Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:36])([F:35])S([O-])(=O)=O.FC(F)(F)[S+]1C2C=CC=CC=2C2C=CC=CC1=2>C(#N)C>[CH3:1][N:2]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:30]([F:36])([F:35])[F:29])[N:5]2[CH2:4][CH2:3]1
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Yield: 66 %

Procedure:
tert-Butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.0 g, 3.27 mmol), potassium carbonate (497.7 mg, 3.60 mmol) and trifluoromethanesulfonate; 5-(trifluoromethyl)dibenzothiophen-5-ium (1.32 g, 3.27 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated at 60° C. for 16 h. The reaction was evaporated to dryness and the residue was dissolved in dichloromethane. The organics were washed with water and brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to give tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (812 mg, 66%). ESI-MS m/z calc. 373.2, found 374.5 (M+1)+; Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.52 (d, J=3.8 Hz, 1H), 5.91 (d, J=3.8 Hz, 1H), 3.98 (t, J=6.0 Hz, 2H), 3.93-3.76 (m, 2H), 3.32 (t, J=6.0 Hz, 2H), 3.26-3.08 (m, 2H), 2.36 (s, 3H), 2.11-1.99 (m, 2H), 1.81-1.65 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][C@H:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[C@@H:4]([O:13]COC)[CH2:3]1.C(=O)([O-])O.[Na+]>Cl.CO>[F:1][C@H:2]1[CH2:3][C@H:4]([OH:13])[C@@H:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[CH2:6]1
Reactant: COCO[C@H]1C[C@@H](F)C[C@@H]1c1ccnn1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1nccc1[C@H]1C[C@@H](F)C[C@@H]1O
Yield: 84.4 %

Procedure:
A solution of the 5-[(1R*,2S*,4S*)-4-fluoro-2-(methoxymethoxy)cyclopentyl]-1-methyl-1H-pyrazole (132 mg, 0.579 mmol) prepared in Example 106c in 2 M hydrochloric acid-methanol (3.0 mL) was stirred at room temperature for 1 hour. To the reaction solution, an aqueous sodium hydrogencarbonate solution (10 mL) was added, and an organic layer was extracted with ethyl acetate (10 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with reverse phase chromatography (30% methanol/water) to yield the title compound (90 mg, 85%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:14][CH2:15][CH2:16][C:17]([C:6]1[CH:7]=[CH:8][C:9]2[NH:1][C:2](=[O:13])[CH:3]3[CH2:12][CH2:11][CH2:10][C:5]=1[C:4]=23)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: O=C1Nc2cccc3c2C1CCC3
Product: O=C(CCCl)c1ccc2c3c1CCCC3C(=O)N2

Procedure:
Using 2a,3,4,5-tetrahydrobenz[cd]indol-2(1H)-one and 3-chloropropionyl chloride, the same procedure as in Reference Example 2 was followed, to yield the title compound as a colorless needle crystal having a melting point of 175° to 178° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH3:3].Cl>O>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH3:1]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(CN(C)C)c1
Agent: Cl
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1CN(C)C
Yield: 110.3 %

Procedure:
To a solution of methyl 2-[(dimethylamino)methyl]-2′-methylbiphenyl-4-carboxylate (687 mg, 2.42 mmol) in water (20 mL) at RT was treated with a 5N aqueous solution of HCl (12 mL, 60 mmol). The reaction mixture was refluxed for 4 hours, and then evaporated under vacuum. The residue was taken up in ACN and evaporated under vacuum to give the title compound as a light yellow powder (719 mg, 96%). 1H NMR (DMSO-d6) δ 13.23 (br s, 1H), 10.31 (br s, 1H), 8.47 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.38-7.31 (m, 4H), 7.20 (d, J=7.2 Hz, 1H), 4.32 (d, J=13.2 Hz, 1H), 3.87 (d, J=13.2 Hz, 1H), 2.61 (s, 3H), 2.50 (s, 3H), 1.98 (s, 3H). HPLC (Method A) Rt 2.52 min (Purity 100.0%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([F:25])[CH:27]=[CH:28][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:33]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:6]=2[N:7]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH2:10][NH:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nc2c(c(N3CCOCC3)n1)CNC2

