Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=Cc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Oc2cccc(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.6 %

Procedure:
3-Hydroxybenzaldehyde (1.0 g, 8.2 mmol) was dissolved in dichloromethane (50 mL). (4-Methylphenyl)boronic acid (2.2 g, 16.4 mmol), triethylamine (5.7 mL, 41.0 mmol) and copper acetate(II) (1.5 g, 8.2 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 days. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (324 mg, yield 19%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:25][C:26]([CH:29]2[CH2:31][CH2:30]2)=[N:27][N:28]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[N:27][N:28]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: ClCc1nnc(C2CC2)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1nnc(C2CC2)o1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x9 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 75 mg, 0.331 mmol) in DMSO (2 mL) followed by sodium tert-butoxide (35.0 mg, 0.364 mmol) and 2-(chloromethyl)-5-cyclopropyl-1,3,4-oxadiazole (68.2 mg, 0.430 mmol). 1H NMR (400 MHz, DMSO-d6) δ 0.92-1.00 (m, 2H), 1.07-1.16 (m, 2H), 2.14-2.25 (m, 1H), 2.92-3.03 (m, 1H), 3.03-3.11 (m, 1H), 3.11-3.20 (m, 1H), 3.34-3.51 (m, 1H), 3.53-3.58 (m, 1H), 3.59-3.72 (m, 1H), 3.85-4.00 (m, 2H), 4.20-4.29 (m, 1H), 4.53-4.63 (m, 1H), 4.79-4.88 (m, 1H), 7.56 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C15H17ClN6O2, 348.11. found 348.2.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([O:16][CH3:17])=[C:10](Br)[CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].[C:19]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)(=[O:26])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:25])=[O:26])[CH:32]=2)[C:11]([O:16][CH3:17])=[C:12]([CH:14]=[O:15])[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1c(Br)cc(S(=O)(=O)NC(C)=O)cc1C=O
Product: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Yield: 51.6 %

Procedure:
Proceeding as in Reference 19, but substituting N-acetyl-3-bromo-5-formyl-4-methoxy-benzenesulfonamide (335 mg, 1.0 mmol) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (373 mg, 1.1 mmol), gave N-acetyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (242 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].CCOC(C)=O>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][N:36]=[N+:37]=[N-:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-2-methanesulfonyloxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (589 mg, 1.14 mmol) in DMF (4.5 mL) was added a solution of sodium azide (371 mg, 5.7 mmol) in water (0.5 mL) and the mixture was stirred at 80° C. under nitrogen atmosphere overnight. EtOAc and a water were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 6:5) to give the desired compound. MS (LC-MS): 464 [MH−Boc]+; tR (HPLC conditions b) 5.73 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[C:16]([CH3:22])[CH2:17]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li:25]CCCC>CCCCC>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[C:16]([CH3:22])[CH-:17]3)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1.[Li+:25]
Reactant: [Li]CCCC
Reactant: CC1=Cc2c(cccc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: CCCCC
Product: Cc1cc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccc2[cH-]1
Product: [Li+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[3′,5′-bis(trifluoromethyl)phenyl]-2-methylindene (2.2 g, 6.5 mmol) was dissolved in 50 mL of pentane. To this solution was added 2.6 mL of n-BuLi (2.5M in hexane) and the reaction was allowed to stir 4 hours at room temperature. A yellow-white solid precipitated from solution and was collected by frit filtration and washed with additional pentane. Yield was 1.6 g (73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH3:14])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([C:28](Cl)=[O:29])[C:24]([Cl:27])=[N:25][CH:26]=1.BrC1C=C(C(O)=O)C(O)=NC=1.O=S(Cl)Cl>CC#N>[Cl:27][C:24]1[C:23]([C:28]([NH:1][C:2]2[C:3]([NH:12][CH2:13][CH3:14])=[N:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:7]=2)=[O:29])=[CH:22][C:21]([Br:20])=[CH:26][N:25]=1
Reactant: CCNc1nc(C(F)(F)F)ccc1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C(O)c1cc(Br)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCNc1nc(C(F)(F)F)ccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.08 h

