Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:11]1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccsc1

Procedure:
The reaction was repeated on a 50 mmol scale with 2-bromobenzaldehyde (5.8 mL), thiophene-3-boronic acid (7.03 g, 0.0555 mol) in ethanol (55 mL), Pd(PPh3)4 (1.7 g, 3 mol %), 2 M aqueous Na2CO3 (55 mL) in toluene (275 mL) to yield crude 2-(3-thienyl)benzaldehyde as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (4200 mg; 10.1 mmol; 1 eq), is dissolved in anhydrous DCM (200 ml). The reaction is put under nitrogen. Triethylamine (7.0 ml; 50.5 mmol; 5 eq) and 1-methylpiperazine (5.61 ml; 50.5 mmol; 5 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. It is washed with water, NH4Cl sat, brine and dried over MgSO4, affording the title compound (4200 mg; 87%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21](Cl)=[O:22])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:21]([C:18]1[S:19][CH:20]=[C:16]([C:14]2[CH:13]=[N:12][C:11]3[N:10]([N:9]=[CH:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[CH:17]=1)=[O:22]
Reactant: CN(C)CCN
Reactant: O=C(Cl)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Reaction time: 8 h

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carbonyl chloride (5-4, 5.0 mg, 0.015 mmol, 1 equiv), diisopropylethylamine (60 TL, 0.030 mmol, 2.0 equiv), and N,N-dimethylethane-1,2-diamine (41 TL, 0.016 mmol, 1.1 equiv) in dichloromethane (1 mL) was mixed and allowed to stand for 8 hours. The reaction mixture was washed with aqueous half-saturated sodium bicarbonate solution (0.5 mL). The organic layer was dried over sodium sulfate and concentrated to give N-[2-(dimethylamino)ethyl]-4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxamide (5-5) as a yellow solid. LRMS m/z: Calc'd for C21H22N5OS (M+H) 392.2, found 392.3.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3C[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(C3CCCC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.NC1C=C([C:77]2[N:78]=[N:79][N:80]([CH2:82][O:83][C:84](=[O:89])[C:85]([CH3:88])([CH3:87])[CH3:86])[N:81]=2)C=CC=1.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH:20]1([C:18]2[C:17]3[CH:16]=[CH:29][CH:28]=[CH:27][C:26]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C:14](=[O:37])[N:13]([CH2:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([C:77]4[N:78]=[N:79][N:80]([CH2:82][O:83][C:84](=[O:89])[C:85]([CH3:87])([CH3:86])[CH3:88])[N:81]=4)[CH:9]=[CH:8][CH:7]=3)=[O:38])[N:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2cccc(N)c2)n1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(-c3nnn(COC(=O)C(C)(C)C)n3)c2)N=C(C2CCCC2)c2ccccc21

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and 2,2-dimethyl-propionic acid 5-(3-amino-phenyl)-tetrazol-2-ylmethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of 2,2-dimethyl-propionic acid 5-(3-{2-[5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-tetrazol-2-ylmethyl ester (Example 10, step a), according to the method of Example 10, step b. 1H NMR (d6-DMSO) 10.11 (1H, s), 8.36 (1H, s), 7.68-7.46 (5H, m), 7.22 (1H, m), 7.16 (1H, d), 6.95 (1H, br), 6.65 (1H, br), 4.64 (2H, m br), 4.35 (1H, m br), 4.00 (1H, m br), 3.00-2.80 (2H, m), 1.95-1.45 (9H, m), 1.40-1.00 (9H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.11; H, 7.00; N, 14.82%; C30H34N8O3.C7H17NO5.0.8CH3CO2H.2.2CH3OH requires C, 56.43; H, 7.31; N, 14.52%.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:36][CH3:37])[C:26](=[O:35])[CH2:27][S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1>[CH2:36]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:7]=1)[C:26](=[O:35])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:37]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CSc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)CSc1ccccc1

Procedure:
(2′-{[Ethyl-(2-phenylsulfanyl-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.291 g, 0.53 mmol) in THF (3 mL) was treated with 1N aqueous LiOH (3 mL) at room temperature overnight. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (30-70% EtOAc in hexanes) to give the title compound. M+H is 518.
Reaction SMILES: [C-:1]#[N:2].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]2[OH:43])=[CH:26][CH:25]=1>C(#N)C.[Zn].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Ni](Br)Br>[C:1]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]2[OH:43])=[CH:26][CH:25]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(O)C1
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [K+]
Agent: [Zn]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(O)C1
Temperature: 60 °C
Reaction time: 20 h
Yield: 55.6 %