Procedure:
A solution of tert-butyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 2) (2.05 g, 6.0 mmol) in TFA (15 ml) and DCM (30 ml) was stirred at room temperature (20° C.) overnight. The material was concentrated in vacuo to give an orange oil, which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@@:5]([OH:16])([C:10]1[S:14][C:13]([SH:15])=[N:12][CH:11]=1)[C:6]([F:9])([F:8])[F:7].[OH-].[K+]>C1COCC1.CO.CCOC(C)=O>[F:9][C:6]([F:7])([F:8])[C@:5]([OH:16])([C:10]1[S:14][C:13]([SH:15])=[N:12][CH:11]=1)[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)C[C@@](O)(c1cnc(S)s1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C[C@@](O)(c1cnc(S)s1)C(F)(F)F
Temperature: 45 °C

Procedure:
To a solution of (3S)-methyl-4,4,4-trifluoro-3-hydroxy-3-(2-mercapto-1,3-thiazol-5-yl)butanoate (enantiomer #1, 7.54 g, 26.2 mmol) in THF (80 ml) and MeOH (40 ml) was added a solution of KOH (39 ml, 2.67 N, 105 mmol). The mixture was heated at 45° C. for 4 h then cooled to room temperature. The reaction mixture was diluted in EtOAc, washed with HCl 10%, brine and dried over MgSO4. The solvent was evaporated to give the title compound in quantitative yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:15])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Reactant: C1COCCN1
Solvent: CC#N
Product: CC(C)OC(=O)C(C(=O)N1CCOCC1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl]acetate (20 g) and morpholine (6.23 acetonitrile (200 ml). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was evaporated to dryness and the residue was dissolved inmethylene chloride (100 ml). The solution was washed with aqueous sodium hydroxide solution and water. After evaporation the residue was recyrstallized from ethyl acetate and n-hexane to give the titled compound. (15.0 g, 71.1%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C=C(C=C[CH:32]=1)C#N>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[CH:32][CH:25]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=350.3 (M+H+).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]([CH:13]=O)=[CH:11][C:10]2[O:15][CH2:16][O:17][C:9]=2[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1OCCOCCOCCOCCOCCOC1>[CH2:16]1[O:17][C:9]2[CH:8]=[CH:7][C:12]([CH:13]=[CH2:1])=[CH:11][C:10]=2[O:15]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a stirred suspension of (methyl)triphenylphosphonium bromide (17.1 g, 48 mmol) and potassium carbonate (6.63 g, 48 mmol) in THF (200 ml) were added piperonal (6.0 g, 40 mmol) and 18-crown-6 (120 mg, 0.46 mmol). The mixture was heated to reflux under nitrogen and refluxed for 36 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated to dryness at 15° C. The resulting solid was stirred in 100 ml cold diethylether to dissolve the desired product, then filtered to remove inorganic salts, and the filtrate evaporated at 15° C. This process was repeated a second time. The product was filtered through 60 g basic alumina (pentane/ether, 24/l) and the solvent removed as before to give 5.36 g (89%) of the liquid styrene. NMR (CDCl3)δ6.89 (1H, singlet), 6.70-6.74 (2H, 2 overlapping singlets), 6.43-6.7 (1H, partially obscured doublet), 5.84 (2H, singlet), 5.50 (1H, doublet), 5.06 (1H, doublet).
Reaction SMILES: [CH3:1][C@@H:2]([NH:22]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:22])=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][CH3:21]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-2-[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 51, 350 mg) in dry dichloromethane (7.5 mL), TFA (2.5 mL, 32.4 mmol) was slowly added and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge (10 g) to afford the title compound as a colourless oil (258 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.S([O-])(O)=O.[Na+].CN(C=O)C>O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1
Reactant: O=Cc1ccccc1F
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 153 °C
Yield: 30.2 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.91 g), 2-fluorobenzaldehyde (1.86 g), sodium hydrogen sulfite (1.56 g), and DMF (10 ml) was stirred with heating under reflux at 153° C. for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.89 g of 2-(2-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound (1E)-F1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:9]([NH2:11])[CH:10]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]2[C:8]([C:12]([S:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:27][NH:11]2)=[CH:7][CH:6]=1
Reactant: Nc1cc(OCCCl)ccc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Temperature: 3 °C