Procedure:
To a cooled solution of 3-amino-2-(ethylamino)-6-trifluoromethyl pyridine (1 g, 4.9 mmol) in MeCN (24 mL) was added solid NaHCO3 (906 mg, 11 mmol). After 5 min, crude 5-bromo-2-chloro-3-pyridinecarbonyl chloride (prepared from 5-bromo-2-hydroxy-3-pyridinecarboxylic acid and SOCl2 [as described by T. W. Gero et al. in Synth. Commun. 1989,19,553-559 (incorporated herein by reference) but with omission of the aqueous work-up] was added (1 equiv., 4.9 mmol). After 2 h, the reaction mixture was poured over ice/H2O (1.5 L) and the resulting solid was filtered, rinsed with H2O and then hexane. After drying under reduced pressure overnight, the title compound was obtained as a light brown solid (1.6 g, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Cl:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl-:14].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][P+:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nnn(-c2ccc(F)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 80 °C

Procedure:
A solution of 1-(4-fluorophenyl)-4-methyl-5-chloromethyl-1,2,3-triazole (754 mg; 3.34 mmol), prepared as described in example 7, and triphenylphosphine (1.1 g; 4.18 mmol) in toluene (33 ml) was heated at 80° C. for 21 hours. Then, the reaction mixture was cooled to room temperature and kept at this temperature overnight. The precipitate was filtered by washing with a little amount of toluene and with ethyl ether. The title compound was obtained as a solid.
Reaction SMILES: COC1C=CC(C[N:10]2[C:15](=[O:16])[CH:14]=[C:13]3[CH2:17][CH2:18][CH2:19][O:20][C:12]3=[N:11]2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[N:11]1[NH:10][C:15](=[O:16])[CH:14]=[C:13]2[CH2:17][CH2:18][CH2:19][O:20][C:12]=12
Reactant: COc1ccc(Cn2nc3c(cc2=O)CCCO3)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc2c(n[nH]1)OCCC2
Temperature: 70 °C
Yield: 88.5 %

Procedure:
2-{[4-(Methyloxy)phenyl]methyl}-6,7-dihydro-2H-pyrano[2,3-c]pyridazin-3(5H)-one (2.75 g, 10.1 mmol) was treated with anisole (10 ml) and TFA (100 ml) and heated at 70° C. for 24 hours. The solution was cooled and evaporated and the residue taken up in 2.5% methanol/dichloromethane. This was applied to a silica gel column, and then elution with this solvent mixture followed by 5% methanol/dichloromethane gave the product as an off white solid (1.36 g, 88%).
Reaction SMILES: C([Li])CCC.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C=CC=CC=1.[C:34]([O:38][C:39](=[O:51])[NH:40][C@@H:41]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:42]=O)([CH3:37])([CH3:36])[CH3:35]>CCCCCC.C1COCC1>[C:34]([O:38][C:39](=[O:51])[NH:40][C@H:41](/[CH:42]=[CH:14]\[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](/C=C\Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, 842 μL (2.1 mmol) 2.5 M n-butyllithium solution in hexane was added to a suspension of 986 mg (2.2 mmol) triphenyl-(2-phenylethyl)phosphonium bromide [can be synthesized, e.g., according to R. W. Hartmann, M. Reichert, Archiv der Pharmazie 333, 145 (2000); K. C. Nicolaou et al., European J. Chem. 1, 467 (1995)] in 125 mL THF at −78° C., and the mixture was then stirred for one hour at 0° C. The reaction mixture was then cooled back to −78° C. and a solution of 500 mg (2.0 mmol) tert-butyl-[(2S)-1-oxo-3-phenylpropan-2-yl]carbamate in 5 mL dry THF was added. The batch was heated to 0° C. and stirred further for three hours at this temperature. The reaction was then terminated by adding saturated aqueous ammonium chloride solution. The mixture was diluted with MTBE, the phases were separated, and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified over a silica gel column using cyclohexane/ethyl acetate 5:1 as the mobile phase. After concentrating the corresponding fractions, 173 mg (25.6% of the theoretical) of the Boc-protected intermediate, tert-butyl-[(2S,3Z)-1,5-diphenylpent-3-en-2-yl]carbamate was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
A solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) in DMF (300 mL) was sparged with Ar, treated with Cs2CO3 (48.2 g, 148 mmol) and 2-chloro-4-hydroxypyridine (10.53 g, 81 mmol), sparged again with Ar and heated at 85° C. overnight. The mixture was cooled to RT, filtered through a bed of silica gel, washed thoroughly with EtOAc, and the filtrate treated with 5% LiCl and stirred overnight. The layers were separated, the aqueous layer extracted with additional EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The residue was dissolved in EtOAc, treated with 5% LiCl, stirred for 1 h, the layers separated and the aqueous layer extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was suspended in MTBE, sonicated and the resulting solid collected via filtration to afford 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (6.06 g, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=2.4, 1H), 8.43-8.39 (m, 2H), 8.06 (dd, J=8.8, 2.8 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.23 (dd, J=5.6, 2.0 Hz, 1H); MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]3[C:16]=2[CH2:17][CH2:18][CH2:19][N:20]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>[Fe].O>[NH2:25][C:24]1[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]2)=[C:16]2[C:21](=[N:22][CH:23]=1)[N:20]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:19][CH2:18][CH2:17]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCCN3C(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCCN3C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Iron powder (0.26 g, 4.6 mmol) was added to a mixture containing tert-butyl 5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-nitro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.60 g, 1.2 mmol), AcOH (9 mL), and water (1 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and filtered. The filtrate was neutralized with saturated aq. NaHCO3. The organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to give the sub-title compound (0.51 g, 90%). LCMS calc. for C23H38N5O4 (M+H)+: m/z=448.3. Found: 448.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.CN(C)[CH:15]=[O:16].N1(C2[CH2:28][CH2:27][S:26][CH2:25][CH:24]=2)CCCC1>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][CH:24]2[C:15](=[O:16])[CH2:28][CH2:27][S:26][CH2:25]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: C1=C(N2CCCC2)CCSC1
Reactant: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)CC2CSCCC2=O)cc1

