Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([OH:23])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([O:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[C:16]2[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)([CH3:30])[CH3:29])[CH3:25]
Reactant: Oc1ccc2[nH]c(Cc3ccccc3)c(-c3ccncc3)c2c1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(Cc3ccccc3)c(-c3ccncc3)c2c1

Procedure:
The above compound was prepared from 2-benzyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[CH2:7]1[C:2]2[NH:18][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:3]=2[CH2:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6]1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 4-oxo-cyclohexanecarboxylic acid (4.05 g, 28.5 mmol) and phenylhydrazine hydrochloride (4.12 g, 28.5 mmol) in EtOH (200 ml) is stirred at reflux for 3 h. Then, the solvent is evaporated and the residue is dissolved in boiling toluene. Precipitating ammonium chloride is filtered off and the clear filtrate is cooled to rt. The resulting precipitate is filtered and tried under high vacuum to give pure subtitle compound as a white solid (5.16 g) in 84% yield. tR (LC-3) 2.21 min; ESI-MS (positive ion): m/z 216.30 [M+H]+(calcd 215.09 for C13H13NO2). 1H-NMR (CDCl3): 2.01 (m, 1H); 2.28 (m, 1H); 2.83 (m, 4H); 3.04 (dd, J=14.8 Hz, 4.7 Hz, 1H); 7.02 (m, 2H); 7.19 (d, J=7.2 Hz, 1H); 7.38 (d, J=7.0 Hz, 1H); 7.63 (s br, 1H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of 4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 10 ml of MeOH:water/3:1. 230 mg of lithium hydroxide monohydrate were added to the solution, and the reaction was stirred at RT for 16 h then at 50° C. for 2 h. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid. Yield 2.2 g.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][NH:10][C:11](=O)[C@H:12]([NH:16][C:17]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20]([C:26]#[N:27])=[CH:19][CH:18]=2)[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][C:11]([C@H:12]([NH:16][C:17]3[C:25]4[CH:24]=[CH:23][S:22][C:21]=4[C:20]([C:26]#[N:27])=[CH:19][CH:18]=3)[C@H:13]([OH:15])[CH3:14])=[N:10][N:9]=2)=[CH:29][CH:30]=1)#[N:2]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of 4-cyano-N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.95 g, 2.26 mmol) in THF (150 mL) was added PS-BEMP (3.1 g, 6.82 mmol, ˜2.2 mmol/g) and p-TsCl (470 mg, 2.46 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH (400 mL). The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (401 mg, 44%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.14 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.83 (d, J=5.6 Hz, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.18 (dd, J=6.5, 8.8 Hz, 1H), 4.72 (b, 1H), 4.61 (m, 1H), 1.50 (d, J=6.2 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[CH2:16]([NH:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17]>ClCCl>[CH2:16]([NH:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([F:7])=[O:22])[CH3:17]
Reactant: CCNc1nc(Cl)ccc1C(=O)O
Reactant: FC1=CC(F)=NN(F)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol) of 2-(ethylamino)-6-chloronicotinic acid in 125 ml of dichloromethane. The mixture is stirred at ambient temperature for 3 hours and then filtered. The solid is rinsed with 50 ml of dichloromethane and the filtrate is washed twice with 60 ml of ice-cold water. The organic phase is dried over Na2SO4 and the solvent is evaporated under reduced pressure. 5.01 g of product are obtained in the form of an orange oil. Yield=99%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:4].[CH3:14]I>CN(C)C=O>[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)#[N:4]
Reactant: N#Cc1n[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(C#N)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.37 g, 60% dispersion in mineral oil) was added to a solution of 3-cyano-1H-indazole (1.20 g, Reference Example 57) in dry dimethylformamide (30 mL) under a nitrogen atmosphere at ambient temperature. The mixture was allowed to stir for 1 hour then treated with methyl iodide (0.85 mL) and stirring was continued for 1 hour. The reaction mixture was then poured into ice-water (15 mL). The precipitated solid was filtered then washed with water and then dried to give the title compound (0.80 g) as a beige solid, m.p. 73° C. 1H NMR [(CD3)2SO]: δ 7.91 (m, 2H); 7.60 (t, 1H); 7.42 (t, 1H); 4.21 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CC(C)COC(=O)Cl
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CC(C)COC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
30 mg of crude 3(4-imidazol-1-ylmethylphenyl)5-iso-butylthiophene-2-sulfonamide (see Example 1(f) above) was dissolved in pyridine (1 mL, dried over 4 Å molecular sieve) and cooled on ice. Pyrrolidinopyridine (11.8 mg, 0.080 mmol) and iso-butyl chloroformate (103.6 μL, 0.80 mmol) were then added to the mixture. The mixture was stirred overnight under a N2 atmosphere at 50° C. Evaporation and co-evaporation with acetonitrile to remove the solvents, followed by purification by column chromatography using 10% MeOH in CHCl3 as eluent gave the title compound (27 mg, 0.057 mmol) in 71% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:9][O:10][C:11]1[C:12]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)=[CH:13][CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: Cc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2ccnc(C)c2)c(OC)n1
Temperature: 80 °C

Procedure:
Degassed 1,2-dimethoxyethane (60 mL) and water (0.5 mL) were added to a flask charged with 4-bromo-2-methylpyridine (1.20 g, 6.98 mmol), methyl 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (C31) (3.07 g, 10.5 mmol), potassium phosphate (4.44 g, 20.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.70 mmol). The mixture was heated to 80° C. for 18 hours, then cooled to room temperature and concentrated in vacuo. Silica gel chromatography (Eluant: ethyl acetate) provided a solid, which was triturated twice with a 1:5 mixture of ethyl acetate and heptane to provide the title compound as a white solid. Yield: 1.68 g, 6.50 mmol, 93%. LCMS m/z 259.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.63 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 7.32 (br d, J=5.5 Hz, 1H), 7.36 (br s, 1H), 7.79 (AB quartet, JAB=7.3 Hz, ΔνAB=24.1 Hz, 2H), 8.57 (d, J=5.0 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:42])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:25]=4[O:37][C:38]([F:41])([F:40])[F:39])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:43])=O)(C)(C)C.[ClH:44]>O1CCCC1.O1CCOCC1>[ClH:44].[CH3:42][N:14]1[C:11]2[CH2:12][CH2:13][NH:8][C:9](=[O:43])[C:10]=2[CH:16]=[C:15]1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[C:28]([N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)[CH:27]=[CH:26][C:25]=2[O:37][C:38]([F:40])([F:41])[F:39])[N:18]=1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4C)CCN(C(=O)OC(C)(C)C)C5=O)n3)c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4C)CCNC5=O)n3)c2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of methyl-2-{2-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-pyrimidin-4-yl}-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (25 mg, 0.037 mmol) in tetrahydrofuran (1 mL), 4M HCl in dioxane (0.4 mL) were added. The solution was stirred at room temperature over night. The solvent was evaporated under vacuo to yield 22 mg (98%) of the title compound as a beige powder.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:55][C:56]1([CH3:65])[O:60][C@@H:59]([CH2:61][CH2:62][CH2:63]O)[CH2:58][O:57]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:63][CH2:62][CH2:61][C@@H:59]3[CH2:58][O:57][C:56]([CH3:65])([CH3:55])[O:60]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC1(C)OC[C@H](CCCO)O1
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CCCOc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of probucol (2.93 g, 5.7 mmole) in 100 ml of THF were added Ph3P (1.63 g, 6.2 mmole) and 3-[2,2-dimethyl-1,3-dioxolane-4(S)-yl]-propanol (1.0 g, 6.2 mmole). The mixture was cooled to 0° C. with an ice bath, and DEAD (1.1 g, 6.2 mmol) was then added dropwise under nitrogen. The mixture was stirred overnight while allowed to warm to room temperature and then heated to reflux. The reaction mixture was cooled and concentrated to an oily residue when HPLC and TLC showed that the new peak ceased to grow. Chromatography on silica gel with gradient solvent from hexanes to 25% EtOAc in hexanes to afford 1.3 g (35.1%) 2,6-di-tert-butyl-4-(1-{3,5-di-tert-butyl-4-[3-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-propoxy]-phenylsulfanyl}-1-methyl-ethylsulfanyl)phenol as a white solid. 1H-NMR (CDCl3) δ 7.53 (s, 2H), 7.45 (s, 2H), 5.37(s, 1H), 4.05–4.17 (m, 2H), 3.71–3.77 (m, 2H), 3.35 (t, J=2.5 Hz, 1H), 1.90–2.00 (m, 2H), 1.63–1.73 (m, 2H), 1.42–1.46 (m, 42H). MS m/z: 676.4429 ([M+NH4]+, 25%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:28]3[NH:34][N:33]=[N:32][N:29]=3)([CH3:31])[CH3:30])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CCCCCC(C)(C)C#N)oc2-c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CCCCCC(C)(C)c3nnn[nH]3)oc2-c2ccc(OC)cc2)cc1
Yield: 50.8 %

Procedure:
5 g of 7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl)-2,2-dimethylheptanenitrile in 12 cm3 of dimethylformamide are treated with twice 2.7 g of sodium azide and twice 4.95 g of triethylamine hydrochloride according to the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 3.5 cm in diameter containing 120 g of silica gel (50 to 200μ). The column is eluted, collecting 50 cm3 fractions, with 0.5 liter of diisopropyl ether and then with 1.3 liters of a diisopropyl ether/ethyl acetate (70:30 by volume) mixture. The fractions emerging at between 0.85 liter and 1.3 liters are concentrated under reduced pressure (0.2 kPa). The solid is taken up with 30 cm3 of diethyl ether and drained, washed with 10 cm3 of diethyl ether and dried. 2.8 g (50%) of 5-{7-[ 4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-methyl-2heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:12]=[O:13])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: COc1c(Cl)cc(N)cc1Br
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(N=C=O)cc1Br
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-chloro-4-methoxyaniline (13.0 g) in toluene (100 ml) was dropwise added to a toluene solution containing 20 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-bromo-5-chloro-4-methoxyphenyl isocyanate (14.4 g). The thus obtained crude substance was added to an isopropanol solution (50 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-bromo-5-chloro-4-methoxyphenyl)carbamate (Compound No. 33) (16.4 g) in a yield of 92% (calculated from the starting 3-bromo-5-chloro-4-methoxyaniline). M.P., 112°-113.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]([O-])(=O)=O.[Na+].BrBr>N(C(C)(CC)C#N)=NC(C)(CC)C#N.ClC1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrBr
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Agent: [Na+]
Solvent: Clc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 5 °C
Yield: 493.9 %

Procedure:
4′-Methyl-2-cyanobiphenyl (105 g, 0.54 mol) and sodium bromate (12.3 g, 0.082 mol) were added to monochlorobenzene (300 g) and the internal temperature was set for 65° C. 2,2′-Azobis(2-methylbutyronitrile) (2.0 g, 0.010 mol) was added, bromine (45.6 g, 0.29 mol) was added dropwise over 5 hr and the reaction mixture was maintained at this temperature for 1 hr. The resulting inorganic salt was filtered off and the reaction mixture was cooled to 5° C. The precipitated crystals were collected by filtration to give 4′-bromomethyl-2-cyanobiphenyl (110 g, 0.405 mol). The yield was 75%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH2:25][CH3:26])[C:23](=[O:27])[N:22]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[C:19]2=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH2:25][CH3:26])[C:23](=[O:27])[N:22]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:30][CH:29]=3)[C:19]2=[N:20][CH:21]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(Cl)cc21
Temperature: 180 °C
Yield: 22.3 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (127 mg) and NaH (18.74 mg) in DMF (2 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:16])[C:8]([F:15])([F:14])[C:9](OCC)=[O:10].O.[NH2:18][NH2:19].O>CCO>[F:14][C:8]([F:15])([CH:7]([OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([NH:18][NH2:19])=[O:10]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C(F)(F)C(O)c1ccccn1
Reaction time: 16 h

Procedure:
To stirring solution of 0.96 g (4.1 mmol) of ethyl 3-(2-pyridyl)-3-hydroxy-2,2-difluoropropanoate, prepared as described by Hallinan and Fried, Tetrahedron Lett., 25, 2301 (1984), in 8 mL of EtOH was added 0.41 g (8.2 mmol) of hydrazine hydrate. After 16 hours, a yellow precipitate had formed. To the reaction was added H2O. The precipitate was filtered and washed with a minimum of H2O. The yield of product was 0.44 g (49%) after drying in a steam cabinet. Analysis calculated for C8H9N3O2F2 (M.W. 217.18): C, 44.24; H, 4.18; N, 19.35. Found: C, 44.07; H, 4.16; N, 19.05.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[C:14]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22](=O)[O:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.CCCCCC>[Br:8][C:5]1([C:22]2[O:21][C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:6]=[CH:7][CH:2]=[CH:3][CH2:4]1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1OC(c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: BrC1(c2oc(-c3ccccc3)c3ccccc23)C=CC=CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
Into a 200-cm3 Schlenk tube filled with argon, 5.0 g (2.12×10−2 mol) of 1,4-dibromobenzene was weighed. Into the Schlenk tube, 100 cm3 of dehydrated THF was poured, whereby a THF solution was prepared. After the THF solution was cooled to −50° C., 12.7 cm3 (1.9×10−2 mol) of a 1.5 mol/L hexane solution of n-butyllithium was added to the THF solution. The solution mixture was agitated for 1.5 hours while being cooled. To the resulting solution mixture, 4 g (1.9×10−2 mol) of 3-phenylphthalide was added. This mixture was cooled for two hours and then warmed to room temperature. To this mixture, 30 cm3 of a 35% aqueous solution of hydrochloric acid was added. This mixture was allowed to stand for one hour, transferred to a separatory funnel, and then subjected to extraction using toluene. The toluene layer in the separatory funnel was sufficiently washed with distilled water and then concentrated. The resulting toluene layer was fractionated by silica gel chromatography using a mixture containing toluene and hexane at a ratio of 1:4, whereby 4.65 g of 1-bromophenyl-3-phenylisobenzofuran was obtained as shown in FIG. 10. The yield of 1-bromophenyl-3-phenylisobenzofuran was 70%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(Cl)ccc1-c1c(F)ccc2c1O[C@@H](CN=[N+]=[N-])CC2
Yield: 83 %

Procedure:
Treatment of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.09 mmol) with sodium azide (0.43 g, 6.54 mmol) in DMSO (15 mL) according to the procedure described for Example 69, Step 9 provided 0.30 g (83%) of (2R)-2-(azidomethyl)-8-(4-chloro-2-methylphenyl)-7-fluorochroman as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[C:8]#[C:9][CH3:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:28][N+:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:37][CH2:36]2)=[CH:31][C:30]=1[O:38][CH2:39][C:40]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=1[F:47].O>CN(C=O)C>[CH2:13]([O:12][C:7]([C:8]1[C:9]([CH3:10])=[N:28][N:29]2[C:30]([O:38][CH2:39][C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=3[F:47])=[CH:31][C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:34]=12)=[O:11])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1ccc(C2CC2)cc1OCc1c(F)cccc1F
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
468 mg (3.4 mmol) of potassium carbonate were added to a mixture of 264 μl (2.3 mmol) of ethyl but-2-ynoate and 540 mg (1.1 mmol) of 1-amino-4-cyclopropyl-2-[(2,6-difluorobenzyl)oxy]pyridinium 2,4,6-trimethylbenzenesulphonate (Example 147A) in 10 ml of DMF. The reaction mixture was stirred at room temperature for 2 h and then poured into 25 ml of water precooled to 5° C. The precipitate was filtered off, washed with water and dried.