Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>[Ni](Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 3.74 g of N-[1-(3,4-difluorophenyl)ethyl]-N-[(4-methylthiophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 4.29 g of nickel chloride lhexahydrate, 1.37 g of sodium borohydride and 80 ml of methanol were reacted, to obtain 796 mg of isomer A and 400 mg of isomer B of the title compound as colorless oils, respectively.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:20](=[O:22])[CH3:21])[CH:8]=[C:9]([C:11](O)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:20](=[O:22])[CH3:21])[CH:8]=[C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C(C)(O)c2ccccc2)c1
Agent: Cl
Solvent: CO
Product: C=C(c1ccccc1)c1cc(C(C)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To 50.0 mg (0.17 mmol) of alcohol 15 in 4 ml of MeOH was added 2 drops of concentrated HCl. The mixture was heated at reflux for 5 min, cooled to RT, quenched with water, and the products extracted with ether. The ether layer was washed (water then brine), dried (MgSO4), filtered and concentrated. Purification by preparative TLC (SiO2, 5% EtOAc-95% hexanes) gave 33.0 mg (0.12 mmol) of 1-[3-t-butyl-5-(1-phenyl-vinyl)-phenyl]-ethanone 16 (71% yield). Rf 0.8; 1H-NMR (CDCl3) δ 1.34 (s, 9H, 3CH3), 2.58 (s, 3H, COCH3), 5.48 (s, 1H,CH=), 5.55 (s, 1H, CH=), 7.34 (m, 5H, Ar--H), 7.56 (t, J=3.7 Hz, 1H, Ar--H), 7.72 (t, J=3.7 Hz, 1H, Ar--H), 7.96 (t, J=3.7 Hz, 1H, Ar--H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:20](=O)([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[O:21]N1C(=O)CCC1=O>O1CCOCC1.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:20](=[O:21])[O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc2cc[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOC(=O)Nc1ccc2cc[nH]c2c1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a yellow, homogeneous solution of 1H-indol-6-amine (1.3007 g, 9.84 mmol) and DIPEA (2.58 mL, 14.76 mmol) in 1,4-dioxane (19.68 mL) under nitrogen was added 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (2.81 g, 10.83 mmol) The reaction was stirred overnight, diluted with EtOAc (1500 mL), washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product (2.666 g, 9.65 mmol, 98% yield) as a light tan solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: O=C(Oc1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 9.4 g (0.1 mole) of phenol, 11.6 g (0.1 mole) of benzoyl chloride and 0.176 g (0.5 mmole) of MoTe2 was warmed at 30° C. There was a vigorous evolution of HCl. After 1 hour the entire mixture had solidified. It was heated at 60° C. for 2 hours, the solid was broken up, washed with water, dissolved in acetone, filtered from MoTe2, and evaporated to give 17.6 g (89 mole %) of white crystalline phenyl benzoate, Mp and mixed mp 70° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]1=[O:25])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:5]1=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@@H](N=[N+]=[N-])C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O

Procedure:
0.3 g of 5% w/w palladium-on-carbon was added to 30 ml of ethanol containing 1.4 g of t-butyl α-[3(S*)-azido-2-oxo-6(R*)-phenylperhydroazepin-1-yl]acetate (Isomer A) [prepared as described in Example 1(h)], and under one atmosphere pressure of hydrogen the reaction mixture was shaken for 4 hours at 40° C. The catalyst was filtered off and the solvent was evaporated under reduced pressure, to give 1.56 g of the title compound as a gummy substance.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1

Procedure:
reacting 4-morpholin-4-ylmethyl-benzene-1,2-diamine with 4-nitro-1H-pyrazole-3-carboxylic acid in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (IIOBt) in N,N-dimethyl formamide (DMF) to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl) 1H-benzimidazole; and (ii) reducing the nitro group by treatment with palladium on carbon under a hydrogen atmosphere; or (i) reacting the 4-amino-1H-pyrazole-3-carboxylic ester with the appropriate carboxylic acid in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in N,N-dimethyl formamide (DMF) or with the appropriate acid chloride in the presence of triethylamine to form the 4-amide-1H-pyrazole carboxylic acid; and (ii) reacting 4-morpholin-4-ylmethyl-benzene-1,2-diamine with the appropriate 4-amide-1H-pyrazole carboxylic acid in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in dimethyl formamide (DMF) to give the [3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH2:15][O:16][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCO)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-ethoxycarbonyl-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.92 g) in a mixture of triethylamine (1.15 ml) and methylene chloride (40 ml) was added methanesulfonyl chloride (0.592 ml) at −78° C., and the mixture was stirred for 1 hour. After completion of the reaction, aqueous sodium hydrogencarbonate was added and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (2.38 g).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][CH:6]([CH2:9][CH3:10])[C:5]1(C(OCC)=O)[C:11]([O:13]CC)=[O:12])(=O)C.CC(O)=O.[ClH:25]>>[ClH:25].[CH2:9]([CH:6]1[CH2:7][CH2:8][NH:4][C@@H:5]1[C:11]([OH:13])=[O:12])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(CC)CCN1C(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCC1CCN[C@@H]1C(=O)O

Procedure:
Diethyl 1-Acetyl-3ethylpyrrolidine-2,2-dicarboxylate (373 g, 0.95 mol) was suspended in 6N HCl (2 L) and HOAc (500 mL) and heated at reflux for 20 h. The reaction mixture was cooled, washed with EtOAc (1 L), then concentrated in vacuo to give an oil which crystallized upon trituration with ether to give the title compound. 1H NMR (D2O) δ4.23 (d, 1H, J=8 Hz), 3.84 (d, 1H, J=8 Hz), 3.15-3.4 (m, 4H), 2.33-2.44 (m, 1H), 2.19-2.4 (m, 1H), 2.02-2.15 (m, 2H), 1.53-1.72 (m, 3H), 1.23-1.43 (m, 2H), 1.0-1.15 (m, 1H), 0.75-0.83 (m, 6H).
Reaction SMILES: Cl.Cl.[CH:3]1([N:9]([CH3:16])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[CH:23][CH:22]=1)=[O:19].C(NC(C)C)(C)C>CN(C)C=O.O1CCCC1>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:18]([N:13]3[CH2:12][CH2:11][CH:10]([N:9]([CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH3:16])[CH2:15][CH2:14]3)=[O:19])=[CH:22][CH:23]=2)=[N:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C1CCCCC1)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C1CCCCC1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from cyclohexyl-methyl-piperidin-4-yl-amine, dihydrochloride and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 2 equivalent of diisopropylamine; dimethylformamide/tetrahydrofuran (2:1). The reaction mixture was evaporated to dryness and the crude product extracted with ethyl acetate from an aqueous HCl solution saturated with sodium chloride, pH 1–2. The title product was crystallized from ethyl acetate during evaporation of the solvent, filtered and dryed in vacoum (45%, white crystals). HPLC-MS m/z=478.2 (M+1), Rt: 3.10 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[C:5]([N+:18]([O-])=O)[CH:4]=1>C(O)C.[Pd]>[NH2:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10]([NH:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: COc1ccc(NC(=O)NC2CCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(NC(=O)NC2CCCC2)c(N)c1
Yield: 92.2 %

Procedure:
To a suspension of 1-(4-methoxy-2-nitrophenyl)-3-cyclopentylurea (0.96 g) in ethanol (15 ml) was added a catalytic amount of 10% palladium/carbon to carry out catalytic reduction at a pressure of 1-2.5 arms at room temperature for 2 hrs. The catalyst was filtered off, the solvent was distilled off and crystallization of the residue from benzene and hexane afforded 1-(2-amino-4-methoxyphenyl)-3-cyclopentylurea (0.79 g, 93%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[C@@H:24]([NH:25][C:26](=[O:56])/[C:27](/[C:49]4[N:50]=[C:51]([NH2:55])[S:52][C:53]=4[Cl:54])=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2Cl)=[O:16])C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[SH2:60].[Na].P(O)(O)([O-])=O.[Na+]>CN(C=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[C@@H:24]([NH:25][C:26](=[O:56])/[C:27](/[C:49]4[N:50]=[C:51]([NH2:55])[S:52][C:53]=4[Cl:54])=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[SH:60])=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CS[C@H]23)c(Cl)s1
Reactant: S
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S)CS[C@H]23)c(Cl)s1
Yield: 190.7 %

Procedure:
To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate diphenylmethyl ester (4.0 g , 4.72 mmol) in DMF (30 mL) cooled to -20° C. was added in one portion powdered sodium hydrogen sulfide hydrate (1.1 g, 19.6 mmol). After 15 min the reaction mixture was poured into 0.5 M monosodium phosphate (about 100 mL), extracted with ethyl acetate and the organic layer was washed thoroughly with water. After concentrating in vacuum the crude title product was obtained as yellow foam 3.8 g (95%). 1H NMR (CDCl3 /CD3OD) δ3.38 (d, 1H, J=15), 4.43 (d, 1H, J=15), 5.03 (d, 1H, J=5), 5.80 (d, 1H, J=5), 5.99 (br s, 1H), 6.80 (s, 1H), 7.05-7.50 (m, 25H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].CI.C(OCC)(=O)C>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
3-Amino-4-chlorobenzoic acid (20.9 g, 0.122 mol) and cecium carbonate (79.5 g, 0.244 mol) were suspended in N,N-dimethylformamide (500 mL), and methyl iodide (7.60 mL, 0.122 mol) was added thereto, and then the reaction mixture was stirred under argon atmosphere at room temperature for 2 hours. Ethyl acetate (250 mL) and diethyl ether (500 mL) were added to the reaction mixture and then the whole was washed with water (1 L). The aqueous layer was extracted with ethyl acetate/diethylether (2/1) (300 mL, 3 times). The combined organic layer was washed with water (500 mL, 4 times) and saturated brine (300 mL) successively. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure to give the titled reference compound (21.82 g) as a pale brown solid. (Yield 97%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])=[CH:10][C:9]=1[N+:21]([O-])=O)(=[O:6])=[O:5]>[Pd]>[OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])=[CH:10][C:9]=1[NH2:21])(=[O:6])=[O:5]
Reactant: O=[N+]([O-])c1cc(CS(=O)(=O)CCO)ccc1CS(=O)(=O)CCO
Agent: [Pd]
Product: Nc1cc(CS(=O)(=O)CCO)ccc1CS(=O)(=O)CCO

Procedure:
The procedure as described in Examples 13 and 14 is repeated, using each time 150 parts of 2,5-bis(hydroxyethylsulfonylmethyl)nitrobenzene as well as each time the aqueous mother liquor and the palladium catalyst of the previous batch to give each time about 128 parts of 2,5-bis(hydroxyethylsulfonylmethyl)aniline of melting point 197° to 199° C. and a purity (diazotization) of >99%, i.e., mother liquor and catalyst can each be recycled at least 10 times without deterioration of the product or reduction of the yield.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].Cl.[O:15]=[C:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C>O1CCCC1>[F:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10]([N:18]2[CH2:19][CH2:20][C:16](=[O:15])[CH2:17]2)(=[O:12])=[O:11])[C:3]=1[C:1]#[N:2]
Reactant: O=C1CCNC1
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1S(=O)(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
110 mg of 2-cyano-3-fluoro-benzenesulfonyl chloride in 5 ml of tetrahydrofuran are treated with 61 mg of 3-oxo-pyrrolidine hydrochloride and with 0.14 ml of triethylamine, and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated in vacuo, the residue is solved in ethyl acetate and washed with a 1M HCl solution. Purification by Flash chromatography (eluent: cyclohexane/ethyl acetate 1:1) affords 21 mg of 2-fluoro-6-(3-oxo-pyrrolidine-1-sulfonyl)-benzonitrile.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@@H:4]([C@H:13]([CH3:16])[O:14][CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Li+].[OH-]>O1CCOCC1.O>[C:6]([NH:5][C@@H:4]([C:3]([OH:17])=[O:2])[C@H:13]([CH3:16])[O:14][CH3:15])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Yield: 90.1 %

Procedure:
To a solution of N-Boc-O-methyl-D-threonine methyl ester (8.09 mmol) in 1,4-dioxane (10 mL) is added a solution of LiOH (24.3 mmol) in water (20 mL). After stirring for 2–3 h, the solvents are removed in vacuo and the residue partitioned between water and ether. The aqueous layer is acidified with solid citric acid to approximately pH 3, then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried with MgSO4, filtered and concentrated in vacuo to yield 1.70 g (90%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]1.O>CS(C)=O>[CH3:12][C:4]1[CH:3]=[C:2]([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ncccc12
Temperature: 120 °C
Yield: 17 %

Procedure:
5.5 g (31 mmol) of 4-chloro-2-methylquinoline and 8.9 g (65 mmol) of potassium carbonate were added to 4.6 g (26 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in 93 cm3 of dimethyl sulfoxide under argon. The reaction mixture was heated at a temperature in the region of 120° C. for 16 h, then it was cooled to a temperature in the region of 20° C. and treated with 250 cm3 of water. The aqueous phase was extracted with 250 cm3 and then 125 cm3 of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with dichloromethane. The fractions comprising the expected product were combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.4 g of methyl 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate were thus obtained in the form of an orange crystalline solid melting at 179° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[N:8]=[C:7]2[NH2:12].[CH3:14][NH:15][C:16]1[N:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:12][C:7]1[C:6]2[C:10](=[C:2]([C:21]3[CH:22]=[C:23]4[C:18](=[CH:19][CH:20]=3)[N:17]=[C:16]([NH:15][CH3:14])[N:25]=[CH:24]4)[C:3]([CH3:13])=[CH:4][CH:5]=2)[N:9]([CH3:11])[N:8]=1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Cc1ccc2c(N)nn(C)c2c1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(N)nn(C)c34)ccc2n1
Temperature: 150 °C
Yield: 77.9 %

Procedure:
A mixture of 7-iodo-1,6-dimethyl-1H-indazol-3-amine (266 mg, 927 μmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (317 mg, 1112 μmol), sodium carbonate (2 M aqueous) (927 μl, 1853 μmol) and tetrakis(triphenylphosphine)palladium (0) (54 mg, 46 μmol) in dioxane (4 mL) was purged with nitrogen in a sealed microwave vial. The mixture was heated in a microwave reactor at 150° C. for 33 min. Sovent was removed in vacuo and the residue was purified by flash chromatography (1-5% MeOH/DCM) to give the title compound (230 mg, 78%). MS (M+H)+ 319.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:29][C:30]1[C:35]([F:36])=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:34][C:35]=1[F:36]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cnc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white solid. HPLC (Condition 4) tR=5.69 min, UPLC-MS (Condition 7) m/z=511.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.65 (m, 1H) 1.84 (m, J=5.90 Hz, 1H) 2.15-2.28 (m, 1H) 2.98 (dd, J=10.95, 7.04 Hz, 1H) 3.11-3.41 (m, 5H) 4.61 (t, J=5.28 Hz, 1H) 7.34 (d, J=9.38 Hz, 2H) 7.83 (d, J=9.38 Hz, 2H) 7.99-8.09 (m, 2H) 8.35 (d, J=1.00 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O:28][B:29](OC)[O:30]C.Cl>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([B:29]([OH:30])[OH:28])=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)c(-c2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
An excess of 1.6M n-BuLi in hexane (50 mL, 80 mmol) was added to a solution of 2-bromo-5-methoxybiphenyl (19.1 g, 72.7 mmol) in 350 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C., trimethylborate (10.4 g, 100 mmol) was added dropwise, the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (150 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give 9.5 g of the 5-methoxybiphenyl-2-ylboronic acid as a white solid (57%).
Reaction SMILES: [K].[C:2]([NH:7][C:8](=[S:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])([O:4]CC)=O.Cl[CH2:16][C:17]#[N:18].C[O-].[K+]>CO>[CH2:10]([O:9][C:8]1[S:14][C:16]([C:17]#[N:18])=[C:2]([OH:4])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: N#CCCl
Reactant: CCCCOC(=S)NC(=O)OCC
Agent: C[O-]
Agent: [K+]
Agent: [K]
Solvent: CO
Product: CCCCOc1nc(O)c(C#N)s1
Reaction time: 5 h

Procedure:
A mixture of 35 g of the potassium salt of n-butyl N-carbethoxy-thiocarbamate, 500 ml of methanol and 7.7 ml of chloroacetonitrile was stirred for 5 hours and then 10.1 g of potassium methylate were added thereto. The reaction mixture was refluxed for 16 hours and was then evaporated to dryness. The residue was dissolved in water and the aqueous phase was washed with ether and then acidified. The acid aqueous phase was extracted with ether and the ether phase was evaporated to dryness to obtain 16 g of 2-n-butoxy-4-hydroxy-5-cyano-thiazole in the form of beige crystals melting at 80° C.