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.74 g, 1.99 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.14 g, 2.08 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[N:14]([CH2:20][CH3:21])[C:15](=[O:19])[C:16](=O)[NH:17][C:12]=2[CH:11]=[N:10]1.O=P(Cl)(Cl)[Cl:24].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:24][C:16]1[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]2[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=[CH:11][C:12]=2[N:17]=1
Reactant: CCn1c(=O)c(=O)[nH]c2cnn(-c3ccc(F)cc3F)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(Cl)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 110 °C

Procedure:
A mixture of 1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione (330 mg, 1.13 mmol) in 5 mL of toluene was treated with POCl3 (0.16 mL, 1.70 mmol) followed by N,N-diisopropylethylamine (0.16 mL, 0.9 mmol). The reaction mixture was heated in an oil bath at 110° C. for 2.5 h. The volatiles were removed on the rotovap and the residue was dissolved in ice cold DCM (20 mL) and washed with NaHCO3 saturated solution, dried over MgSO4, filtered and concentrated affording 5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one as a brown amorphous solid. The material was used without further purification. MS (ES+): 311.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2Cl)[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[N:7]([CH3:26])[C:6]=1[CH3:27])=[O:4].[Na].[CH2:29]([O:31][C:32](=[O:35])[CH2:33][SH:34])[CH3:30]>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[S:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:35])[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[N:7]([CH3:26])[C:6]=1[CH3:27])=[O:4]
Reactant: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1C1C(C(=O)OC)=C(C)N(C)C(C)=C1C(=O)OC
Yield: 72 %

Procedure:
A solution of 19.7 g of 1,2,6-trimethyl-(2-chloro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (melting point 190°C) in 200 ml of alcohol is heated to reflux and 60 ml of a solution of 2.3 g of sodium in 100 ml of alcohol, together with 13.2 g of mercaptoacetic acid ethyl ester, are added thereto. The mixture is refluxed for 15 hours and thereafter filtered and evaporated. The precipitate obtained after adding a little ether is recrystallized from methanol to yield yellow crystals of melting point 118°C. Yield: 72% of theory.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2)=C.I([O-])(=O)(=O)=[O:13].[Na+].O1CCOCC1>O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH:1]([C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2)=[O:13]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc2ncccc2[nH]1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
A mixture of vinylimidazo[4,5-b]pyridine (1 eq.), osmium tetroxide (0.1 eq.), sodium periodate (3-4 eq.), 1,4-dioxane (30 ml/mmol), and water (25 ml/mmol) is stirred for 15-30 min at ambient temperature. The resulting slurry is diluted with even amounts of water and ethyl acetate. After filtration through Celite®, the organic phase is dried over sodium sulfate, concentrated in vacuo and purified via flash chromatography to yield the respective formylimidazo[4,5-b]pyridine.
Reaction SMILES: [C:1]1([C:7]2[N:20]=[N:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11](=O)[NH:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>P(Cl)(Cl)(Cl)=O>[Cl:23][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[N:19]=[N:20][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]=2[N:10]=1
Reactant: O=c1[nH]c2cc(-c3ccccc3)nnc2c2ccccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(-c3ccccc3)nnc2c2ccccc12
Reaction time: 3.5 h
Yield: 80 %

