Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N+:26]#[C-:27])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CO.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:26]=[CH:27][O:35][C:28]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#[N+]C(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: c1ccc(COc2ccc(-c3ncoc3-c3ccncc3)cc2)cc1
Yield: 61.2 %

Procedure:
A mixture of 1-((4-(Benzyloxy)phenyl)isocyanomethylsulfonyl)-4-methylbenzene (4.3 g, 11.4 mmol), isonicotinaldehyde (1.34 g, 12.5 mmol) and K2CO3 (3.15 g, 22.8 mmol) in methanol (96 mL) and DME (30 mL) was heated at reflux for 5 h. After removal of solvent, the residue was purified by silica gel chromatography (2:1 hexane/EtOAc) to provide 2.29 g (84%) of a white solid. 1H NMR (400 MHz, CDCl3) δ: 5.12v (s, 2H), 7.03 (d, 2H), 7.46 (m, 6H), 7.56 (d, 2H), 7.61 (d, 2H), 8.02 (s, 1H), 8.58 (d, 2H). MS m/z: 329 [M+1]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]>CN(C=O)C>[N:1]1([CH2:17][C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:24][CH2:25]2)=[O:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc21)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzimidazole (0.785 g, 0.7 mmol) was taken in dry DMF (15 ml) and dry potassium carbonate (340 mg) and KI (20 mg) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration gave material that on purification by flash chromatography (CHCl3/MeOH) afforded pure product: 1H NMR (300 MHz, CDCl3): δ 8.10-7.65 (m, 4H), 7.26 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.79-3.66 (m, 4H), 3.14 (br, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].[CH2:7]([O:14][CH2:15][C:16](=[O:38])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][CH2:15][C:16]([OH:38])([CH2:5][CH2:4][CH:3]=[CH2:2])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCCBr
Reactant: CCCCCCCCCCCCCCCCCCOCCC(=O)COCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)(CCOCCCCCCCCCCCCCCCCCC)COCc1ccccc1
Reaction time: 1 h

Procedure:
1.12 g (8 mmol) of 4-bromo-1-butene in 15 ml of dry ether was reacted with 200 mg of magnesium turnings at reflux under a nitrogen atmosphere for 1 hour. The resulting Grignard reagent was cooled to -60° C. and then treated with 2.22 g (5 mmol) of the compound prepared in (b) above in 30 ml of ether. After 1 hour at -60° C., the mixture was warmed overnight to room temperature and then quenched with a saturated aqueous ammonium acetate solution and partitioned. The organic layer was then washed twice with ammonium acetate, washed with a saturated sodium chloride solution and dried over magnesium sulfate, after which time the solvent was removed under reduced pressure. Purification of the crude product was effected on silica gel employing a mixture of petroleum ether and diethyl ether as the eluent to yield a low melting solid.
Reaction SMILES: C(N[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=O)C.Cl.C([OH:34])C>O>[OH:34][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:27])([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CCO
Reactant: CC(=O)NC(=Cc1ccc(Oc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Agent: Cl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc(C=C(O)C(=O)O)cc3)ccc21

Procedure:
1.6 g of (4 mmol) of α-acetamido-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)cinnamic acid, 25 ml of concentrated hydrochloric acid and 25 ml of ethyl alcohol were introduced into a round-bottomed flask and the mixture was heated at reflux for eight hours. The reaction medium was poured into water and extracted with ethyl acetate, and the organic phase was decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was triturated in a mixture of hexane and ethyl ether (80:20) and the mixture was filtered. 1.06 g (72%) of the expected acid was recovered, having a melting point of 207°-10° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li]CCCC.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([O:33][CH:34]([CH3:36])[CH3:35])[C:19]([F:32])=[C:20]([CH:31]=1)/[CH:21]=[N:22]/[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH3:14]>C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([N:22]([CH2:21][C:20]2[CH:31]=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=[C:18]([O:33][CH:34]([CH3:36])[CH3:35])[C:19]=2[F:32])[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cs2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19.3 %