Procedure:
A solution of 23.7 g (0.10 mole) of p-methoxyphenacyl bromide in 50 ml. of dimethylformamide is added dropwise under nitrogen to a cold stirred solution of 16.9 g (0.10 mole) of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran [Example 1 (a)] and 10 ml. of dimethylformamide. After 5 hours the reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate, and concentrated to an oil which solidifies. The solid is suspended in methanol. The mixture is filtered and the filtrate is concentrated to a solid. The resulting solid is recrystallized from methanol and then from acetic acid to give off-white crystals of 3-(4-methoxyphenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, m.p. 123° to 125°C.
Reaction SMILES: S(Cl)(Cl)=O.[Na].[C:6]([OH:9])(=[O:8])[CH3:7].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[CH3:15]O>>[NH:10]1[CH:14]=[C:13]([CH2:7][C:6]([O:9][CH3:15])=[O:8])[N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: CO
Reactant: CC(=O)O
Agent: [Na]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Thionyl chloride (3 mL, 41.1 mmol) was added slowly over the course of 30 mins to a 0° C. solution of imidazole acetic acid sodium salt (1.84 g, 10.0 mmol) in MeOH (40 mL) and the solution was stirred at RT overnight and evaporated. Aqueous NH4OH was slowly added and the solution was extracted with 9:1 CH2Cl2:MeOH to provide the title compound (1.18 g, 84%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (d, J=5.22 Hz, 1H), 7.02 (br. s., 1H), 3.63-3.82 (m, 5H).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH:12]([OH:13])[CH2:11][N:10]([C:14](=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:9]1)=O)C>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([N:10]1[CH2:9][CH:8]([CH2:6][OH:5])[CH:12]([OH:13])[CH2:11]1)=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CN(C(=O)CCCCCNC(=O)OCc2ccccc2)CC1O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCCCCC(=O)N1CC(O)C(CO)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of lithium borohydride (0.305 g, 13 mmol) in anhydrous tetrahydrofuran (25 mL) was added a solution of ethyl ester 62 (3.74 g, 9.2 mmol) in THF (25 mL) over a period of 30 mins at 0° C. After the addition the reaction mixture was brought to room temperature and stirred further under argon. The completion of the reaction was ascertained by TLC after 4 h. (Rf=0.4 in 10% MeOH/CHCl3). The reaction mixture was evaporated to dryness and cooled to 0° C. To the residue 3N HCl (40 mL) was added slowly. After stirring for 30 mins the product was extracted with dichloromethane (3×75 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Organic layer was filtered and evaporated to dryness. Compound 63 was purified by column chromatography first by eluting with dichloromethane/methanol (5%) (3.2 g, 92%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:21][CH2:22][CH3:23])=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]=1[S:9][CH2:10][C:11]#[N:12])#[N:2].[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:8](=[N:7][C:6]([N:31]3[CH2:32][CH2:33][C:28]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:29][CH2:30]3)=[CH:5][C:4]=2[CH2:21][CH2:22][CH3:23])[S:9][C:10]=1[C:11]#[N:12]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC#N)c1C#N
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1cc(N2CCC3(CC2)OCCO3)nc2sc(C#N)c(N)c12
Temperature: 100 °C
Yield: 87.6 %