Procedure:
Phosphorus oxychloride (760 ml), 3-phenyl-pyridazino[4,3-c]isoquinolin-6(5H)-one (74 g, 0.27 mol) and phosphorus pentachloride (58 g, 0.278 mol) in a 2 litre flask are heated to reflux temperature with stirring. Heating is continued for about 3.5 hours, then a solution is obtained which is evaporated under reduced pressure to eliminate the phosphorus oxychloride excess. The solid is taken up with benzene and then evaporated to dryness in order to eliminate all the unreacted phosphorus oxychloride. Then the reaction mass is taken up with methylene chloride (1500 ml) and washed with 10% aqueous ammonium acetate (two times; first with 800 ml and then with 400 ml), and subsequently with water up to neutrality. The methylene chloride phase is dried on magnesium sulfate and the solvent is evaporated under reduced pressure. The solid residue is disaggregated and washed with methylene chloride (300 ml) and filtered, yielding 6-chloro-3-phenyl-pyridazino-[4,3-c]isoquinoline (63 g). By concentrating the mother liquors to dryness and crystallizing the obtained solid from acetone, 11 g of the same product is obtained. These two crops of 6-chloro 3-phenylpyridazino[4,3-c]isoquinoline derivatives are pooled and recrystallized from acetone, with a 90% overall yield. The product has a melting point of 177°-178° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:16][CH:15]=3)[C:11]([C:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=3)=[CH:12]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(C(C)(C)C)cc3)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(34.0 mg, 81%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.6 mg, 0.082 mmol) and 4-t-butylphenylsulfonyl chloride (37.2 mg, 0.16 mmol); HRMS-FAB+ for C30H38N2O3S: calculated MH+ : 507.26813; found: 507.27183.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([C:7](=[O:9])[CH3:15])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1OC
Reactant: NC(=O)c1ccccc1
Product: COc1cc(Br)cc(C(C)=O)c1OC

Procedure:
5-Bromo-2,3-dimethoxybenzoic acid (2 g) was converted to the benzamide derivative analogously to O3.043, and the latter to the title compound analogously to O2.059. 1.1 g of the title compound were obtained. LC-MS rt: 3.70 min [M+H]+: 259.0 (met. d)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:5][C:6](=O)[C:7]=1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To a suspension of methyl 2-(4-methyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (5.97 g; 19.42 mmol) in dry toluene (40 mL) under nitrogen atmosphere were carefully added phosphorus oxychloride (18.05 mL; 194 mmol) and dimethylaniline (1.961 mL, 15.54 mmol). The reaction was heated to reflux for 3 h and after cooling at room temperature, the volatiles were removed under reduced pressure and the remaining residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The product was extracted twice with ethyl acetate and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 2.45g (39%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:13](C(N[O-])=O)=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].C(=O)=O.C(#[N:32])C>>[CH2:1]([O:11][C:12]1[C:13]([NH2:32])=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cc2ccccc2cc1C(=O)N[O-]
Reactant: CC#N
Agent: O=C=O
Agent: [Na+]
Product: CCCCCCCCCCOc1cc2ccccc2cc1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Two liter of acetonitrile was added to 510 g of sodium 3-decyloxy-2-naphthalenehydroxamate obtained above, and stirred for about 30 minutes at 60° C. Thereupon, evolution of carbon dioxide gas was confirmed. The reaction mixture was further stirred with heating for 1 hour. Then, the insoluble matter (3,3'-didecyloxy-2-2'-dinaphthylurea) was filtered out, and the filtrate was concentrated. The residue was dissolved in 1 liter of ethyl acetate, and washed 3 times with 500 ml of water. The organic layer was separated from the aqueous layer, dried with Glauber's salt, and then concentrated. Thus, 323 g of whitish orange 3-decyloxy-2-naphthylamine (Compound 1) was obtained in a 84% yield. The melting point of the product was 64°-65.5° C.