Procedure:
To a solution of 2,4-dibromothiazole (100 mg, 0.412 mmol) in 2 mL THF was added BuLi (1.6 M in THF, 283 μL, 0.453 mmol). The mixture was stirred at −78° C. for 15 min, then a solution of Intermediate 7.3 (134 mg, 0.412 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at −78° C. for 30 min, was allowed to warm to rt, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) followed by preparative HPLC purification to afford 39 mg of Intermediate 16.1.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1.O>C(OC(=O)C)(=O)C>[C:1]([O:4][CH:14]([C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 10 h
Yield: 43 %

Procedure:
A pinch of sodium acetate was added to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-ethane in 100 ml of acetic anhydride and the mixture was then kept for 10 hours at a temperature of 100° C. Thereafter the solution was cooled and stirred into 1,000 ml of water. A smeary, crystalline mass precipitated, which was taken up in chloroform. The chloroform solution was washed with sodium bicarbonate and water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue crystallized on adding petroleum ether. 13 g (43% of theory) of 1-acetoxy-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethane of melting point 92°-96° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1.O>CN(C)C=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)c1ccc(F)cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 72 h
Yield: 36 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70.0 mg, 0.16 mmol) synthesized in Example (38d) and 5-fluoro-2-(methylsulfonyl)pyridine (35.0 mg, 0.20 mmol) synthesized in Example (65b) were dissolved in N,N-dimethylformamide (5 mL), and stirring was carried out at 90° C. for 3 days under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, followed by extraction with ethyl acetate (30 mL), and washing was carried out with saturated brine (30 ml), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-40%) to afford the desired compound (28 mg, yield 35%) as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@:13]2([OH:30])[C:20]3[N:16]([CH:17]=[N:18][CH:19]=3)[C@@H:15]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=3[F:29])[CH2:14]2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)CCC>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>[F:29][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=1[C@@H:15]1[N:16]2[CH:17]=[N:18][CH:19]=[C:20]2[C@@:13]([OH:30])([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:8]=2)[CH2:14]1)[C:27]#[N:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(OS(=O)(=O)C(F)(F)F)c3)c3cncn32)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(-c4ncccn4)c3)c3cncn32)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A solution of 3-((5R,7S)-5-(4-cyano-2-fluorophenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)phenyl trifluoromethanesulfonate (20 mg, 0.043 mmol), 2-tributylstannanyl-pyrimidine (47.4 mg, 0.128 mmol) and palladium tetrakis (9.89 mg, 8.56 μmol) in toluene (400 μL) was allowed to stir at 100° C. for overnight. The crude was cooled and concentrated. The crude was partitioned between water and CH2Cl2. The aq. layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was filtered through a plug of silica using EtOAc/heptane. Part of the residue was then purified via HPLC, using 10-90% MeCN/H2O to give 2 mg of the entitled product. MS 398.1 (M+H); LCMS condition B, retention time 0.95 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.06 (dd, 1H), 3.41 (dd, 1H), 5.76-5.90 (m, 1H), 7.04 (s, 1H), 7.14 (t, 1H), 7.28 (t, 1H), 7.34-7.43 (m, 2H), 7.46 (t, 1H), 7.62 (dd, 1H), 7.68 (s, 1H), 8.30-8.40 (m, 1H), 8.52 (t, 1H), 8.73 (d, 2H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][C:9](=[O:32])[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]1[S:12][C:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][C:15]=1[C:16](OCC)=[O:17])(=O)C.IC>C(O)C>[CH3:5][N:8]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:12][C:11]=2[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]1=[O:32]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)sc1N(CC(C)C)C(=O)NC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccccc3)sc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