Procedure:
A suspension of 20 mg (0.30 mmol) of activated zinc powder, 76 mg (1.17 mmol) of potassium cyanide, 52 mg (0.20 mmol) of triphenylphosphine and 74 mg (0.10 mmol) of bis(triphenylphosphine)-nickel(II) dibromide in 2 ml of acetonitrile was heated at 60° C. under argon for 5 minutes. 356 mg (1.00 mmol) of tert-butyl (3RS,4RS)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate in solid form were added thereto. The green suspension was stirred at 60° C. under argon for 20 hours. The resulting dark brown suspension was filtered over Speedex and the insoluble material was washed with methylene chloride. The filtrate was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product (416 mg) was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 168 mg (56% of theory) of tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-hydroxy-piperidine-1-carboxylate as a colourless solid; MS: 302 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][NH:25][CH:26]3[CH3:31])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[CH:30][C:21]=4[C:18]4[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=4)[CH:26]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(-c3ccc(F)nc3)cccc21
Product: CC1c2cccc(-c3ccc(F)nc3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[C:21]([CH:22]4[CH2:27][O:26][CH2:25][CH2:24][O:23]4)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=3[N:17]=2)=[O:11])[CH2:3][CH2:2]1>CO.ClCCl.[Pd]>[O:23]1[CH2:24][CH2:25][O:26][CH2:27][CH:22]1[C:21]1[C:15]2[S:14][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:30]=[CH:31][N:32]=[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:8]=3)=[N:17][C:16]=2[C:18]([O:28][CH3:29])=[CH:19][CH:20]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C4=CCOCC4)c3)nc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a stirred solution of 130 mg (0.29 mmol) (±)-2-(3,6-dihydro-2H-pyran-4-yl)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide in 10 ml methanol and 10 ml dichloromethane was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. Flash chromatography (2/49/49 methanol/dichloromethane/ethyl acetate) followed by trituration in ether afforded 60 mg (46%) (±)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Yield: 76.3 %

Procedure:
To a solution of 5.80 gm (0.0211 mole) of the compound of Example 15 in 50 ml of CH2Cl2 was added 3.03 g (0.03 mole) of triethylamine, 384 mg (0.003 mole) of 4-dimethylaminopyridine and 2.78 g (0.03 mole) of propionyl chloride. The mixture was heated at reflux for 15 hours, cooled, and partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give a thick oil which crystallized on trituration with toluene-hexane. The resulting white solid was collected to give 5.32 gm of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1,2,4-triazolo [3,4-a]phthalazin3-yl)propanamide; mp 164-166° C. (ethanol-ether). Calculated: C, 58.16; H, 6.71, N, 25.44. Found: C, 58.17; H, 6.70; N, 25.67.
Reaction SMILES: CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH2:26])[CH2:20]2.C1CCN2C(=NCCC2)CC1.[CH3:38][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>C(Cl)Cl.Cl>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH:26][S:41]([CH:39]([CH3:40])[CH3:38])(=[O:43])=[O:42])[CH2:20]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
(R)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (7.88 mmol, 3.5 g) was suspended in DCM (40 mL) and DBU (23.63 mmol, 3.53 mL, 3.60 g) was added. The mixture was purged with nitrogen and cooled in an ice bath before dropwise addition of propane-2-sulfonyl chloride (15.75 mmol, 1.760 mL, 2.246 g). Stirring was continued at 0° C. for 1 h before allowing to come to room temperature. The mixture was diluted with DCM (100 mL) and 1N HCl (100 mL) and the phases mixed and separated. The aqueous phase was further extracted with DCM (2×100 mL) before combined organics were washed with brine. Concentration gave a light yellow oil which was purified on silica eluting with 75% DCM/heptane then neat DCM. Desired fractions were collected and concentrated to give (R)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide as a colourless oil (2.18 g, 87%). 1H NMR (400 MHz, CDCl3) δ 1.39 (d, 6H) 2.88 (m, 2H) 3.17 (sept, 1H) 3.28 (m, 2H) 4.27 (m, 2H) 7.08 (d, 1H) 7.30 (d, 1H) 7.35 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+](CC)CC)[CH3:21]>>[F:15][B-:16]([F:19])([F:18])[F:17].[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[NH:8])[O:7][CH2:20][CH3:21])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CCCOc1cc(C)ccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCCOc1cc(C)ccc1C(=N)OCC