Procedure:
Trifluoro-methanesulfonic acid 5-cyano-6-cyanomethylsulfanyl-4-propyl-pyridin-2-yl ester (1.83 g, 5.00 mmol) (see Example 1, Method B) and 1,4-dioxa-8-aza-spiro[4.5]decane (0.66 mL, 5.00 mmol) were suspended in 3 mL of dioxane. Triethylamine (0.84 mL, 6.0 mmol) was added. The reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) at 100° C. for 2 h. The reaction mixture was poured into water and the resulting solid was collected by filtration and recrystallized from acetonitrile to give 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile as a yellow solid (1.57 g, 88%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH:22]([NH2:24])[CH3:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[ClH:11].[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:24][CH:22]([C:18]2([C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:19][CH2:20][CH2:21]2)[CH3:23])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(N)C1(c2ccc(Cl)cc2)CCC1
Solvent: Cc1ccccc1
Product: COc1ccc(CNC(C)C2(c3ccc(Cl)cc3)CCC2)cc1
Product: Cl
Temperature: 25 °C

Procedure:
A solution of p-anisaldehyde (6.43 g) and 1-[1-(4-chlorophenyl)cyclobutyl]ethylamine (see Example 1(b) of published British Patent Specification No. 2098602) in the form of its free base (9.09 g) in dry toluene (50 ml) was heated under reflux for 20 hours under nitrogen and water was removed by means of a Dean-Stark apparatus. The reaction mixture was cooled and solid sodium borohydride (4.1 g) was added. Methanol (40 ml) was added dropwise at a temperature of 25°-30° C. The mixture was heated under reflux for one hour and the methanol and toluene removed by evaporation. The residue was cooled to ambient temperature and excess 5N hydrochloric acid added. The mixture was then basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was washed and shaken with 5N hydrochloric acid to give a white solid which was recrystallised from ethanol to give N-(4-methoxybenzyl)-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 225°-228° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH3:33])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19][CH2:20][CH2:21]Cl)[C:16]([O:23][CH3:24])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:25]#[N:26].[Cl:34][C:35]1[CH:63]=[C:62]([Cl:64])[C:61]([O:65][CH3:66])=[CH:60][C:36]=1[NH:37][C:38]1[C:47]2[C:42](=[CH:43][C:44]3[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH2:55][CH2:56]Cl)=[CH:48][C:45]=3[CH:46]=2)[N:41]=[CH:40][C:39]=1[C:58]#[N:59].[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.[I-].[Na+]>COCCOC>[Cl:34][C:35]1[CH:63]=[C:62]([Cl:64])[C:61]([O:65][CH3:66])=[CH:60][C:36]=1[NH:37][C:38]1[C:47]2[C:42](=[CH:43][C:44]3[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH2:55][CH2:56][N:71]4[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]4)=[CH:48][C:45]=3[CH:46]=2)[N:41]=[CH:40][C:39]=1[C:58]#[N:59].[Cl:1][C:2]1[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH3:33])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19][CH2:20][CH2:21][N:71]4[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]4)[C:16]([O:23][CH3:24])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:25]#[N:26]
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCCl)cc4cc23)c(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCN5CCN(C)CC5)cc4cc23)c(Cl)cc1Cl
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCN5CCN(C)CC5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 0.4 g (0.8 mmol) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 1.25 ml (11.27 mmol) of 1-methyl piperazine and 0.05 g of sodium iodide in 2.0 mL of ethylene glycol dimethyl ether is heated at 90° C. for 2 hours under nitrogen. The mixture is cooled, the solvent is removed in vacuo and the resulting residue is stirred with saturated solution of sodium bicarbonate. The crude solid is collected by filtration, washed with water, and dried in vacuo. Purification is carried out by silica gel chromatography, eluting with a gradient of 92:8 to 85:15 methylene chloride/methanol to yield 0.149 g of 4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 141–150° C. and 0.203 g of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 132–135° C.