Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[CH:14]=[C:13]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:12]4=[CH:11][C:10]=3[O:9][CH2:8][C:7]=2[CH:21]=1)=[CH2:2].C1C(=O)N([Br:29])C(=O)C1.[OH2:30]>C1COCC1.CS(C)=O.CCOC(C)=O.O=[Mn]=O>[Br:29][CH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[CH:14]=[C:13]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:12]4=[CH:11][C:10]=3[O:9][CH2:8][C:7]=2[CH:21]=1)=[O:30]
Reactant: O
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Temperature: 25 °C
Reaction time: 0.55 h
Yield: 56 %

Procedure:
3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (9.98 g, 36.1 mmol) was dissolved in a stirred solution of THF (70 mL), DMSO (70 mL) and H2O (35 mL). NBS (6.75 g, 37.9 mmol) was added in a single portion and the reaction mixture was stirred at RT for 33 min. Upon completion, the reaction medium was diluted with EtOAc and washed twice with H2O and once with brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude bromohydrin was suspended in DCM (200 mL) and treated with activated MnO2 (62.7 g, 722 mmol). After stirring for 15 h at RT, the reaction mixture was filtered over celite and the filter cake was rinsed several times with DCM. The combined filtrate (˜400 mL) was treated with MeOH (˜100 mL) and the mixture was gradually concentrated under reduced pressure, causing solid material to precipitate from solution. When the liquid volume reached ˜200 mL, the solid was filtered off and rinsed with MeOH. The concentration/precipitation/filtration/rinsing sequence was performed 2× more, resulting in the collection of 3 crops of powdered 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.49 g, 56% over 2 steps).
Reaction SMILES: O[CH2:2][C@@H:3](N)[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.CC(C)C[C@H]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])CO.[Cl-].C([NH3+])C(C)C.[C:41]([C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[S:51])=[CH:45][CH:44]=1)#[N:42]>>[C:41]([C:43]1[CH:44]=[CH:45][C:46]([N:49]=[C:50]2[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:2][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[S:51]2)=[CH:47][CH:48]=1)#[N:42]
Reactant: CC(C)CN[C@H](CO)CC(C)C
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: CC(C)C[C@H](N)CO
Agent: CC(C)C[NH3+]
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: [Cl-]
Solvent: NCCO
Product: CC(C)CC1CN(CC(C)C)C(=Nc2ccc(C#N)cc2)S1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S)-4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride as described in Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride according to Method C1f to give 2-(4-cyanophenylimino)-3,5-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:11]([N:14]1[C:18]([NH2:19])=[N:17][N:16]=[N:15]1)[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:19][C:18]1[N:14]([CH2:11][CH2:12][CH3:13])[N:15]=[N:16][N:17]=1)=[O:7]
Reactant: CCCn1nnnc1N
Reactant: O=C(O)c1cccc(Br)c1
Product: CCCn1nnnc1NC(=O)c1cccc(Br)c1
Yield: 34 %

Procedure:
Employing 0.25 g (1.2 mmol) of 3-bromo-benzoic acid and 0.16 g (1.2 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.8:0.1:0.1) gave the product in 34% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH3:7].[CH2:23]([Br:26])[CH:24]=[CH2:25]>CC(C)=O>[Br-:26].[CH2:25]([N+:8]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH3:7])[CH:24]=[CH2:23]
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: C=CCBr
Solvent: CC(C)=O
Product: C=CC[N+](CCOCCOC)(CCOCCOC)CCOCCOC
Product: [Br-]

Procedure:
Into a 500 ml flask fitted with a reflux condenser and a heating mantle was placed tris(3,6-dioxaheptyl)amine (14.55 g, 45 mmoles) and 150 ml acetone. Allyl bromide (6.53 g, 54 mmoles, 20% excess) was added and the solution brought to reflux. After 28 hours the 1H-NMR spectrum indicated that the starting amine had been consumed. Removal of the solvent in vacuo gave crude product, N-(2-propeny)-N,N,N-tris(3,6-dioxaheptyl)ammonium bromide, as an amber oil (yield 19.66 g, 98%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[CH2:19][CH:20]([C:22]([OH:24])=[O:23])[NH2:21]>>[NH4+:3].[C:22]([CH:20]([NH:21][C:2]1[C:11]([C:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:18]1[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=1[F:16])([OH:24])=[O:23]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccccc1F)C(=O)O
Product: O=C([O-])c1cc2cc(Cl)ccc2nc1NC(Cc1ccccc1F)C(=O)O
Product: [NH4+]
Yield: 58 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-fluoro-DL-phenylalanine to provide the title compound in 58% yield as yellow needles (recrystallization from MeOH/NH4OH).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].[CH2:28]=O>C(O)(=O)C>[CH2:23]([N:25]([CH2:28][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH2:26][CH3:27])[CH3:24]
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Reactant: C=O
Reactant: CCNCC
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.322 g (1.083 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 0.13 g (1.3 mmol) of diethylamine and 0.11 g (1.3 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[CH3:14][NH:15][O:16][CH3:17].CC1C=CC=C(C)N=1>ClCCl>[CH3:14][N:15]([O:16][CH3:17])[C:3](=[O:4])[CH:2]([F:6])[F:1]
Reactant: O=C(O)C(F)F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CON(C)C(=O)C(F)F
Temperature: 35 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of difluoroacetic acid (4.1 g, 42.7 mmol) in dry dichloromethane (80 ml), under N2, was treated with oxalyl chloride (5.69 g, 44.8 mmol). After stirring at 35° C. for 3 h, the reaction was cooled to 0° C. and treated with N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.2 mmol), then cooled to -20° C., and treated dropwise with 2,6-dimethylpyridine (19.86 ml, 171 mmol). The reaction was allowed to warm up to room temperature over 2 h then quenched by the addition of ice and water. Orthophosphoric acid (2M) was added until the aqueous layer reached pH4. The aqueous and organic phases were separated and the organic layer was washed with 2M orthophosphoric acid (2×50 ml). The organic layer was dried (Na2SO4) then concentrated in vacuo and the residue was distilled to afford the title compound (D5) as a clear oil (3.72 g, 63%) b.p. 60° C. at 1.5 mm Hg (Kugelrohr).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.[C:14]1([CH3:27])[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([CH2:25][NH2:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.[CH2:28](O)[CH2:29][CH3:30]>C(O)CCC>[CH:29]([C@H:12]1[CH2:11][O:10][C:9](=[O:13])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][CH2:25][C:23]2[O:22][N:21]=[C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:27])=[CH:19][CH:18]=3)[N:24]=2)[N:7]=1)([CH3:30])[CH3:28]
Reactant: Cc1ccc(-c2noc(CN)n2)cc1
Reactant: O=C1OCCN1c1ccnc(F)n1
Reactant: CCCO
Solvent: CCCCO
Product: Cc1ccc(-c2noc(CNc3nccc(N4C(=O)OC[C@@H]4C(C)C)n3)n2)cc1
Temperature: 150 °C
Yield: 54.2 %

Procedure:
A solution of 3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (100 mg, 0.444 mmol), (3-(p-tolyl)-1,2,4-oxadiazol-5-yl)methanamine (84 mg, 0.444 mmol, 1.0 equiv), and TEA (0.186 mL, 1.332 mmol, 3.0 equiv) in butan-1-ol (2 mL) was heated at 100° C. for 90 min. Addition of propan-1-ol (1 ml) and heated at 150° C. for 60 min. The reaction mixture was concentrated in vacuo. Flash column (silica, 24 g) eluting w/0-30% EtOAc/DCM afforded (S)-4-Isopropyl-3-{2-[(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-pyrimidin-4-yl}-oxazolidin-2-one (95 mg, white foam) in 54.2% yield. HRMS(B) m/z 394.1753 2.38 Min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH3:14])[N:8]=2)[S:5][CH:6]=1.[I:15]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:15][C:11]1[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[N:8][N:9]([CH2:12][CH2:13][CH3:14])[CH:10]=1
Reactant: CCCn1ccc(-c2cc(C)cs2)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(I)c(-c2cc(C)cs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 3-(4-methyl-2-thienyl)-1-propyl-1H-pyrazole (6.2 mmol) in 16 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (6.6 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.77 g 4-iodo-3-(4-methyl-2-thienyl)-1-propyl-1H-pyrazole (85% yield).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26](Cl)=[O:27])=[CH:20][CH:19]=1>O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:26](=[O:27])[O:25][CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A suspension of 2,2′-azanediyldiethanol (7.3 ml, 76.09 mmol), sodium carbonate (18.33 g, 172.94 mmol), acetone (125 ml), and water (125 ml) at 0° C. was treated dropwise over a 15 minute period with Cbz-Cl (10.25 ml, 69.17 mmol). The suspension was stirred an additional 3 hours at 0° C. The suspension was diluted with water (500 ml) and extracted with CHCl3 (2×250 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with MeOH/DCM, 0→10% over 40 minutes) to give the title compound (12.5 g, yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[O:32])[CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1csc2nc(N)nc(N3CCNCC3)c12
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(OC)cc4)CC3)c12
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of Example 20 (70 mg, 0.23 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-methoxyphenyl isocyanate (31 μL, 0.24 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 3% methanol in dichloromethane), yielding the title compound (61 mg) as a white powder. 13C NMR δ (75 MHz, CD3OD) 171.65, 162.60, 160.54, 159.64, 155.32, 154.73, 133.60, 127.71, 124.13, 121.41 (2C), 113.30 (2C), 106.19, 60.79, 54.73, 47.93 (2C), 43.38 (2C), 13.73. MS (m/z) 457 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:14][OH:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10]1)(=O)C.[OH-].[Na+].Cl>CN(C)C=O>[OH:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:14][OH:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10]1
Reactant: CC(=O)OCCON=C1Oc2ccccc2C1=NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCCON=C1Oc2ccccc2C1=NO
Yield: 31.5 %

