydrochloric acid and extracted with two 150 ml portions of diethyl ether. The extracts were combined, washed with 200 ml of 2 N aqueous hydrochloric acid, and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel to give 2-chloro-3-methyl-[1,1'-biphenyl] (0.4 g).