Sodium ethoxide (1.96 g) was added to a solution of N′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea (2.90 g) in ethanol (40 ml) under nitrogen. The mixture was stirred for 20 hours then iodomethane (1.80 ml) was added. The mixture was heated to reflux for 3 hours and then allowed to cool to room temperature and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate twice. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with diethyl ether:isohexane (1:1) to give an oil which was recrystallised from diethyl ether/isohexane to give the title compound (1.70 g).
Reaction SMILES: [C-:1]#[N:2].[K+].[S:4]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][S:4][CH:5]=1)[C:1]#[N:2]
Reactant: O=Cc1ccsc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC(O)c1ccsc1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of KCN (18.6 g, 286 mmol) in methanol (100 mL) was added thiophene-3-carbaldehyde (20 mL, 178 mmol) at 0° C. under nitrogen atmosphere. Then acetic acid (4.4 mL) was added dropwise at 0° C. After 30 minutes, the mixture was warmed to 15° C. and stirred for 20 hours. NaHCO3 (15 g) was added. The mixture was concentrated and extracted with ethyl acetate (200 mL). The organic mixture was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:10) to afford hydroxy-thiophen-3-yl-acetonitrile. (Yield 15 g, 60%). LC-MS: [M+Na]+ 162.
Reaction SMILES: [CH2:1](OCC1C=CC=CC=1)C1C=CC=CC=1.[NH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([N:28]3[C:32]([C:33]4[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42]CC5C=CC=CC=5)=[CH:35][C:34]=4[O:50]CC4C=CC=CC=4)=[N:31][N:30]=[C:29]3[OH:58])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[OH:58][C:29]1[N:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][CH2:17][NH:16][CH3:1])[CH:20]=[CH:21]3)[C:32]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[C:36]([OH:42])=[CH:35][C:34]=2[OH:50])=[N:31][N:30]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(ccn3CCN)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CNCCn1ccc2cc(-n3c(O)nnc3-c3cc(C(C)C)c(O)cc3O)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The benzylether[4-(1-(2-aminoethyl)-1H-indol-5-yl)-5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4H-1,2,4-triazol-3-ol; 188 mg, 0.33 mmol) was dissolved in 6 ml degassed THF/methanol (1:1). 50 mg Pd/C (10%) was added and the mixture stirred under hydrogen (balloon) at rt for 5 h. After filtration the solvent was removed and the crude purified by chromatography on silica with DCM/MeOH (5-20%)/NH4OH (0.5%) to yield 71 mg (0.18 mmol) 4-(5-hydroxy-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol. This amine (50 mg, 0.125) was added to 4-(2,5-dioxopyrrolidin-1-yl)butanoic acid (26 mg, 0.14 mmol), EDC (38 mg, 0.2 mmol) and HOBt (27 mg, 0.2 mmol) in 1.5 ml DMF at rt. The mixture was stirred for 12 h and then ethyl acetate and water added. The aq. Phase was extracted twice with ethyl acetate and the combined organic extracts washed with brine and dried over MgSO4. The crude was purified by chromatography on silica with DCM/MeOH (3-10%) to yield 34 mg (0.061 mmol) product.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([C:18]#[N:19])=[CH:14][NH:15]2)=[CH:10][C:9]=1[O:21][CH3:22]>C(O)(=O)C>[CH3:22][O:21][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[O:6][CH2:5][CH2:4][O:3][CH3:2])[NH:15][CH:14]=[C:13]([C:18]#[N:19])[C:12]2=[O:20]
Reactant: COCCO
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1F
Agent: [Na]
Solvent: CC(=O)O
Product: COCCOc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (84 mg, 3.67 mmol) is added to 3.6 mL of 2-methoxyethanol and the mixture is heated at reflux for 90 minutes. 7-Fluoro-6-methoxy-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile (200 mg, 0.92 mmol) is added and the reaction mixture is heated at reflux for 4 hours then stirred at room temperature overnight. The reaction mixture is poured into ice water and acidified with acetic acid. The solids are collected by filtration, washing with ethyl acetate and hexane, to provide 234 mg of 6-methoxy-7-(2-methoxyethoxy)-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile, mp>300° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4]1.[F:20]C1C=CC=C2C=1NC=C2C1CCC(=O)C1>>[F:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:6][CH2:7][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4]1
Reactant: O=C1CCC(c2c[nH]c3c(F)cccc23)C1
Reactant: CN(C)C1CCC(c2c[nH]c3ccc(C#N)cc23)C1
Product: CN(C)C1CCC(c2c[nH]c3c(F)cccc23)C1
Yield: 59 %

Procedure:
By the method of Compound 3, using 3-(7-fluoro-1H-indol-3-yl)-cyclopentanone (217 mg, 1.0 mMol) as starting material, 3-(7-fluoro-1H-indol-3-yl)-cyclopentyl-dimethylamine (144 mg, 59%) was obtained. 1H NMR (400 MHz, d4MeOH) δ ppm 1.74 (m, 3 H) 2.17 (m, 3 H) 2.34 (d, J=2.20 Hz, 6 H) 2.84 (m, 1 H) 3.34 (m, 1 H) 6.77 (dd, J=11.13, 8.19 Hz, 1 H) 6.90 (m, J=10.39, 5.07, 4.83, 2.45 Hz, 1 H) 7.05 (d, J=15.16 Hz, 1 H) 7.33 (t, J=7.70 Hz, 1 H). LCMS (XTERRA C18 S5 4.6×50 mm) tR, 1.130 min., MH+ 247.29.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:14][NH:13][C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:23]Br>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:14][NH:13][C:12]2[N:15]=[CH:16][C:17]([Br:23])=[CH:18][C:11]=2[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C[C@H]2CNc3ncccc3CN2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CN[C@@H](Cc1ccccc1)CN2
Reaction time: 8 h

Procedure:
(S)-3-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine (60 mg, 0.25 mmol) was dissolved into acetic acid (1 mL). Bromine (15 μL, 0.3 mmol) was added and the reaction was stirred overnight. Methylene chloride (10 mL) was added and the solution was washed with 1 N NaOH (1 mL) and brine (1 mL), dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (3 mL) and precipitated with diethyl ether. The title compound was collected as an orange solid (80 mg, 100%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.42 (s, 1H), 7.37-7.17 (m, 5H), 5.42-5.00 (bs, 2H), 3.96-3.75 (m, 2H), 3.45-3.40 (m, 1H), 3.30-3.20 (m, 1H), 2.98-2.91 (m, 1H), 2.87-2.73 (m, 2H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:17])[CH2:14][CH2:15]O)[CH:10]=[CH:11][CH:12]=1>CCOCC>[Br:2][CH2:15][CH2:14][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=1)[CH3:17]
Reactant: COc1cccc(C(C)CCO)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1cccc(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3-methoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title product.
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:4])[CH3:2]
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)C(=NO)c1ccccc1
Solvent: ClCCl
Product: CCP(=O)(ON=C(C(=O)OC)c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following the procedure of Example 2, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride is reacted with methyl 2-hydroxyimino-2-phenylacetate (357 mg, 1.5 eq.) in methylene chloride, with stirring at RT for 24 hours. The reaction is worked up and purified as in Example 2 to give methyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]-2-phenylacetate.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12]CCOCCOCCOCCO.C(N(CC)CC)C>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of p-toluenesulfonyl chloride (9.82 g, 51.5 mmol) in 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethanol, (20 g, 103 mmol) at 0° C. was added dropwise triethylamine (13 ml, 93 mmol). The suspension was stirred at 0° C. for 1 hour and then at room temperature for another 16 hours. The resulting mixture was dissolved in dichloromethane (350 ml). The clear and colourless solution that was obtained was extracted with 1 M hydrochloric acid (2×100 ml) and once with water (200 ml). The organic phase was dried (MgSO4), filtered and evaporated to afford a colourless oil. The crude product was purified by flash chromatography using ethyl acetate. Tetraethylene glycol ditosylate, eluted first followed by toluene-4Sulfonic acid 2-{2-[2-(2-hydroxy-ethoxy)ethoxy]-ethoxy}-ethyl ester, as a colourless oil; 8.89 g (49%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].C([Li])CCC.Cl[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]2[N:26]([CH3:29])[CH:27]=[N:28][C:15]=12.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]2[N:26]([CH3:29])[CH:27]=[N:28][C:15]=12
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CN(C)CCCO
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.1 g. of 3-dimethylaminopropan-1-ol in 100 ml. of dry benzene are added 4 ml. of a 20% solution of butyl lithium in hexane. The mixture is stirred at room temperature for 15 minutes. After this time, 2.5 g. of 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester are added and the solution is heated at reflux temperature with stirring for 12 hours. After cooling, the solution is shaken with 50 ml. of a saturated aqueous sodium carbonate solution. The benzene layer is separated, dried with calcium chloride and evaporated to dryness. The remaining oily residue, 7-[3-(dimethylamino)propoxy]-3,5 -dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, is purified by distillation, yield 2.2 g. (85%); b.p. 175°-180° /0.01 mm.