Procedure:
At 20° C., 5.28 g (0.02 mol) of 2-(3-hydroxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XVI-1) in 20 ml of dimethylformamide are stirred with 4.24 g (0.048 mol) of 45% strength aqueous sodium hydroxide solution for 3 hours. The mixture is acidified with 2 N hydrochloric acid and extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. According to HPLC analysis, the crude product contains 23.4% of the stereoisomer A and 4.1% of the stereoisomer B of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-oxime (X-1). Stirring the crude product with diethyl ether affords 1.4 g (28.5% of theory) of crystalline benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-oxime (X-1) consisting of 84.7% of stereoisomer A and 6% of stereoisomer B (HPLC).
Reaction SMILES: [C:1]12([CH2:11]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)C1)[CH2:8]2.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.CC1C(B2OC(C)(C)C(C)(C)[O:26]2)=C(C)NN=1>>[C:1]12([CH2:11][N:16]3[CH:15]=[C:14]([Cl:13])[CH:18]=[N:17]3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[O:26]1)[CH2:10]2
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cn[nH]c1
Product: Clc1cnn(CC23CC4CC(CC(C4)O2)C3)c1

Procedure:
The title compound was prepared by substituting EXAMPLE 13A for 1-adamantanemethanol and 4-chloro-1H-pyrazole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 2A.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[C:1]1([C:7]#[C:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(C#Cc2ccccc2)ccn1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
0.728 mL (6.5 mmol) of phenyl acetylene was added to a mixture of 10.1 g (5 mmol) of 4-bromopicolinic acid, 91 mg (0.13 mmol) of dichlorobis(triphenylphosphine)-palladium(II), 29 mg (0.15 mmol) of copper(I) iodide, 10 mL of triethylamine and 2 mL of DMF and heated at 80° C. overnight. The reaction mixture was filtered. The filtrate was concentrated and partitioned between 5 mL of 2 N Na2CO3 solution, 25 mL of water and 30 mL of ether. The aqueous layer was separated and washed again with ether (30 mL). 10% aq. HCl was added to adjust the pH to 5. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layers were dried over sodium sulfate. Evaporation of the solvents in vacuo gave 1.028 g (4.61 mmol, 92%) of 4-phenylethynyl-pyridine-2-carboxylic acid. LCMS: 224 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCN1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)NCCN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 98.3 %

Procedure:
A solution of 1.68 g (4.59 mmol) of 1-[[2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine (I a-25) and 1.05 g (5.5 mmol) of p-toluenesulfonic acid monohydrate in 75 ml of toluene was refluxed for 25 hr. using a Dean-Stark trap containing 10 g of Molecular Sieves-4A. By proceeding as in Example 67, 1.57 g of the objective compound (I a-29) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:32])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-phenylpyrrolidin-1-yl)quinolin-7-yl]ethanone (0.0226 g, 0.0644 mmol) and ammonium acetate (0.0496 g, 0.644 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.16 mL, 0.16 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN3 (M+H)+: m/z=352.2; Found: 352.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH2:33]([O:32][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[C:22]([CH2:21][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])[CH:23]=[N:24]2)=[CH:29][CH:28]=1)[CH3:34]
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CCOc1ccc2cc(CCl)cnc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc2cc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cnc2c1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (112 mg, 511 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.48 mL, 0.96 mmol) at RT followed by CCH 29190 (110 mg, 426 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 47 mg of 4-((7-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. The free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.09 M HCl in MeOH (4 mL) and the solution was stirred for 5 min at RT, and concentrated at 40° C. under vacuum to afford 4-((7-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 30 as a yellow solid (56 mg, 28% yield).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]#[N:20]>N1C=CC=CC=1.C(OCC)C>[Br-:1].[C:19]([C:3]1[CH2:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=2)[NH:5][C:4]=1[CH2:18][N+:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1)#[N:20]
Reactant: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)c(Br)c1C#N
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CC1=C(C[n+]2ccccc2)NN(c2ncc(C(F)(F)F)cc2Cl)C1
Product: [Br-]
Yield: 121.1 %

Procedure:
A solution of 13.6 grams (0.044 mole) of 5-bromo-methyl-4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole in 41 mL of pyridine was stirred at ambient temperature for three hours. After this time, the reaction mixture was slurried in 350 mL of diethyl ether and filtered. The filter cake was washed with additional diethyl ether. The filter cake was dried, yielding 11.9 grams of 1-[4-cyano-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-ylmethyl]-pyridinium bromide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16]>C(OCC)(=O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:17][CH2:14][CH2:15][CH3:16])[NH:7][C:6]=2[CH:8]=1
Reactant: CCCN
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: CCOC(C)=O
Product: CCCNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and n-propylamine by a procedure analogous to the procedure described in example 1Bb, except that the mixture was stirred for 16 h at 60° C.; mp 258°-261° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.89 (t, 3H), 1.52 (sext, 2H), 3.15 (q, 2H), 7.05 (s, 1H), 7.29 (br. s, 1H), 10.95 (br. s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:25])=[O:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylic acid (33.00 g), methyl iodide (8.5 mL), potassium carbonate (18.88 g) and N,N-dimethylformamide (300 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (33.48 g, yield 97%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 53-54° C.