Procedure:
reaction of 4-methyl-2-propoxybenzamide (11.96 g) with triethyloxonium tetrafluoroborate yielded crude ethyl 4-methyl-2-propoxybenzimidate tetrafluoroborate which on reaction with a saturated solution of ethanolic ammonia and treatment with hydrochloric acid yielded 4-methyl-2-propoxybenzamidine hydrochloride, (8.74 g), m.p. 228-30° C.;
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([S:11](/[CH:14]=[CH:15]/[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N:23]4[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[NH:25][C:24]4=[O:31])=[CH:18][C:17]=3[CH3:32])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:22][C:21]1[CH:20]=[C:19]([N:23]2[C:27]([CH3:28])([CH3:29])[C:26](=[O:30])[NH:25][C:24]2=[O:31])[CH:18]=[C:17]([CH3:32])[C:16]=1/[CH:15]=[CH:14]/[S:11]([N:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1)(=[O:13])=[O:12]
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC(=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of (E)-1-(4-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylsulfonyl)vinyl)-3,5-dimethylphenyl)-5,5-dimeth ylimidazolidine-2,4-dione (1.2 g, 2.58 mmol) in tetrahydrofuran (26 mL), a 2 N aqueous hydrochloric acid solution (26 mL, 52 mmol) was added dropwise over ten minutes. The mixture was stirred at 60° C. for two hours. The reaction mixture was cooled, followed by adjustment of its pH to 7 using a 2 N aqueous sodium hydroxide solution, and this mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to afford (E)-1-(3,5-dimethyl-4-(2-((4-oxopiperidin-1-yl)sulfonyl)vinyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (998 mg, 92%).
Reaction SMILES: C([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:14][CH3:15])[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[N:10]=1)[C:6]([OH:16])=[O:5])[CH3:15]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(=O)O)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-ethyl-6-methyl-isonicotinic acid tert-butyl ester in DCM (10 mL) is treated with TFA (10 mL) and the mixture stirred at rt for 0.5 h. The mixture is evaporated and the residue dried under HV to give 2-ethyl-6-methyl-isonicotinic acid; LC-MS: tR=0.28 min, [M+1]+=166.25.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][C:20]([CH:1]2[CH:10]3[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][NH:2]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C1CCC2CNCCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)C1NCCC2CCCCC21

Procedure:
To 5.0 g of decahydroisoquinoline (mixture of cis and trans isomers), 20 mL of methylene chloride and 50 mL of 15% aqueous sodium hydroxide solution was added at 10°-15° a solution of 7 mL of phenylacetyl chloride in 20 mL of methylene chloride. Removal of the solvent from the dried organic layer and crystallizaiton of the residue from hexanes gave 3.12 g of 2-phenylacetyldecahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[N:13]([O-])=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>O>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][N:13]=[C:4]2[OH:5]
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1n[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (50 g) in water (200 mL) was added HCl (46 mL). To the mixture was added aqueous NaNO2 solution (17.7 g/37 mL) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. To the reaction solution was added dropwise aqueous Na2SO3 solution (79.3 g/200 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. To the mixture was added HCl (70 mL), and the mixture was stirred at room temperature for 18 hours and then at 80° C. for 4 hours. The precipitated solid was dissolved by basifying the reaction solution, and then the solution was acidified to precipitate a solid. The solid was collected by filtration and dried under reduced pressure to give Compound Q2 (36 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])=[O:19])=[C:4](Cl)[CH:3]=1.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:12]([CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[N:11]=[CH:10][C:9]=3[C:18](=[O:19])[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CNC(=O)c2cnn(C3CCOC3)c2-c2ccc(Br)cc2Cl)c(OC)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cnn(C4CCOC4)c3c3ccc(Br)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.6 %

Procedure:
(±)-5-(4-bromo-2-chlorophenyl)-N-(2,4-dimethoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide (1.26 g) was dissolved in THF (25 mL), and KTB (597 mg) was added at 0° C. The mixture was stirred for 12 hours while gradually warming to room temperature. The reaction mixture was cooled to 0° C., and water was added, followed by filtration. The filtration residue was separately stored. The filtrate was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 70%). The resulting fraction and the filtration residue obtained above were combined and concentrated to give the title compound (488 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10](=O)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Br)(Br)([Br:21])=O.C(=O)(O)[O-].[Na+].O>ClCCl>[Br:21][C:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Temperature: 83 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrle (400 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83° C. over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed, The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H NMR was 0.3% acetonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]=[N+:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccc2ccccc21
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1cn(C)c2ccccc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride.