Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][C@H:12]([N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:13][OH:14])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([N:43]=[C:44]=[O:45])[CH:39]=[CH:40][C:41]=1[Cl:42]>ClCCl.CN(C)C=O>[Cl:35][C:36]1[CH:37]=[C:38]([NH:43][C:44]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:3]4([CH2:4][CH2:5]4)[C@H:2]([OH:1])[CH2:9]3)[CH2:16][CH2:17]2)=[O:45])[CH:39]=[CH:40][C:41]=1[Cl:42]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCNCCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCC(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 0.066 g (0.21 mmol) of 4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-[1,4]diazepan-5-one (example 51B) 1.3 ml of N,N-dimethylformamide was treated at room temperature with 0.097 ml (0.70 mmol) of triethylamine and 0.088 ml (0.70 mmol) of chlorotrimethylsilane. The suspension was diluted with 1 ml of dichloromethane and stirred over night at room temperature. A solution of 0.044 g (0.23 mmol) of 3,4-dichlorophenyl isocyanate was added and stirred for 3 h at room temperature. The reaction was evaporated under reduced pressure, redissolved in 2 ml of methanol and 0.2 ml of 1 M aq. hydrochloric acid solution and after 5 min again evaporated. Partitioning between sat. aq. sodium hydrogencarbonate solution and dichloromethane (3×), drying of the organic phase over Na2SO4 and purification by flash silica gel column (dichloromethane/methanol 95:5 to 4:1) yielded 0.065 g (61%) of the title compound as yellow foam. MS: 499.2 (MH+, 2Cl).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]>[OH-].[Na+].[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)/C=C/c1ccc2cnccc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of (E)-3-(1,6-naphthyridin-2-yl)acrylic acid (300 mg, 1.50 mmol) and Pd/C (30 mg, 10%) in 1 N sodium hydroxide aqueous solution (8 mL) was stirred under H2 for 8 h at room temperature, and then filtered. The solution was acidified to pH 4 with 1 N aqueous hydrogen chloride solution. The precipitate was collected by filtration and dried in vacuum to give 220 mg of the product as a yellow solid. MS (ESI): m/z 203.1 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:5](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of thionyl chloride (6 mL) and the benzoic acid was heated at reflux until the starting benzoic acid dissolved. Excess thionyl chloride was removed under reduced pressure leaving the crude acid chloride as a low melting solid which was used without further purification. The crude acid chloride was dissolved in CH2Cl2 (20 mL) and cooled to −10° C. To this stirred solution was added triethylamine (4 mL), followed by the dropwise addition of diethylamine (1.4 equivalents). The heterogeneous reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was transferred to a separatory funnel containing H2O (20 mL). The organic layer was separated and washed with 5% HCl (2×25 mL), H2O (25 ml), and dried over Na2SO4. The solvent was removed under reduced pressure to afford the product N,N-diethyl benzamide.
Reaction SMILES: [CH2:1](N(CC)CC)C.CN(C)C=O.C[Sn](C)(C)C.[C:18]1([CH:24]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:25]2[C:33]3[C:28](=[CH:29][C:30](Br)=[CH:31][CH:32]=3)[C:27]3([C:46]4[C:37](=[CH:38][C:39]5[O:44][CH2:43][CH2:42][O:41][C:40]=5[CH:45]=4)[O:36][CH2:35]3)[C:26]2=[O:47])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[C:18]1([CH:24]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:25]2[C:33]3[C:28](=[CH:29][C:30]([CH3:1])=[CH:31][CH:32]=3)[C:27]3([C:46]4[C:37](=[CH:38][C:39]5[O:44][CH2:43][CH2:42][O:41][C:40]=5[CH:45]=4)[O:36][CH2:35]3)[C:26]2=[O:47])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(Br)cc2C12COc1cc3c(cc12)OCCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Temperature: 110 °C
Yield: 85.9 %

Procedure:
To a 10 mL reaction vessel was added tri-o-tolylphosphine (0.022 g, 0.075 mmol), palladium acetate trimer (0.013 g, 0.020 mmol), triethylamine (0.13 g, 1.30 mmol), N,N-dimethylformamide (1.5 mL), tetramethyltin (0.20 g, 1.1 mmol) and 1′-(diphenylmethyl)-5′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.50 g, 0.93 mmol). The reaction vessel was sealed, heated at 110° C. for 16 h, allowed to cool to ambient temperature and poured into water (50 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 15% ethyl acetate in hexanes followed by recrystallization from diethyl ether to afford 1′-(diphenylmethyl)-5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.38 g, 86%) as a colorless solid: MS (ES+) m/z 476.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C)CCN(C)C.C([Li])CCC.CN([CH:33]=[O:34])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:33]=[O:34])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.0 g, 3.91 mmol) in anhydrous THF (50 mL) was added N,N,N′,N′-tetramethylethylenediamine (0.68 mL, 4.53 mmol) and the resulting mixture was cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 1.9 mL, 4.75 mmol) was added dropwise and the resulting suspension allowed to warm to −30° C. over 1 h. The reaction mixture was cooled to −78° C. and treated with DMF (0.7 mL, 9.04 mmol), then stirred at RT for 30 min. The reaction mixture was cooled to 0° C. before an aqueous solution of HCl (0.5 M) was added and the mixture stirred for another 30 min. The precipitate that formed was collected by filtration, washed twice with water then dried in vacuo at 70° C. for 3 h. The title compound was obtained as a pale yellow solid (1.0 g 90%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:24]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of diisopropylamine (7.87 mL, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via cannula, and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×30 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid as a white solid. HRMS: calcd for C14H17ClO3, 268.0866. found (ESI_FT), 291.0748.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([CH:37]3[CH2:41][CH2:40][CH2:39][NH:38]3)[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]4=[O:36])=[N:28][CH:29]=3)=[CH:22][C:16]=2[N:15]=1>C(Cl)(Cl)Cl>[C:1]([N:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[C:20]1[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[O:36])=[N:28][CH:29]=2)=[CH:22][C:16]2[N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=3)[NH:18][C:17]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccccn1-c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cn1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-n2ccccc2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.003 ml of acetic anhydride was added to a chloroform (1 ml) solution of 6.5 mg of 5′-((2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazol-5-yl)oxy)-2H-1,2′-bipyridin-2-one enantiomer A obtained in Example 554, and the reaction liquid was stirred at room temperature for 30 minutes. The reaction solvent was evaporated away, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain one chiral form of the entitled compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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:23][C:22]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[CH:3][C:4]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ccc(F)c(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ccc(F)c(-c2ccc(C)cc2)c1
Yield: 97.1 %

Procedure:
A solution of 0.3 g of the product from Example 3 in 15 ml of dimethoxyethane was admixed with 0.2 g of 4-methylphenylboronic acid, 0.17 g of sodium carbonate, 2 ml of water and 40 mg of tetrakis(triphenylphosphine)palladium(0) and refluxed for 20 hours. The mixture was then poured into water and extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide solution and then with water and dried. Distillative removal of the solvent and silica gel chromatography (MtBE: cyclohexane=9:1) gave 0.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])([F:34])[CH3:33].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:32]([F:31])([F:34])[CH3:33])[CH:36]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC(F)(F)c1cccc(N)c1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(C)(F)F)c3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 6.6 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.273 g, 0.736 mmol), thionyl chloride (2.0 mL), 3-(1,1-difluoroethyl)aniline (Intermediate-39, 0.120 g, 0.736 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.025 g of the desired product. 1HNMR (DMSO d6): δ 1.57 (s, 6H), 1.97 (t, J=19.2 Hz, 3H), 3.10 (s, 2H), 7.26-7.32 (m, 3H), 7.35-7.48 (m, 3H), 7.62 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 9.85 (s, 1H), 11.00 (s, 2H); MS [M−H]−: 513.14.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1F)[C:27]#[N:28]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:23])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To 4-(benzyloxy)pyridin-2(1H)-one (0.358 g, 1.779 mmol) under nitrogen was added DMF (5 mL) to produce a tan suspension. To the reaction was added NaH (60% in oil) (0.074 g, 1.860 mmol) and stirred for 1.5 hours and then 3,4-difluorobenzonitrile (0.225 g, 1.618 mmol) was added. The reaction was placed in a 90° C. oil bath for 2 hours. To the tan suspension was added 50 mL of EtOAc and the mixture washed with 4×25 mL of water, dried over MgSO4, filtered and concentrated to give 0.42 g pale yellow solids. This material was purified by flash chromatography (1-5% MeOH in CH2Cl2) to yield product (263 mg, 0.805 mmol, 50%) as a tan solid. MS (ESI) 321.2 (M+1).
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[SH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6]
Reactant: Sc1ccc2ccccc2c1
Reactant: CO/C=C/C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)/C=C/Sc1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 16.7 %

Procedure:
To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 15.0 ml, 0.13 mol) and 2-naphthalenethiol (21.16 g, 0.13 mol) in benzene (180 ml) was added p-toluene sulfonic acid-monohydrate (75 mg, 0.4 mmol), followed by heating, while stirring, on an oil bath at 50° C. for 70 minutes. After ice cooling, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extracting with ethyl acetate four times. The ethyl acetate layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine twice and then dried with anhydrous magnesium sulfate. After concentrating under a reduced pressure, the residue was treated with the column chromatography (670 g, n-hexane:methylene chloride:ethyl acetate=1:0:0-1:3:0-2:0:1), followed by recrystallizing from n-hexane-ethyl ether to thereby obtain the titled compound as a light brown crystalline.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][CH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6]1)[CH:2]=C.I([O-])(=O)(=O)=[O:24].[Na+].C(OC)(C)(C)C>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[CH2:21]([CH:13]([CH2:12][CH2:11][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([O:4][CH2:1][CH:2]=[O:24])[CH2:6]1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:22]
Reactant: C=CCO[C@@H]1CCC[C@H](CCC(CC)C(=O)OC(C)(C)C)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CCC(CC[C@H]1CCC[C@@H](OCC=O)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 9 h

Procedure:
770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate are dissolved in 50 ml of diethyl ether, and 1.59 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 2.56 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 9 hours, a further 12.8 ml of the osmium tetroxide solution are added, and stirring at room temperature is continued for a further 3 hours. 200 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 710 mg of tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate as a yellow-brown oil. C18H32O4 (312.45), Rf(n-heptane:ethyl acetate=5:1)=0.15.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:31](=[O:33])[NH2:32])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:31]([NH2:32])=[O:33])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:40][CH2:39]1
Reactant: CN(C)CCN1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(CCN(C)C)CC4)cc32)sc1C(N)=O)c1ccccc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
136 mg of crude (1-{5-carbamoyl-4-[(1R)-1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate (example 101, step 1) are dissolved in 5 ml dichloromethane. Under N2 atmosphere N,N-dimethyl-2-piperazin-1-ylethanamine (218 mg) is added. The reaction mixture is stirred at 40° C. for 2 hours and 2 hours at room temperature. It is then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[CH:18]1([O:24][CH2:3][C:4]2[N:5]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: OC1CCCCC1
Agent: Cl
Solvent: CC#N
Product: Clc1cc(Cl)cc(Cn2ccnc2COC2CCCCC2)c1
Temperature: 120 °C
Yield: 10.1 %

Procedure:
2-(Chloromethyl)-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (100 mg, 0.32 mmol), cyclohexanol (160 mg, 1.6 mmol) and acetonitrile (1 mL) were combined in a Smith Process Vial. The reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) microwave at 120° C. for 30 min. The heterogeneous solution was filtered and the solid was washed with acetonitrile. The filtrate was concentrated and the resulting semi-solid was partitioned between CH2Cl2 (10 mL) and 5% Na2CO3 (5 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the desired product (11 mg, 10%); MS m/z 339 [C17H20Cl2N2O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:17][CH:16]=1)=[C:5]2[O:33]CC.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:32])[F:31])=[CH:24][CH:23]=3)=[CH:17][CH:16]=1)[C:5]2=[O:33]
Reactant: CCOc1c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)nc2cc(OC)c(Cl)cc12
Agent: Br
Solvent: CC(=O)O
Product: COc1cc2[nH]c(C)c(-c3ccc(Oc4ccc(OC(F)(F)F)cc4)cc3)c(=O)c2cc1Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
To a solution of 6-chloro-4-ethoxy-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (1.16 g, 2.30 mmol) in acetic acid (10 ml) was added a 50% aqueous hydrobromic acid solution (5 ml). The reaction mixture was stirred 24 hours at 90° C., cooled and concentrated in vacuo. The resulting residue was resuspended in water, neutralized with 2 N NaOH and filtered. The collected solid was triturated with dichloromethane and filtered to provide 923 mg 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (84% yield) as a white powder. 1H NMR (400 MHz, CDCl3) δ 11.97 (s, 1H), 8.05 (s, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.12 (s, 1H), 7.08 (d, J=8.7 Hz, 2H), 3.97 (s, 3H), 2.26 (s, 3H). HRMS (EI+) m/z for C24H17ClF3NO4: calculated 475.0798, found 475.0801.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12]C)[CH:8]=[CH:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc2cccc(Cl)c2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cccc(Cl)c2c1

Procedure:
The title compound was prepared by reacting 8-chloro-2-methoxynaphthalene (10.25 g, 53.4 mmol) with boron tribromide (67 mL of 1N solution, 67 mmol) according to method D to yield 8.76 g (92%) of a yellow solid. An analytical sample was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 95–100° C.; 1H NMR (DMSO-d6): δ 7.18 (1H, dd, J=2.37 Hz, J=8.85 Hz), 7.23–7.28 (1H, m), 7.41 (1H, d, J=2.28 Hz), 7.59 (1H, d, J=7.37 Hz), 7.81 (1H, d, J=8.15 Hz), 7.87 (1H, d, J=8.86 Hz), 10.17 (1H, s); MS m/z 177/179 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3c(OC)c(OC)ccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 391(MH+).